198 results on '"Wang, Xujun"'
Search Results
152. Genetic differences in hepatic lipid peroxidation potential and iron levels in mice
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Gerhard, Glenn S, primary, Kaufmann, Elizabeth J, additional, Wang, Xujun, additional, Erikson, Keith M, additional, Abraham, Joseph, additional, Grundy, Martin, additional, Beard, John L, additional, and Chorney, Michael J, additional
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- 2002
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153. Overexpression of [Na.sup.+]/[Ca.sup.2+] exchanger alters contractility and SR [Ca.sup.2+] content in adult rat myocytes
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Zhang, Xue-Qian, Song, Jianliang, Rothblum, Lawrence I., Lun, Mingyue, Wang, Xujun, Ding, Fan, Dunn, Jeremy, Lytton, Jonathan, McDermott, Paul J., and Cheung, Joseph Y.
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Heart -- Contraction ,Heart muscle -- Physiological aspects ,Cell interaction -- Physiological aspects ,Excitation (Physiology) -- Research ,Biological sciences - Abstract
Overexpression of [Na.sup.+]/[Ca.sup.2+] exchanger alters contractility and SR [Ca.sup.2+] content in adult rat myocytes. Am J Physiol Heart Circ Physiol 281: H2079-H2088, 2001.--The functional consequences of overexpression of rat heart [Na.sup.+]/[Ca.sup.2+] exchanger (NCX1) were investigated in adult rat myocytes in primary culture. When maintained under continued electrical field stimulation conditions, cultured adult rat myocytes retained normal contractile function compared with freshly isolated myocytes for at least 48 h. Infection of myocytes by adenovirus expressing green fluorescent protein (GFP) resulted in > 95% infection as ascertained by GFP fluorescence, but contraction amplitude at 6-, 24-, and 48-h postinfection was not affected. When they were examined 48 h after infection, myocytes infected by adenovirus expressing both GFP and NCX1 had similar cell sizes but exhibited significantly altered contraction amplitudes and intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]) transients, and lower resting and diastolic [[[Ca.sup.2+]].sub.i] when compared with myocytes infected by the adenovirus expressing GFP alone. The effects of NCX1 overexpression on sarcoplasmic reticulum (SR) [Ca.sup.2+] content depended on extracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.o]), with a decrease at low [[[Ca.sup.2+]].sub.o] and an increase at high [[[Ca.sup.2+]].sub.o]. The half-times for [[[Ca.sup.2+]].sub.i] transient decline were similar, suggesting little to no changes in SR [Ca.sup.2+]-ATPase activity. Western blots demonstrated a significant (P [less than or equal to] 0.02) threefold increase in NCX1 but no changes in SR [Ca.sup.2+]-ATPase and calsequestrin abundance in myocytes 48 h after infection by adenovirus expressing both GFP and NCX1 compared with those infected by adenovirus expressing GFP alone. We conclude that overexpression of NCX1 in adult rat myocytes incubated at high [[[Ca.sup.2+]].sub.o] resulted in enhanced [Ca.sup.2+] influx via reverse NCX1 function, as evidenced by greater SR [Ca.sup.2+] content, larger twitch, and [[[Ca.sup.2+]].sub.i] transient amplitudes. Forward NCX1 function was also increased, as indicated by lower resting and diastolic [[[Ca.sup.2+]].sub.i]. excitation-contraction coupling; fura 2; cardiac myocyte culture; video imaging
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- 2001
154. Overexpression of Na+/Ca2+exchanger alters contractility and SR Ca2+content in adult rat myocytes
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Zhang, Xue-Qian, primary, Song, Jianliang, additional, Rothblum, Lawrence I., additional, Lun, Mingyue, additional, Wang, Xujun, additional, Ding, Fan, additional, Dunn, Jeremy, additional, Lytton, Jonathan, additional, McDermott, Paul J., additional, and Cheung, Joseph Y., additional
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- 2001
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155. Characterization of the complete chloroplast genome sequence of Tinospora sagittata and its phylogenetic implications.
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Peng, Cuiying, Liang, Junsheng, Xie, Qiaoying, Wang, Xujun, and Guo, Wei
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NUCLEOTIDE sequencing ,CHLOROPLAST DNA ,CHINESE medicine - Abstract
Tinospora sagittata is a perennial vine of the family Menispermaceae and distributed in Hunan, Hubei, Guangxi, and Sichuan province of P. R. China. It has been used in Chinese traditional medicine for centuries. The chloroplast (cp) genome of T. sagittata, characterized using Illumina technology, is 163,662 bp in size. There are a total of 130 genes, coding for 85 proteins, 37 tRNAs, and 8 rRNAs. Phylogenetic relationship analysis based on 16 complete cp genome sequences exhibited that T. sagittata was phylogenetically closer to Menispermum dauricum and Stephania japonica. [ABSTRACT FROM AUTHOR]
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- 2020
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156. Transcription factor-pathway co-expression analysis reveals cooperation between SP1 and ESR1 on dysregulating cell cycle arrest in non-hyperdiploid multiple myeloma
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Wang, Xujun, Yan, Zhenyu, Fulciniti, Mariateresa, Li, Yingxiang, Gkotzamanidou, Maria, Amin, Samir B, Shah, Parantu K, Zhang, Yong, Munshi, Nikhil C, and Li, Cheng
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co-expression ,cell cycle arrest ,multiple myeloma ,hyperdiploid - Abstract
Multiple myeloma is a hematological cancer of plasma B-cells and remains incurable. Two major subtypes of myeloma, hyperdiploid (HMM) and non-hyperdiploid myeloma (NHMM), have distinct chromosomal alterations and different survival outcomes. Transcription factors (TrFs) have been implicated in myeloma oncogenesis but their dysregulation in myeloma subtypes are less studied. Here we develop a TrF-pathway co-expression analysis to identify altered co-expression between two sample types. We apply the method to the two myeloma subtypes and the cell cycle arrest pathway, which is significantly differentially expressed between the two subtypes. We find that TrFs MYC, NF-κB and HOXA9 have significantly lower co-expression with cell cycle arrest in HMM, co-occurring with their over-activation in HMM. In contrast, TrFs ESR1, SP1 and E2F1 have significantly lower co-expression with cell cycle arrest in NHMM. SP1 ChIP targets are enriched by cell cycle arrest genes. These results motivate a cooperation model of ESR1 and SP1 in regulating cell cycle arrest, and a hypothesis that their over-activation in NHMM disrupts proper regulation of cell cycle arrest. Co-targeting ESR1 and SP1 shows a synergistic effect on inhibiting myeloma proliferation in NHMM cell lines. Therefore, studying TrF-pathway co-expression dysregulation in human cancers facilitates forming novel hypotheses towards clinical utility.
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- 2014
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157. Abstract 16387: IP3 Receptors are Master Regulators of Cardiac Healing in Post-Ischemic Heart Failure
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Santulli, Gaetano, Morelli, Marco B, Matarese, Alessandro, and Wang, Xujun
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Introduction:Recent genome-wide association studies have evidenced a significant association between gain-of-function mutations in genes encoding for Inositol 1,4,5-trisphosphate receptors(IP3Rs) and ischemic heart disease. Three isoforms of IP3Rs have been identified in mammals (IP3R1-3) and their expression pattern is overlapping and redundant. To our knowledge, functional studies examining the exact role of IP3Rs in post-ischemic cardiac remodeling are missing.Hypothesis:We hypothesize that IP3Rs play a key role in the activation of cardiac myo-fibroblasts (myo-FBs) in myocardial infarction (MI).Methods and Results:We performed an integrated set of in vivo, ex vivo, and in vitroexperiments aiming at identifying the role of myo-FB IP3Rs in post-ischemic cardiac remodeling. We generated cardiac myo-FB-specific triple IP3R knock-out (IP3RTKO) mice (Cre/loxrecombination; Promoter: Periostin,an established marker labeling activated FBs following cardiac injury, selectively upregulated in activated myo-FBs but not in quiescent FBs), allowing us to overcome the difficulties encountered following the KO or KD of a single IP3R, a strategy that has been shown to induce compensatory upregulation of the other isoforms. IP3RTKOmice exhibit a significantly (p<0.001) reduced interstitial cardiac fibrosis and chronic inflammation, and attenuated myocardial dysfunction following MI compared with control IP3Rfloxor PeriostinCrelittermates. IP3R ablation also reduced the expression of pro-inflammatory interleukins and chemokine ligands. Moreover, FBs lacking IP3Rs display significantly reduced migratory and secretory capacities, a finding confirmed both in murine and human FBs. Mechanistically, we show that IP3Rs regulate inter-organelle calcium fluxes between endoplasmic reticulum (ER) and mitochondria, autophagy/mitophagy, mitochondrial unfolded protein response (UPR), oxidative stress, and ER stress in primary isolated myo-FBs following ischemic injury.Conclusions:Our results indicate for the first time that IP3Rs are essential for the regulation of activation and persistence of myo-FBs, playing a crucial role in cardiac fibrosis post-MI through a mechanism that involves UPR and autophagy.
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- 2019
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158. Abstract 16384: Dual Microrna-Targeting Rescues the Impaired Mitochondrial Unfolded Protein Response in Heart Failure
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Morelli, Marco, Wang, Xujun, Matarese, Alessandro, Chavez, Christopher, and Santulli, Gaetano
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Introduction:The mitochondrial unfolded protein response (UPRmt) is an evolutionary conserved process evoked when the mitochondrial protein folding environment is compromised. The major regulators of the UPRmtinclude Activating Transcription Factor 5(ATF5) and Lon Peptidase 1(LONP1). UPRmthas been recently shown to be involved in cardiac pressure overload; however, its functional role in post-ischemic heart failure (HF) and its regulation by non-coding RNAs have never been investigated hitherto.Hypothesis:We hypothesize that UPRmtis a key process in the pathophysiology of post-ischemic HF and is regulated by specific microRNAs (miRNAs, miRs).Methods:To test the mechanistic role of miRs in the modulation of UPRmtin HF we combined bioinformatic approaches (to identify miRs targeting the crucial players of UPRmt) with an in vivomurine model of ischemic HF (coronary ligation).Results:We identified and biologically validated in vitrovia luciferase assay two miRs, namely miR-129-5p and miR-489, as specific modulators of the expression of ATF5 and LONP1, respectively. Four weeks after LAD ligation both miRs were significantly (p<0.01) upregulated in the left ventricle compared to sham conditions, whereas their respective targets, ATF5 and LONP1, were markedly downregulated, both at the mRNA and protein level. These alterations were accompanied by perturbations in UPRmtand also in endoplasmic reticulum UPR (UPRER), including upregulation of HSP60, HSP10, and mtDNAj, as well as the three main arms of ER stress. A dual miR in vivotargeting, using miR-129-5p and miR-489 antagomirs, significantly improved the UPRmtresponse and overall cardiac function, whereas single approaches yielded minimal results. Intriguingly, despite having as a main target a mitochondrial protease (LONP1), antagomiR-489 alone had significant effects on the modulation of UPRER. These results were further supported by ex vivoexperiments in primary isolated cardiomyocytes, in terms of contractility and mitochondrial dynamics and function (including fission/fusion and Seahorse assays).Conclusions:Taken together our results indicate that miR-129-5p and miR489 regulate UPRmtin cardiomyocytes in post-ischemic HF via specific targeting of ATF5 and LONP1.
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- 2019
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159. Abstract 16389: Exosomal MicroRNAs Regulate Myofibroblast Activation in Myocardial Infarction
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Wang, Xujun, Chavez, Christopher, Sardu, Celestino, and Santulli, Gaetano
- Abstract
Introduction:Mounting evidence has shown that exosomal non-coding-RNAs play a pivotal role in cell-cell communication. However, their contribution in the phenoconversion of cardiac fibroblasts to active myofibroblasts in myocardial infarction (MI) has not been investigated.Hypothesis:We hypothesize that exosomal microRNAs (miRs) are involved in the activation of myofibroblasts following ischemic injury.Methods:We tested our hypothesis trough means of bioinformatic tools and a murine model of MI, obtained via surgical ligation of the left anterior coronary artery; we measured the expression levels of a set of miRs in fibroblasts and cardiomyocyte-derived exosomes; we used miR inhibitors and mimics to evaluate post-MI myofibroblast phenoconversion.Results:Compared with SHAM conditions, miR-92a was significantly (p<.01) upregulated (absolute values) in cardiomyocyte-derived exosomes as well as in fibroblasts isolated at different time points after MI. This miRs was shown to specifically target SMAD7 (Mothers against decapentaplegic homolog 7), an established inhibitor of ?SMA (?-Smooth muscleactin)expression (a fundamental player in myofibroblast activation); such interaction was predicted using bioinformatic tools and validated via luciferase assays. Furthermore, primary isolated cardiac fibroblasts were activated both when incubated with exosomes derived from ischemic cardiomyocytes and when cultured in conditioned medium of post-MI cardiomyocytes, whereas no significant effects were observed after incubation with exosomes or medium from sham cardiomyocytes. Myofibroblast activation was assessed measuring the expression of ?SMA, periostin, collagen I/III, fibroblast activation protein, and fibronectin ED-A. Additionally, miR-92a regulated the post-MI inflammatory response (also in terms of IL-6 and CXCL1). Inhibiting exosome release (GW4869 10?M 12h) significantly attenuated all these responses. The mechanistic contribution of miR-92a to fibroblast phenoconversion was further confirmed using miR-92a mimics and inhibitors.Conclusions:Taken together, our findings indicate that miR-92a is transferred to fibroblasts in form of exosomal cargo, and is crucial for post-MI activation of myofibroblasts.
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- 2019
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160. Stress Hyperglycemia Drives the Risk of Hospitalization for Chest Pain in Patients With Ischemia and Nonobstructive Coronary Arteries (INOCA)
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Pasquale Mone, Angela Lombardi, Luigi Salemme, Angelo Cioppa, Grigore Popusoi, Fahimeh Varzideh, Antonella Pansini, Stanislovas S. Jankauskas, Imma Forzano, Roberta Avvisato, Xujun Wang, Tullio Tesorio, Gaetano Santulli, Mone, Pasquale, Lombardi, Angela, Salemme, Luigi, Cioppa, Angelo, Popusoi, Grigore, Varzideh, Fahimeh, Pansini, Antonella, Jankauskas, Stanislovas S, Forzano, Imma, Avvisato, Roberta, Wang, Xujun, Tesorio, Tullio, and Santulli, Gaetano
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Advanced and Specialized Nursing ,Endocrinology, Diabetes and Metabolism ,Internal Medicine - Abstract
OBJECTIVE Ischemia with nonobstructive coronary arteries (INOCA) is a prevailing finding in patients with angina. However, the main factors underlying the risk of being rehospitalized for chest pain in patients with INOCA remain mostly unknown. RESEARCH DESIGN AND METHODS We evaluated INOCA patients referred to the “Casa di Cura Montevergine” in Mercogliano (Avellino), Italy, from January 2016 to January 2021 for percutaneous coronary intervention (PCI). In these subjects, we assessed the impact of the stress hyperglycemia ratio (SHR), defined as the ratio of mmol/L blood glucose and % HbA1c, on the risk of rehospitalization for chest pain. RESULTS A total of 2,874 patients with INOCA successfully completed the study. At the 1-year follow-up, the risk of rehospitalization for chest pain was significantly higher (P < 0.001) in INOCA patients with SHR >1 compared to patients with SHR ≤1. These findings were confirmed by multivariable analyses (adjusting for potential confounders, including age, BMI, blood pressure, heart rate, chronic kidney disease, and cholesterol), propensity score matching, and inverse probability of treatment weighting. CONCLUSIONS Our data indicate, to our knowledge for the first time, that SHR on hospital admission significantly and independently increases the risk of rehospitalization for chest pain in INOCA patients.
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- 2023
161. Exosomal miR-145 and miR-885 regulate thrombosis in COVID-19
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Jessica Gambardella, Urna Kansakar, Celestino Sardu, Vincenzo Messina, Stanislovas S. Jankauskas, Raffaele Marfella, Paolo Maggi, Xujun Wang, Pasquale Mone, Giuseppe Paolisso, Daniela Sorriento, Gaetano Santulli, Gambardella, Jessica, Kansakar, Urna, Sardu, Celestino, Messina, Vincenzo, Jankauskas, Stanislovas S, Marfella, Raffaele, Maggi, Paolo, Wang, Xujun, Mone, Pasquale, Paolisso, Giuseppe, Sorriento, Daniela, Santulli, Gaetano, and S Jankauskas, Stanislova
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Pharmacology ,heart/cardiac ,cardiovascular disease ,endothelial cell ,Molecular Medicine ,MicroRNA ,thrombosis - Abstract
We hypothesized that exosomal microRNAs could be implied in the pathogenesis of thromboembolic complications in coronavirus disease 2019 (COVID-19). We isolated circulating exosomes from patients with COVID-19, and then we divided our population in two arms based on the D-dimer level on hospital admission. We observed that exosomal miR-145 and miR-885 significantly correlate with D-dimer levels. Moreover, we demonstrate that human endothelial cells express the main cofactors needed for the internalization of the "Severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), including angiotensin converting enzyme 2, transmembrane protease serine 2, and CD-147. Interestingly, human endothelial cells treated with serum from COVID-19 patients release significantly less miR-145 and miR-885, exhibit increased apoptosis, and display significantly impaired angiogenetic properties compared with cells treated with non-COVID-19 serum. Taken together, our data indicate that exosomal miR-145 and miR-885 are essential in modulating thromboembolic events in COVID-19. SIGNIFICANCE STATEMENT: This work demonstrates for the first time that two specific microRNAs (namely miR-145 and miR-885) contained in circulating exosomes are functionally involved in thromboembolic events in COVID-19. These findings are especially relevant to the general audience when considering the emerging prominence of post-acute sequelae of COVID-19 systemic manifestations known as Long COVID.
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- 2023
162. Cardiac Remodeling After Myocardial Infarction: Functional Contribution of microRNAs to Inflammation and Fibrosis
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Fahimeh Varzideh, Urna Kansakar, Kwame Donkor, Scott Wilson, Stanislovas S. Jankauskas, Pasquale Mone, Xujun Wang, Angela Lombardi, Gaetano Santulli, Varzideh, Fahimeh, Kansakar, Urna, Donkor, Kwame, Wilson, Scott, Jankauskas, Stanislovas S, Mone, Pasquale, Wang, Xujun, Lombardi, Angela, and Santulli, Gaetano
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clinical trials ,epigenetics ,non-coding RNA ,heart failure ,oxidative stress ,clinical trial ,cardiac remodeling ,Cardiology and Cardiovascular Medicine ,drug development ,ischemic heart disease ,epigenetic - Abstract
After an ischemic injury, the heart undergoes a complex process of structural and functional remodeling that involves several steps, including inflammatory and fibrotic responses. In this review, we are focusing on the contribution of microRNAs in the regulation of inflammation and fibrosis after myocardial infarction. We summarize the most updated studies exploring the interactions between microRNAs and key regulators of inflammation and fibroblast activation and we discuss the recent discoveries, including clinical applications, in these rapidly advancing fields.
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- 2022
163. Cardiomyocyte‐derived exosomal microRNA‐92a mediates post‐ischemic myofibroblast activation both in vitro and ex vivo
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Xujun Wang, Gaetano Santulli, Marco Bruno Morelli, Celestino Sardu, Alessandro Matarese, Wang, Xujun, Bruno Morelli, Marco, Matarese, Alessandro, Sardu, Celestino, Santulli, Gaetano, Wang, Xu, and Morelli Marco, Bruno
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lcsh:Diseases of the circulatory (Cardiovascular) system ,Myocardial Infarction ,Apoptosis ,030204 cardiovascular system & hematology ,Periostin ,Exosomes ,Exosome ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,In vivo ,Original Research Articles ,Animals ,Medicine ,Myocytes, Cardiac ,Original Research Article ,030212 general & internal medicine ,Myofibroblasts ,Cells, Cultured ,Myofibroblast ,business.industry ,Cell Differentiation ,MicroRNA ,Microvesicles ,In vitro ,Up-Regulation ,Cell biology ,Disease Models, Animal ,MicroRNAs ,lcsh:RC666-701 ,Epigenetics ,Cardiology and Cardiovascular Medicine ,business ,Ex vivo - Abstract
Aims We hypothesize that specific microRNAs (miRNAs) within cardiomyocyte‐derived exosomes play a pivotal role in the phenoconversion of cardiac myofibroblasts following myocardial infarction (MI). Methods and results We used an established murine model of MI, obtained in vivo via ligation of the left anterior descending coronary artery. We isolated adult cardiomyocytes and fibroblasts, and we assessed the functional role of cardiomyocyte‐derived exosomes and their molecular cargo in the activation of cardiac fibroblasts. We identified and biologically validated miR‐92a as a transcriptional regulator of mothers against DPP homologues 7 (SMAD7), a known inhibitor of α‐smooth muscle actin (α‐SMA), established marker of myofibroblast activation. We found that miR‐92a was significantly (P < 0.05) upregulated in cardiomyocyte‐derived exosomes and in fibroblasts isolated after MI compared with SHAM conditions (n ≥ 6/group). We tested the activation of myofibroblasts by measuring the expression levels of αSMA, periostin, and collagen. Primary isolated cardiac fibroblasts were activated both when incubated with cardiomyocyte‐derived exosomes isolated from ischemic cardiomyocytes and when cultured in conditioned medium of post‐MI cardiomyocytes, whereas no significant difference was observed following incubation with exosomes or medium from sham cardiomyocytes. These effects were attenuated when an inhibitor of exosome secretion, GW4869 (10 μM for 12 h) was included in the experimental setting. Through means of specific miR‐92a mimic and miR‐92a inhibitor, we also verified the mechanistic contribution of miR‐92a to the activation of cardiac fibroblasts. Conclusions Our results indicate for the first time that miR‐92a is transferred to fibroblasts in form of exosomal cargo and is critical for cardiac myofibroblast activation.
- Published
- 2020
164. Re: Differential benefits of physical training associated or not with L-Arginine supplementation in rats with metabolic syndrome: Evaluation of cardiovascular, autonomic and metabolic parameters
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Mone, Pasquale, Wang, Xujun, Trimarco, Valentina, and Santulli, Gaetano
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165. miR-24 targets SARS-CoV-2 co-factor Neuropilin-1 in human brain microvascular endothelial cells: Insights for COVID-19 neurological manifestations
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Gaetano Santulli, Pasquale Mone, Stanislovas S. Jankauskas, Jessica Gambardella, Alessandro Matarese, Xujun Wang, Mone, Pasquale, Gambardella, Jessica, Wang, Xujun, Jankauskas, Stanislovas S, Matarese, Alessandro, and Santulli, Gaetano
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Angiogenesis ,media_common.quotation_subject ,Regulator ,Human brain ,Biology ,In vitro ,Cell biology ,medicine.anatomical_structure ,Cell culture ,microRNA ,Neuropilin 1 ,cardiovascular system ,medicine ,Internalization ,media_common - Abstract
Neuropilin-1 is a transmembrane glycoprotein that has been implicated in several processes including angiogenesis and immunity. Recent evidence has also shown that it is implied in the cellular internalization of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). We hypothesized that specific microRNAs can target Neuropilin-1. By combining bioinformatic and functional approaches, we identified miR-24 as a regulator of Neuropilin-1 transcription. Since Neuropilin-1 has been shown to play a key role in the endothelium-mediated regulation of the blood-brain barrier, we validated miR-24 as a functional modulator of Neuropilin-1 in human brain microvascular endothelial cells (hBMECs), which are the most suitable cell line for an in vitro blood–brain barrier model.
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- 2021
166. Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence
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Gaetano Santulli, Marco Bruno Morelli, Jessica Gambardella, Celestino Sardu, Xujun Wang, Raffaele Marfella, Sardu, Celestino, Gambardella, Jessica, Bruno Morelli, Marco, X, Wang, Marfella, Raffaele, Santulli, Gaetano, and Wang, Xujun
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medicine.medical_specialty ,Endothelium ,endothelium ,coronavirus ,lcsh:Medicine ,Disease ,Review ,030204 cardiovascular system & hematology ,heparin ,03 medical and health sciences ,0302 clinical medicine ,Diabetes mellitus ,Internal medicine ,medicine ,030304 developmental biology ,COVID ,0303 health sciences ,Kawasaki disease ,business.industry ,lcsh:R ,ACE2, acute kidney injury ,Acute kidney injury ,blood pressure ,General Medicine ,medicine.disease ,Thrombosis ,Blood pressure ,medicine.anatomical_structure ,cytokine storm ,catepsin ,business ,Kidney disease - Abstract
The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic disorders, and diabetes mellitus) indicate that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report a systematic and comprehensive evaluation of both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ in COVID-19, providing a mechanistic rationale behind its systemic manifestations.
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- 2020
167. Macrophages release miRNAs in response to Doxorubicin with a potential role in indirect cardiac damage.
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Buonaiuto A, Gambardella J, Santulli G, Fiordelisi A, Wang X, Prevete N, Sommella E, Avvisato R, Cerasuolo FA, Altobelli GG, Ciccarelli M, Morisco C, Sadoshima J, Iaccarino G, and Sorriento D
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- Animals, Humans, Antibiotics, Antineoplastic adverse effects, Gene Expression Regulation drug effects, Mice, MicroRNAs metabolism, MicroRNAs genetics, Doxorubicin adverse effects, Macrophages metabolism, Macrophages drug effects, Cardiotoxicity
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- 2024
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168. Macrophages participate in doxorubicin-induced cardiac damage.
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Cerasuolo FA, Gambardella J, Santulli G, Fiordelisi A, Wang X, Prevete N, Sommella E, Avvisato R, Buonaiuto A, Altobelli GG, Ciccarelli M, Morisco C, Sadoshima J, Iaccarino G, and Sorriento D
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- Animals, Antibiotics, Antineoplastic adverse effects, Cardiotoxicity, Humans, Myocardium pathology, Myocardium metabolism, Myocytes, Cardiac drug effects, Myocytes, Cardiac pathology, Myocytes, Cardiac metabolism, Doxorubicin adverse effects, Macrophages drug effects, Macrophages metabolism
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- 2024
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169. Wnt5 controls splenic myelopoiesis and neutrophil functional ambivalency during DSS-induced colitis.
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Luan Y, Hu J, Wang Q, Wang X, Li W, Qu R, Yang C, Rajendran BK, Zhou H, Liu P, Zhang N, Shi Y, Liu Y, Tang W, Lu J, and Wu D
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- Animals, Mice, Myelopoiesis, Bone Marrow, Neutrophils, Colitis chemically induced
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Neutrophils are important innate immune cells with plasticity, heterogenicity, and functional ambivalency. While bone marrow is often regarded as the primary source of neutrophil production, the roles of extramedullary production in regulating neutrophil plasticity and heterogenicity in autoimmune diseases remain poorly understood. Here, we report that the lack of wingless-type MMTV integration site family member 5 (WNT5) unleashes anti-inflammatory protection against colitis in mice, accompanied by reduced colonic CD8
+ T cell activation and enhanced splenic extramedullary myelopoiesis. In addition, colitis upregulates WNT5 expression in splenic stromal cells. The ablation of WNT5 leads to increased splenic production of hematopoietic niche factors, as well as elevated numbers of splenic neutrophils with heightened CD8+ T cell suppressive capability, in part due to elevated CD101 expression and attenuated pro-inflammatory activities. Thus, our study reveals a mechanism by which neutrophil plasticity and heterogenicity are regulated in colitis through WNT5 and highlights the role of splenic neutrophil production in shaping inflammatory outcomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)- Published
- 2024
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170. The complete chloroplast genome sequence of Calanthe sieboldii (orchidaceae).
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Peng C, Liao D, Liu K, Wang X, and Guo W
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Calanthe sieboldii Decne. ex Regel is a terrestrial orchid with high ornamental and commercial value. In the present study, the chloroplast genome of C. sieboldii was characterized using Illumina technology. The chloroplast genome is 158,345 bp in length with a total AT content of 63.28%. There are 127 genes, comprising 37 tRNA genes, 82 protein-coding genes, and 8 rRNA genes. Phylogenetic relationship analysis was performed using common protein-coding genes extracted from 13 chloroplast genomes of Orchidaceae. It was revealed that C. sieboldi was sister to C. hancockii and closely clustered with C. aristulifera and C. henryi . These findings provide valuable genomic resources that are helpful for further phylogenetic and evolutionary studies of Calanthe ., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)
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- 2024
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171. Cell surface RNAs control neutrophil recruitment.
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Zhang N, Tang W, Torres L, Wang X, Ajaj Y, Zhu L, Luan Y, Zhou H, Wang Y, Zhang D, Kurbatov V, Khan SA, Kumar P, Hidalgo A, Wu D, and Lu J
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- Animals, Mice, Nucleotide Transport Proteins genetics, Nucleotide Transport Proteins metabolism, Endothelial Cells metabolism, Neutrophil Infiltration, Neutrophils metabolism, RNA chemistry, RNA metabolism
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RNAs localizing to the outer cell surface have been recently identified in mammalian cells, including RNAs with glycan modifications known as glycoRNAs. However, the functional significance of cell surface RNAs and their production are poorly known. We report that cell surface RNAs are critical for neutrophil recruitment and that the mammalian homologs of the sid-1 RNA transporter are required for glycoRNA expression. Cell surface RNAs can be readily detected in murine neutrophils, the elimination of which substantially impairs neutrophil recruitment to inflammatory sites in vivo and reduces neutrophils' adhesion to and migration through endothelial cells. Neutrophil glycoRNAs are predominantly on cell surface, important for neutrophil-endothelial interactions, and can be recognized by P-selectin (Selp). Knockdown of the murine Sidt genes abolishes neutrophil glycoRNAs and functionally mimics the loss of cell surface RNAs. Our data demonstrate the biological importance of cell surface glycoRNAs and highlight a noncanonical dimension of RNA-mediated cellular functions., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2024
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172. Reference Genes Screening and Gene Expression Patterns Analysis Involved in Gelsenicine Biosynthesis under Different Hormone Treatments in Gelsemium elegans .
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Zhang Y, Mu D, Wang L, Wang X, Wilson IW, Chen W, Wang J, Liu Z, Qiu D, and Tang Q
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- Real-Time Polymerase Chain Reaction methods, Gene Expression Profiling methods, Reference Standards, Gene Expression, Hormones, Gelsemium genetics
- Abstract
Reverse transcription quantitative polymerase chain reaction (RT-qPCR) is an accurate method for quantifying gene expression levels. Choosing appropriate reference genes to normalize the data is essential for reducing errors. Gelsemium elegans is a highly poisonous but important medicinal plant used for analgesic and anti-swelling purposes. Gelsenicine is one of the vital active ingredients, and its biosynthesis pathway remains to be determined. In this study, G. elegans leaf tissue with and without the application of one of four hormones (SA, MeJA, ETH, and ABA) known to affect gelsenicine synthesis, was analyzed using ten candidate reference genes. The gene stability was evaluated using GeNorm, NormFinder, BestKeeper, ∆CT, and RefFinder. The results showed that the optimal stable reference genes varied among the different treatments and that at least two reference genes were required for accurate quantification. The expression patterns of 15 genes related to the gelsenicine upstream biosynthesis pathway was determined by RT-qPCR using the relevant reference genes identified. Three genes 8-HGO , LAMT , and STR , were found to have a strong correlation with the amount of gelsenicine measured in the different samples. This research is the first study to examine the reference genes of G. elegans under different hormone treatments and will be useful for future molecular analyses of this medically important plant species.
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- 2023
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173. Infiltrating macrophages amplify doxorubicin-induced cardiac damage: role of catecholamines.
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Gambardella J, Santulli G, Fiordelisi A, Cerasuolo FA, Wang X, Prevete N, Sommella E, Avvisato R, Buonaiuto A, Altobelli GG, Rinaldi L, Chiuso F, Feliciello A, Dal Piaz F, Campiglia P, Ciccarelli M, Morisco C, Sadoshima J, Iaccarino G, and Sorriento D
- Subjects
- Rats, Mice, Animals, Mice, Inbred C57BL, Apoptosis, Myocytes, Cardiac metabolism, Macrophages, Oxidative Stress, Catecholamines metabolism, Doxorubicin adverse effects
- Abstract
Background: The functional contribution of non-myocyte cardiac cells, such as inflammatory cells, in the setup of heart failure in response to doxorubicin (Dox) is recently becoming of growing interest., Objectives: The study aims to evaluate the role of macrophages in cardiac damage elicited by Dox treatment., Methods: C57BL/6 mice were treated with one intraperitoneal injection of Dox (20 mg/kg) and followed up for 5 days by cardiac ultrasounds (CUS), histological, and flow cytometry evaluations. We also tested the impact of Dox in macrophage-depleted mice. Rat cardiomyoblasts were directly treated with Dox (D-Dox) or with a conditioned medium from cultured murine macrophages treated with Dox (M-Dox)., Results: In response to Dox, macrophage infiltration preceded cardiac damage. Macrophage depletion prevents Dox-induced damage, suggesting a key role of these cells in promoting cardiotoxicity. To evaluate the crosstalk between macrophages and cardiac cells in response to DOX, we compared the effects of D-Dox and M-Dox in vitro. Cell vitality was lower in cardiomyoblasts and apoptosis was higher in response to M-Dox compared with D-Dox. These events were linked to p53-induced mitochondria morphology, function, and autophagy alterations. We identify a mechanistic role of catecholamines released by Dox-activated macrophages that lead to mitochondrial apoptosis of cardiac cells through β-AR stimulation., Conclusions: Our data indicate that crosstalk between macrophages and cardiac cells participates in cardiac damage in response to Dox., (© 2023. The Author(s).)
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- 2023
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174. Re: Differential benefits of physical training associated or not with L-Arginine supplementation in rats with metabolic syndrome: Evaluation of cardiovascular, autonomic and metabolic parameters.
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Mone P, Wang X, Trimarco V, and Santulli G
- Subjects
- Rats, Animals, Rats, Wistar, Heart, Dietary Supplements, Arginine pharmacology, Metabolic Syndrome complications, Physical Conditioning, Animal
- Abstract
Competing Interests: Declaration of Competing Interest There is no conflict of interest in this study.
- Published
- 2023
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175. Ketone Bodies Rescue Mitochondrial Dysfunction Via Epigenetic Remodeling.
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Gambardella J, Jankauskas SS, Kansakar U, Varzideh F, Avvisato R, Prevete N, Sidoli S, Mone P, Wang X, Lombardi A, and Santulli G
- Abstract
Ischemic cardiac disease is a major cause of mortality worldwide. However, the exact molecular processes underlying this disorder are not fully known. This study includes a comprehensive and coordinated set of in vivo and in vitro experiments using human cardiac specimens from patients with postischemic heart failure (HF) and healthy control subjects, a murine model of HF, and cellular systems. These approaches identified for the first time a specific pattern of maladaptive chromatin remodeling, namely a double methylation of histone 3 at lysine 27 and a single methylation at lysine 36 (H3_K27me2K36me1) consistently induced by ischemic injury in all these settings: human HF; murine HF; and in vitro models. Mechanistically, this work demonstrates that this histone modification mediates the ischemia-induced transcriptional repression of PPARG coactivator 1α (PGC1α), master regulator of mitochondrial function and biogenesis. Intriguingly, both the augmented H3_K27me2K36me1 and the mitochondrial dysfunction ensued by PGC1α down-regulation were significantly attenuated by the treatment with β-hydroxybutyrate, the most abundant ketone body in humans, revealing a novel pathway coupling metabolism to gene expression. Taken together, these findings establish maladaptive chromatin remodeling as a key mechanism in postischemic heart injury, functionally modulated by ketone bodies., Competing Interests: Prof Santulli has received support in part from the National Institutes of Health (NIH): National Heart, Lung, and Blood Institute (NHLBI: R01-HL164772, R01-HL159062, R01-HL146691, T32-HL144456), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK: R01-DK123259, R01-DK033823), National Center for Advancing Translational Sciences (NCATS: UL1-TR002556-06, UM1-TR004400) to Dr Santulli, from the Diabetes Action Research and Education Foundation (to Dr Santulli), and from the Monique Weill-Caulier and Irma T. Hirschl Trusts (to Dr Santulli). Dr Gambardella has received support from a postdoctoral fellowship of the American Heart Association (AHA-20POST35211151). Dr Jankauskas has received support from a postdoctoral fellowship of the American Heart Association (AHA-21POST836407). Dr Kansakar has received support from a postdoctoral fellowship of the American Heart Association (AHA-23POST1026190). Dr Varzideh has received support from a postdoctoral fellowship of the American Heart Association (AHA-22POST915561). Dr Sidoli has received support from the Leukemia Research Foundation (Hollis Brownstein New Investigator Research Grant), Relay Therapeutics, Deerfield (Xseed award), Merck, AFAR (Sagol Network GerOmics award), and the NIH Office of the Director (1S10-OD030286-01). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)
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- 2023
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176. Transition metal-doped germanium oxide nanozyme with enhanced enzyme-like activity for rapid detection of pesticide residues in water samples.
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Zeng Z, Wang X, Yang T, Li Y, Liu X, Zhang P, Feng B, and Qing T
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- Hydrogen Peroxide analysis, Simazine analysis, Palladium chemistry, Water analysis, Colorimetry, Pesticide Residues analysis
- Abstract
Designing highly active nanozymes for bioanalysis and environmental sensing remains a challenge. In this study, transition metal, palladium (Pd) and iron (Fe), doped germanium oxide (GeO
2 ) nanozyme was designed and optimized. Compared with the pristine GeO2 nanozyme, the transition metal doped GeO2 nanozyme have lower Michaelis-Menten constants and higher catalytic activity, indicating that the Pd and Fe doped GeO2 nanozyme not only enhance their affinity for the substrate but also improve its catalytic activity. In addition, a colorimetric sensor based on the GeO2 @Pd-H2 O2 -TMB system was constructed for the visual detection of simazine in water samples due to the good affinity between TMB and simazine. This sensor has good selectivity and sensitivity with a detection limit of 6.21 μM because of the highest catalytic performance of GeO2 @Pd nanozyme. This study broadens the application of nanozymes in environmental field and other nanozymes can also be enhanced in activity by simple transition metal doping., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)- Published
- 2023
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177. Cancer Cell Resistance to IFNγ Can Occur via Enhanced Double-Strand Break Repair Pathway Activity.
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Han T, Wang X, Shi S, Zhang W, Wang J, Wu Q, Li Z, Fu J, Zheng R, Zhang J, Tang Q, Zhang P, and Wang C
- Subjects
- Humans, Interferon-gamma pharmacology, Interferon-gamma genetics, DNA Repair, Cell Line, DNA Breaks, Double-Stranded, Neoplasms drug therapy, Neoplasms genetics
- Abstract
The pleiotropic cytokine interferon-gamma (IFNγ) is associated with cytostatic, antiproliferation, and proapoptotic functions in cancer cells. However, resistance to IFNγ occurs in many cancer cells, and the underlying mechanism is not fully understood. To investigate potential IFNγ-resistance mechanisms, we performed IFNγ-sensitivity screens in more than 40 cancer cell lines and characterized the sensitive and resistant cell lines. By applying CRISPR screening and transcriptomic profiling in both IFNγ-sensitive and IFNγ-resistant cells, we discovered that activation of double-strand break (DSB) repair genes could result in IFNγ resistance in cancer cells. Suppression of single-strand break (SSB) repair genes increased the dependency on DSB repair genes after IFNγ treatment. Furthermore, inhibition of the DSB repair pathway exhibited a synergistic effect with IFNγ treatment both in vitro and in vivo. The relationship between the activation of DSB repair genes and IFNγ resistance was further confirmed in clinical tumor profiles from The Cancer Genome Atlas (TCGA) and immune checkpoint blockade (ICB) cohorts. Our study provides comprehensive resources and evidence to elucidate a mechanism of IFNγ resistance in cancer and has the potential to inform combination therapies to overcome immunotherapy resistance., (©2023 American Association for Cancer Research.)
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- 2023
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178. Stress Hyperglycemia Drives the Risk of Hospitalization for Chest Pain in Patients With Ischemia and Nonobstructive Coronary Arteries (INOCA).
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Mone P, Lombardi A, Salemme L, Cioppa A, Popusoi G, Varzideh F, Pansini A, Jankauskas SS, Forzano I, Avvisato R, Wang X, Tesorio T, and Santulli G
- Subjects
- Humans, Coronary Vessels, Hospitalization, Chest Pain etiology, Ischemia, Percutaneous Coronary Intervention, Hyperglycemia, Coronary Artery Disease complications
- Abstract
Objective: Ischemia with nonobstructive coronary arteries (INOCA) is a prevailing finding in patients with angina. However, the main factors underlying the risk of being rehospitalized for chest pain in patients with INOCA remain mostly unknown., Research Design and Methods: We evaluated INOCA patients referred to the "Casa di Cura Montevergine" in Mercogliano (Avellino), Italy, from January 2016 to January 2021 for percutaneous coronary intervention (PCI). In these subjects, we assessed the impact of the stress hyperglycemia ratio (SHR), defined as the ratio of mmol/L blood glucose and % HbA1c, on the risk of rehospitalization for chest pain., Results: A total of 2,874 patients with INOCA successfully completed the study. At the 1-year follow-up, the risk of rehospitalization for chest pain was significantly higher (P < 0.001) in INOCA patients with SHR >1 compared to patients with SHR ≤1. These findings were confirmed by multivariable analyses (adjusting for potential confounders, including age, BMI, blood pressure, heart rate, chronic kidney disease, and cholesterol), propensity score matching, and inverse probability of treatment weighting., Conclusions: Our data indicate, to our knowledge for the first time, that SHR on hospital admission significantly and independently increases the risk of rehospitalization for chest pain in INOCA patients., (© 2023 by the American Diabetes Association.)
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- 2023
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179. COVID-19 Causes Ferroptosis and Oxidative Stress in Human Endothelial Cells.
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Jankauskas SS, Kansakar U, Sardu C, Varzideh F, Avvisato R, Wang X, Matarese A, Marfella R, Ziosi M, Gambardella J, and Santulli G
- Abstract
Oxidative stress and endothelial dysfunction have been shown to play crucial roles in the pathophysiology of COVID-19 (coronavirus disease 2019). On these grounds, we sought to investigate the impact of COVID-19 on lipid peroxidation and ferroptosis in human endothelial cells. We hypothesized that oxidative stress and lipid peroxidation induced by COVID-19 in endothelial cells could be linked to the disease outcome. Thus, we collected serum from COVID-19 patients on hospital admission, and we incubated these sera with human endothelial cells, comparing the effects on the generation of reactive oxygen species (ROS) and lipid peroxidation between patients who survived and patients who did not survive. We found that the serum from non-survivors significantly increased lipid peroxidation. Moreover, serum from non-survivors markedly regulated the expression levels of the main markers of ferroptosis, including GPX4, SLC7A11, FTH1, and SAT1, a response that was rescued by silencing TNFR1 on endothelial cells. Taken together, our data indicate that serum from patients who did not survive COVID-19 triggers lipid peroxidation in human endothelial cells.
- Published
- 2023
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180. Exosomal miR-145 and miR-885 Regulate Thrombosis in COVID-19.
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Gambardella J, Kansakar U, Sardu C, Messina V, Jankauskas SS, Marfella R, Maggi P, Wang X, Mone P, Paolisso G, Sorriento D, and Santulli G
- Subjects
- Humans, Endothelial Cells, SARS-CoV-2, COVID-19 complications, MicroRNAs genetics, MicroRNAs metabolism, Post-Acute COVID-19 Syndrome genetics, Post-Acute COVID-19 Syndrome metabolism, Thrombosis genetics, Thrombosis metabolism, Thrombosis virology, Exosomes metabolism
- Abstract
We hypothesized that exosomal microRNAs could be implied in the pathogenesis of thromboembolic complications in coronavirus disease 2019 (COVID-19). We isolated circulating exosomes from patients with COVID-19, and then we divided our population in two arms based on the D-dimer level on hospital admission. We observed that exosomal miR-145 and miR-885 significantly correlate with D-dimer levels. Moreover, we demonstrate that human endothelial cells express the main cofactors needed for the internalization of the "Severe acute respiratory syndrome coronavirus 2" (SARS-CoV-2), including angiotensin converting enzyme 2, transmembrane protease serine 2, and CD-147. Interestingly, human endothelial cells treated with serum from COVID-19 patients release significantly less miR-145 and miR-885, exhibit increased apoptosis, and display significantly impaired angiogenetic properties compared with cells treated with non-COVID-19 serum. Taken together, our data indicate that exosomal miR-145 and miR-885 are essential in modulating thromboembolic events in COVID-19. SIGNIFICANCE STATEMENT: This work demonstrates for the first time that two specific microRNAs (namely miR-145 and miR-885) contained in circulating exosomes are functionally involved in thromboembolic events in COVID-19. These findings are especially relevant to the general audience when considering the emerging prominence of post-acute sequelae of COVID-19 systemic manifestations known as Long COVID., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2023
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181. Efficient and recyclable degradation of organic dye pollutants by CeO 2 @ZIF-8 nanozyme-based non-photocatalytic system.
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Yang T, Liu X, Zeng Z, Wang X, Zhang P, Feng B, Tian K, and Qing T
- Subjects
- Photolysis, Azo Compounds, Catalysis, Coloring Agents, Environmental Pollutants
- Abstract
Advanced oxidation processes-based catalysis system as the most typical pollutant degradation technology always suffer from poor durability and photo-dependent. Inspired by the fact that some nanomaterials exhibit catalytic properties closer to natural enzymes, a high peroxidase-like activity and stability CeO
2 @ZIF-8 nanozyme was synthesized in this study for non-photodegradation of dyes pollution. Multiple characterization techniques were applied to prove the successful synthesis of the nanozyme. The influence of different parameters on the catalytic degradation of organic dye by nanozyme was investigated. This nanozyme achieved a maximum degradation efficiency of 99.81% for methyl orange and maintained its catalytic performance in repeated experiments. Possible degradation intermediates and pathways for methyl orange were then proposed. In addition, the CeO2 @ZIF-8 loaded starch/agarose films were prepared for the portable and recyclable remediation of real dye wastewater, which maintained more than 80% degradation efficiency after 5 successive cycles. These results suggested that nanozyme based non-photocatalytic system is a potential catalyst for dye degradation and it opens a new avenue to develop high-performance and recyclable catalysts for pollutant remediation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)- Published
- 2023
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182. Ten-Eleven-Translocation Genes in Cancer.
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Wang Y, Wang X, and Lu J
- Subjects
- Humans, DNA Methylation, Mutation, 5-Methylcytosine, Mixed Function Oxygenases genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Hematologic Neoplasms genetics
- Abstract
The Ten-Eleven-Translocation (TET) family of genes, including TET1, TET2, and TET3, play critical roles in the oxidation of 5-methylcytosine marks in both DNA and RNA, thereby regulating the epigenome and epitranscriptome in cells. These genes are frequently mutated in both hematopoietic malignancies and in solid cancers. TET2, in particular, is one of the most frequently mutated genes in clonal hematopoiesis in the general population, which impacts both the transformation of hematopoietic malignancies and the immune responses in solid tumors. While much has been learned in the 14 years since the discovery of TETs' biochemical function and mutations, many important questions remain. This review covers several aspects of TET-related biology to discuss key yet unanswered questions. What are the functions of different forms of TET mutations found in human cancers? How does TET2 mutation enable pre-malignant hematopoietic expansion? How does TET2 mutation cooperate with partner lesions to cause transformation? And how do TET mutations affect immune responses in solid cancers., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2023
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183. How I Learned is How I Teach - Perspectives on How Faculty Surgeons Approach Informed Consent Education.
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White EM, Esposito AC, Kurbatov V, Wang X, Caty MG, Laurans M, and Yoo PS
- Subjects
- Humans, Education, Medical, Graduate methods, Informed Consent, Faculty, Clinical Competence, Internship and Residency, Surgeons, General Surgery education
- Abstract
Objective: To understand the variability of surgical attending experience and perspectives regarding informed consent and how it impacts resident education DESIGN: A novel survey was distributed electronically to explore faculty surgeon's personal learning experience, knowledge, clinical practice, teaching preferences and beliefs regarding informed consent. Chi-square and Kruskal-Wallis testing was performed to look for associations and a cluster analysis was performed to elucidate additional patterns among., Setting: Single, tertiary, university-affiliated health care system (Yale New Haven Health in Connecticut), including 6 teaching hospitals., Participants: Clinical faculty within the Department of Surgery., Results: A total of 85 surgeons responded (49% response rate), representing 17 specialties, both private practice and university and/or hospital-employed, with a range of years in practice. Across all ages, specialties, the most common method for both learning (86%) and teaching (82%) informed consent was observation of the attending. Respondents who stated they learned by observing attendings were more likely to report that they teach by having trainees observe them (OR 8.5, 95% CI 1.3-56.5) and participants who recalled learning by having attendings observe them were more likely to observe their trainees (OR 4.1, 95% CI 1.5-11.2).Cluster analysis revealed 5 different attending phenotypes with significant heterogeneity between groups. A cluster of younger attendings reported the least diverse learning experience and high levels of concern for legal liability and resident competency. They engaged in few strategies for teaching residents. By comparison, the cluster that reported the most diverse learning experience also reported the richest diversity of teaching strategies to residents but rarely allowed residents to perform consent with their patients. Meanwhile, 2 other cluster provided a more balanced experience with some opportunities for practice with patients and some diversity of teaching- these clusters, respectively, consist of older, experienced general surgeons and surgeons in trauma and/or critical care., Conclusions: Surgeon's demographics, personal experiences, and specialty appear to significantly influence their teaching styles and the educational experience residents receive regarding informed consent., (Copyright © 2022 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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184. Updated ACC/AHA/HFSA 2022 guidelines on heart failure: what is new? From epidemiology to clinical management.
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Santulli G, Wang X, and Mone P
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- Humans, Cardiology, Heart Failure diagnosis, Heart Failure epidemiology, Heart Failure therapy
- Published
- 2022
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185. Single-Cell Transcriptome Identifies Drug-Resistance Signature and Immunosuppressive Microenvironment in Metastatic Small Cell Lung Cancer (Advanced Genetics 2/03).
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Zhang J, Zhang H, Zhang L, Li D, Qi M, Zhang L, Yu H, Wang D, Jiang G, Wang X, Zhu X, and Zhang P
- Abstract
Single-Cell RNA Sequencing This cover illustrates the work of Xujun Wang, Xianmin Zhu, Peng Zhang, and co-workers in article number 2100060 which reveals the drug-resistance signature and immunosuppressive microenvironment in small cell lung cancer (SCLC) by single-cell RNA-sequencing. "Wu Song Fought the Tiger" comes from the famous Chinese novel: Outlaws of the Marsh. In the cover, the warrior Wu Song stands for the doctors and researchers. The tiger bearing "SCLC" on its face is dangerous for its sharp teeth and claws (early metastasis and drug resistance) and the surrounding water bubbles (immune infiltration). In addition, 2022 is the Year of the Tiger., (© 2022 The Authors. Advanced Genetics published by Wiley Periodicals LLC.)
- Published
- 2022
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186. Cardiac Remodeling After Myocardial Infarction: Functional Contribution of microRNAs to Inflammation and Fibrosis.
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Varzideh F, Kansakar U, Donkor K, Wilson S, Jankauskas SS, Mone P, Wang X, Lombardi A, and Santulli G
- Abstract
After an ischemic injury, the heart undergoes a complex process of structural and functional remodeling that involves several steps, including inflammatory and fibrotic responses. In this review, we are focusing on the contribution of microRNAs in the regulation of inflammation and fibrosis after myocardial infarction. We summarize the most updated studies exploring the interactions between microRNAs and key regulators of inflammation and fibroblast activation and we discuss the recent discoveries, including clinical applications, in these rapidly advancing fields., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Varzideh, Kansakar, Donkor, Wilson, Jankauskas, Mone, Wang, Lombardi and Santulli.)
- Published
- 2022
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187. Phosphorene grain boundary effect on phonon transport and phononic applications.
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Wang X, Wang Q, Liu X, Huang Z, and Liu X
- Abstract
Grain boundaries (GBs) widely exist in black phosphorene (BP), which plays a vital role in determining the properties of 2D materials. Significant GB effect on the thermal boundary resistance in BP structures is found by using molecular dynamics calculations and lattice dynamic analysis. A remarkably high interface thermal resistance is observed. By analyzing the strain distribution and phonon vibrational spectra, we reveal this high thermal resistance originates from phonon localization and strong phonon boundary scattering induced by the local stress at the GB area. Particularly, it is interesting to find that the partial phonon modes display weak localization when GBs present. The fraction of atoms participating in a particular phonon vibrational mode has been quantified through the calculation of phonon participation ratio. In addition, the thermal boundary resistance is found size-dependent, which further induces interesting thermal rectification effect in the BP structures. A high rectification ratio is obtained by adjusting the structural length and temperature bias. These findings provide a through insight into the GB effects on individual phonon mode transmission across the GBs, and highlight that the GB effect is an important factor and should be taken into account for the applications of BP-based phononic devices., (© 2022 IOP Publishing Ltd.)
- Published
- 2022
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188. IP3 receptor orchestrates maladaptive vascular responses in heart failure.
- Author
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Dridi H, Santulli G, Gambardella J, Jankauskas SS, Yuan Q, Yang J, Reiken S, Wang X, Wronska A, Liu X, Lacampagne A, and Marks AR
- Subjects
- Animals, Heart Failure genetics, Heart Failure physiopathology, Humans, Inositol 1,4,5-Trisphosphate Receptors genetics, Mice, Mice, Knockout, Muscle, Smooth, Vascular physiopathology, Calcium Signaling, Heart Failure metabolism, Inositol 1,4,5-Trisphosphate Receptors metabolism, Muscle, Smooth, Vascular metabolism, Myocytes, Smooth Muscle metabolism, Vasoconstriction
- Abstract
Patients with heart failure (HF) have augmented vascular tone, which increases cardiac workload, impairing ventricular output and promoting further myocardial dysfunction. The molecular mechanisms underlying the maladaptive vascular responses observed in HF are not fully understood. Vascular smooth muscle cells (VSMCs) control vasoconstriction via a Ca2+-dependent process, in which the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) on the sarcoplasmic reticulum (SR) plays a major role. To dissect the mechanistic contribution of intracellular Ca2+ release to the increased vascular tone observed in HF, we analyzed the remodeling of IP3R1 in aortic tissues from patients with HF and from controls. VSMC IP3R1 channels from patients with HF and HF mice were hyperphosphorylated by both serine and tyrosine kinases. VSMCs isolated from IP3R1VSMC-/- mice exhibited blunted Ca2+ responses to angiotensin II (ATII) and norepinephrine compared with control VSMCs. IP3R1VSMC-/- mice displayed significantly reduced responses to ATII, both in vivo and ex vivo. HF IP3R1VSMC-/- mice developed significantly less afterload compared with HF IP3R1fl/fl mice and exhibited significantly attenuated progression toward decompensated HF and reduced interstitial fibrosis. Ca2+-dependent phosphorylation of the MLC by MLCK activated VSMC contraction. MLC phosphorylation was markedly increased in VSMCs from patients with HF and HF mice but reduced in VSMCs from HF IP3R1VSMC-/- mice and HF WT mice treated with ML-7. Taken together, our data indicate that VSMC IP3R1 is a major effector of increased vascular tone, which contributes to increased cardiac afterload and decompensation in HF.
- Published
- 2022
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189. A Retinoic Acid Receptor β 2 Agonist Improves Cardiac Function in a Heart Failure Model.
- Author
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Tang XH, Gambardella J, Jankauskas S, Wang X, Santulli G, Gudas LJ, and Levi R
- Subjects
- Animals, Benzoates pharmacology, Heart Failure metabolism, Heart Failure physiopathology, Male, Mice, Mice, Inbred C57BL, Oxidative Stress drug effects, Oxidative Stress physiology, Receptors, Retinoic Acid metabolism, Thiazoles pharmacology, Benzoates therapeutic use, Disease Models, Animal, Heart Failure drug therapy, Receptors, Retinoic Acid agonists, Thiazoles therapeutic use
- Abstract
We previously demonstrated that the selective retinoic acid receptor (RAR) β
2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. We hypothesized that by decreasing oxidative stress and consequent fibrogenesis, AC261066 could attenuate the development of contractile dysfunction in post-ischemic heart failure (HF). We tested this hypothesis in vivo using an established murine model of myocardial infarction (MI), obtained by permanent occlusion of the left anterior descending coronary artery. Treating mice with AC261066 in drinking water significantly attenuated the post-MI deterioration of echocardiographic indices of cardiac function, diminished remodeling, and reduced oxidative stress, as evidenced by a decrease in malondialdehyde level and p38 mitogen-activated protein kinase expression in cardiomyocytes. The effects of AC261066 were also associated with a decrease in interstitial fibrosis, as shown by a marked reduction in collagen deposition and α -smooth muscle actin expression. In cardiac murine fibroblasts subjected to hypoxia, AC261066 reversed hypoxia-induced decreases in superoxide dismutase 2 and angiopoietin-like 4 transcriptional levels as well as the increase in NADPH oxidase 2 mRNA, demonstrating that the post-MI cardioprotective effects of AC261066 are associated with an action at the fibroblast level. Thus, AC261066 alleviates post-MI cardiac dysfunction by modulating a set of genes involved in the oxidant/antioxidant balance. These AC261066 responsive genes diminish interstitial fibrogenesis and remodeling. Since MI is a recognized major cause of HF, our data identify RAR β2 as a potential pharmacological target in the treatment of HF. SIGNIFICANCE STATEMENT: A previous report showed that the selective retinoic acid receptor (RAR) β2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. This study shows that AC261066 attenuates the development of contractile dysfunction and maladaptive remodeling in post-ischemic heart failure (HF) by modulating a set of genes involved in oxidant/antioxidant balance. Since myocardial infarction is a recognized major cause of HF, these data identify RAR β2 as a potential pharmacological target in the treatment of HF., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)- Published
- 2021
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190. Novel low-temperature H 2 S removal technology by developing yellow phosphorus and phosphate rock slurry as absorbent.
- Author
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Mei Y, Dai J, Wang X, Nie Y, and He D
- Abstract
Recycling hazardous gas of H
2 S is one of the most important strategies to promote sustainable development. Herein, a novel method regarding purifying H2 S is proposed by using yellow phosphorus and phosphate rock slurry as absorbent. The H2 SO4 , formed in situ by H2 S conversion, can be devoted to decompose phosphate rock, and the spent absorption slurry was applied as raw material for the production of phosphorus chemical products. According to the characterization analysis, it was found that H2 S was first oxidized to SO2 via O2 as well as O3 induced by P4 . Subsequently, the generated SO2 dissolved rapidly in water to form H2 SO4 , and then reacted with the main component of phosphate rock, CaMg(CO3 )2 . Most notably, the active substances, such as, O3 , SO4 •- and OH•, produced in the reaction process, can oxidize H2 S and HS- to these sulfur products. In addition, trace amounts of Fe3+ and Mn2+ that were dissolved from phosphate rock displayed a promotional effect on the formation of active substances. Consequently, as high as 85% of H2 S removal efficiency can be obtained even under acidic condition and low temperature. The proposed H2 S purification method offers a promising option for sulfur recovery and H2 S pollution control., (Copyright © 2021 Elsevier B.V. All rights reserved.)- Published
- 2021
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191. Single-cell analysis of pancreatic ductal adenocarcinoma identifies a novel fibroblast subtype associated with poor prognosis but better immunotherapy response.
- Author
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Wang Y, Liang Y, Xu H, Zhang X, Mao T, Cui J, Yao J, Wang Y, Jiao F, Xiao X, Hu J, Xia Q, Zhang X, Wang X, Sun Y, Fu D, Shen L, Xu X, Xue J, and Wang L
- Abstract
The current pathological and molecular classification of pancreatic ductal adenocarcinoma (PDAC) provides limited guidance for treatment options, especially for immunotherapy. Cancer-associated fibroblasts (CAFs) are major players of desmoplastic stroma in PDAC, modulating tumor progression and therapeutic response. Using single-cell RNA sequencing, we explored the intertumoral heterogeneity among PDAC patients with different degrees of desmoplasia. We found substantial intertumoral heterogeneity in CAFs, ductal cancer cells, and immune cells between the extremely dense and loose types of PDACs (dense-type, high desmoplasia; loose-type, low desmoplasia). Notably, no difference in CAF abundance was detected, but a novel subtype of CAFs with a highly activated metabolic state (meCAFs) was found in loose-type PDAC compared to dense-type PDAC. MeCAFs had highly active glycolysis, whereas the corresponding cancer cells used oxidative phosphorylation as a major metabolic mode rather than glycolysis. We found that the proportion and activity of immune cells were much higher in loose-type PDAC than in dense-type PDAC. Then, the clinical significance of the CAF subtypes was further validated in our PDAC cohort and a public database. PDAC patients with abundant meCAFs had a higher risk of metastasis and a poor prognosis but showed a dramatically better response to immunotherapy (64.71% objective response rate, one complete response). We characterized the intertumoral heterogeneity of cellular components, immune activity, and metabolic status between dense- and loose-type PDACs and identified meCAFs as a novel CAF subtype critical for PDAC progression and the susceptibility to immunotherapy.
- Published
- 2021
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192. miR-24 targets SARS-CoV-2 co-factor Neuropilin-1 in human brain microvascular endothelial cells: Insights for COVID-19 neurological manifestations.
- Author
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Mone P, Gambardella J, Wang X, Jankauskas SS, Matarese A, and Santulli G
- Abstract
Neuropilin-1 is a transmembrane glycoprotein that has been implicated in several processes including angiogenesis and immunity. Recent evidence has also shown that it is implied in the cellular internalization of the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19). We hypothesized that specific microRNAs can target Neuropilin-1. By combining bioinformatic and functional approaches, we identified miR-24 as a regulator of Neuropilin-1 transcription. Since Neuropilin-1 has been shown to play a key role in the endothelium-mediated regulation of the blood-brain barrier, we validated miR-24 as a functional modulator of Neuropilin-1 in human brain microvascular endothelial cells (hBMECs), which are the most suitable cell line for an in vitro bloodâ€"brain barrier model.
- Published
- 2021
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193. Role of Endothelial G Protein-Coupled Receptor Kinase 2 in Angioedema.
- Author
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Gambardella J, Sorriento D, Bova M, Rusciano M, Loffredo S, Wang X, Petraroli A, Carucci L, Mormile I, Oliveti M, Bruno Morelli M, Fiordelisi A, Spadaro G, Campiglia P, Sala M, Trimarco B, Iaccarino G, Santulli G, and Ciccarelli M
- Subjects
- Animals, Calcium metabolism, Endothelial Cells drug effects, Endothelial Cells metabolism, Endothelium, Vascular drug effects, Humans, Mice, Nitric Oxide metabolism, Phosphorylation drug effects, Signal Transduction drug effects, Angioedema metabolism, Bradykinin pharmacology, Endothelium, Vascular metabolism, G-Protein-Coupled Receptor Kinase 2 metabolism
- Abstract
Excessive BK (bradykinin) stimulation is responsible for the exaggerated permeabilization of the endothelium in angioedema. However, the molecular mechanisms underlying these responses have not been investigated. BK receptors are Gq-protein-coupled receptors phosphorylated by GRK2 (G protein-coupled receptor kinase 2) with a hitherto unknown biological and pathophysiological significance. In the present study, we sought to identify the functional role of GRK2 in angioedema through the regulation of BK signaling. We found that the accumulation of cytosolic Ca
2+ in endothelial cells induced by BK was sensitive to GRK2 activity, as it was significantly augmented by inhibiting the kinase. Accordingly, permeabilization and NO production induced by BK were enhanced, as well. In vivo, mice with reduced GRK2 levels in the endothelium (Tie2-CRE/GRK2fl+/fl - ) exhibited an increased response to BK in terms of vascular permeability and extravasation. Finally, patients with reduced GRK2 levels displayed a severe phenotype of angioedema. Taken together, these findings establish GRK2 as a novel pivotal regulator of BK signaling with an essential role in the pathophysiology of vascular permeability and angioedema.- Published
- 2020
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194. Publisher Correction: MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors.
- Author
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Chen X, Burkhardt DB, Hartman AA, Hu X, Eastman AE, Sun C, Wang X, Zhong M, Krishnaswamy S, and Guo S
- Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
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- View/download PDF
195. MLL-AF9 initiates transformation from fast-proliferating myeloid progenitors.
- Author
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Chen X, Burkhardt DB, Hartman AA, Hu X, Eastman AE, Sun C, Wang X, Zhong M, Krishnaswamy S, and Guo S
- Subjects
- Animals, Cell Cycle drug effects, Cell Cycle genetics, Cell Differentiation drug effects, Cell Differentiation genetics, Cell Proliferation drug effects, Cell Proliferation genetics, Cell Transformation, Neoplastic drug effects, Cyclin D1 metabolism, Disease Models, Animal, Female, Gene Knock-In Techniques, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Male, Mice, Transgenic, Piperazines administration & dosage, Primary Cell Culture, Prognosis, Pyridines administration & dosage, Cell Transformation, Neoplastic genetics, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute genetics, Myeloid Progenitor Cells pathology, Myeloid-Lymphoid Leukemia Protein genetics, Oncogene Proteins, Fusion genetics
- Abstract
Cancer is a hyper-proliferative disease. Whether the proliferative state originates from the cell-of-origin or emerges later remains difficult to resolve. By tracking de novo transformation from normal hematopoietic progenitors expressing an acute myeloid leukemia (AML) oncogene MLL-AF9, we reveal that the cell cycle rate heterogeneity among granulocyte-macrophage progenitors (GMPs) determines their probability of transformation. A fast cell cycle intrinsic to these progenitors provide permissiveness for transformation, with the fastest cycling 3% GMPs acquiring malignancy with near certainty. Molecularly, we propose that MLL-AF9 preserves gene expression of the cellular states in which it is expressed. As such, when expressed in the naturally-existing, rapidly-cycling immature myeloid progenitors, this cell state becomes perpetuated, yielding malignancy. In humans, high CCND1 expression predicts worse prognosis for MLL fusion AMLs. Our work elucidates one of the earliest steps toward malignancy and suggests that modifying the cycling state of the cell-of-origin could be a preventative approach against malignancy.
- Published
- 2019
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196. Transcription Factors Contribute to Differential Expression in Cellular Pathways in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma.
- Author
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Liu S, Wang X, Qin W, Genchev GZ, and Lu H
- Subjects
- Adenocarcinoma of Lung pathology, Carcinoma, Squamous Cell pathology, Gene Expression Profiling, Humans, Lung Neoplasms pathology, Regression Analysis, Reproducibility of Results, Adenocarcinoma of Lung genetics, Carcinoma, Squamous Cell genetics, Gene Expression Regulation, Neoplastic, Lung Neoplasms genetics, Signal Transduction genetics, Transcription Factors metabolism
- Abstract
Lung cancers are broadly classified into small cell lung cancers and non-small cell lung cancers (NSCLC). Lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are two common subtypes of NSCLC, and despite the fact that both occur in lung tissues, these two subtypes show a number of different pathological characteristics. To investigate the differences and seek potential therapy targets, we used bioinformatics methods to analyze RNA-Seq data from different aspects. The previous studies and comparative pathway enrichment analysis on publicly available data showed that expressed or inhibited genes are different in two cancer subtypes through important pathways. Some of these genes could not only affect cell function through expression, but also could regulate other genes' expression by binding to a specific DNA sequence. This kind of genes is called transcription factor (TF) or sequence-specific DNA-binding factor. Transcription factors play important roles in controlling gene expression in carcinoma pathways. Our results revealed transcription factors that may cause differential expression of genes in cellular pathways of LUAD and LUSC, which provide new clues for study and treatment. Once such TF is NFE2l2 which may regulate genes in the Wnt signaling pathway, and the MAPK signaling pathway, thus leading to an increase the cell growth, cell division, and gene transcription. Another TF-XBP1 has high correlation with genes related to cell adhesion molecules and cytokine-cytokine receptor interaction pathways that may further affect the immune system. Moreover, the two TF and high correlated genes also show similar patterns in an independent GEO data set.
- Published
- 2018
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197. Relation Between Crystal Structure and Electrochemical Performance of LiNi 1/3 Zn x Co 1/3- x Mn 1/3 O₂ (0.000 ≤ x ≤ 0.133).
- Author
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Wang X, Wan Y, Wang R, Xu X, Wang H, Chang M, Yuan F, Ge X, Shao W, and Xu S
- Abstract
LiNi1/3ZnxCo1/3-xMn1/3O2 (0.000 ≤ x ≤ 0.133) hollow microspheres are synthesized using MnO2 hollow microspheres both as a self-template and Mn source. These hollow microspheres, ~4 μm in diameter, are composed of approximately 300 nm basic nanoparticles. The XRD patterns of LiNi1/3ZnxCo1/3-xMn1/3O2 were analyzed by the RIETAN-FP program, and the obtained samples have a layered α-NaFeO2 structure. Electrochemical performances of the samples were carried out between 2.5 V and 4.5 V. The behavior of the lattice parameters is consistent with Cycling performance and rate performance change with increase of x. Compared with the others, the sample of x = 0.133 exhibits a relatively superior electrochemical performance. The specific capacity of x = 0.133 was increased by 10.7% than no-doped. In addition, the cyclic voltammograms curves of the second cycle show no significant alteration compared with the first cycle and the electrochemical impedance of zinc doping sample showed smaller transfer resistance than the no-doping sample.
- Published
- 2018
- Full Text
- View/download PDF
198. Modulation of splicing catalysis for therapeutic targeting of leukemia with mutations in genes encoding spliceosomal proteins.
- Author
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Lee SC, Dvinge H, Kim E, Cho H, Micol JB, Chung YR, Durham BH, Yoshimi A, Kim YJ, Thomas M, Lobry C, Chen CW, Pastore A, Taylor J, Wang X, Krivtsov A, Armstrong SA, Palacino J, Buonamici S, Smith PG, Bradley RK, and Abdel-Wahab O
- Subjects
- Anemia, Aplastic genetics, Animals, Bone Marrow Diseases genetics, Bone Marrow Failure Disorders, Bone Marrow Transplantation, Catalysis, Cell Line, Tumor, Epoxy Compounds pharmacology, Flow Cytometry, Gene Knock-In Techniques, Hemizygote, Hemoglobinuria, Paroxysmal genetics, Humans, Macrolides pharmacology, Mice, Mice, Knockout, Mutation, Neoplasm Transplantation, RNA Splicing drug effects, RNA Splicing genetics, Reverse Transcriptase Polymerase Chain Reaction, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics, Serine-Arginine Splicing Factors genetics, Spliceosomes genetics
- Abstract
Mutations in genes encoding splicing factors (which we refer to as spliceosomal genes) are commonly found in patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). These mutations recurrently affect specific amino acid residues, leading to perturbed normal splice site and exon recognition. Spliceosomal gene mutations are always heterozygous and rarely occur together with one another, suggesting that cells may tolerate only a partial deviation from normal splicing activity. To test this hypothesis, we engineered mice to express a mutated allele of serine/arginine-rich splicing factor 2 (Srsf2(P95H))-which commonly occurs in individuals with MDS and AML-in an inducible, hemizygous manner in hematopoietic cells. These mice rapidly succumbed to fatal bone marrow failure, demonstrating that Srsf2-mutated cells depend on the wild-type Srsf2 allele for survival. In the context of leukemia, treatment with the spliceosome inhibitor E7107 (refs. 7,8) resulted in substantial reductions in leukemic burden, specifically in isogenic mouse leukemias and patient-derived xenograft AMLs carrying spliceosomal mutations. Whereas E7107 treatment of mice resulted in widespread intron retention and cassette exon skipping in leukemic cells regardless of Srsf2 genotype, the magnitude of splicing inhibition following E7107 treatment was greater in Srsf2-mutated than in Srsf2-wild-type leukemia, consistent with the differential effect of E7107 on survival. Collectively, these data provide genetic and pharmacologic evidence that leukemias with spliceosomal gene mutations are preferentially susceptible to additional splicing perturbations in vivo as compared to leukemias without such mutations. Modulation of spliceosome function may thus provide a new therapeutic avenue in genetically defined subsets of individuals with MDS or AML.
- Published
- 2016
- Full Text
- View/download PDF
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