Publications by authors named "Shudong Wang"

175 Publications

Discovery of a potent, highly selective, and orally bioavailable inhibitor of CDK8 through a structure-based optimisation.

Eur J Med Chem 2021 Mar 26;218:113391. Epub 2021 Mar 26.

Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia. Electronic address:

CDK8 is deregulated in multiple types of human cancer and is viewed as a therapeutic target for the treatment of the disease. Accordingly, the search for small-molecule inhibitors of CDK8 is being intensified. Capitalising on our initial discovery of AU1-100, a potent CDK8 inhibitor yet with a limited degree of kinase selectivity, a structure-based optimisation was carried out, with a series of new multi-substituted pyridines rationally designed, chemically prepared and biologically evaluated. Such endeavour has culminated in the identification of 42, a more potent CDK8 inhibitor with superior kinomic selectivity and oral bioavailability. The mechanism underlying the anti-proliferative effect of 42 on MV4-11 cells was studied, revealing that the compound arrested the G1 cell cycle and triggered apoptosis. The low risk of hepato- and cardio-toxicity of 42 was estimated. These findings merit further investigation of 42 as a targeted cancer therapeutic.
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http://dx.doi.org/10.1016/j.ejmech.2021.113391DOI Listing
March 2021

Sulforaphane prevents angiotensin II-induced cardiomyopathy by activation of Nrf2 through epigenetic modification.

J Cell Mol Med 2021 Apr 1. Epub 2021 Apr 1.

Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China.

Nuclear factor erythroid 2-related factor (Nrf2) is an important regulator of cellular antioxidant defence. We previously showed that SFN prevented Ang II-induced cardiac damage via activation of Nrf2. However, the underlying mechanism of SFN's persistent cardiac protection remains unclear. This study aimed to explore the potential of SFN in activating cardiac Nrf2 through epigenetic mechanisms. Wild-type mice were injected subcutaneously with Ang II, with or without SFN. Administration of chronic Ang II-induced cardiac inflammatory factor expression, oxidative damage, fibrosis and cardiac remodelling and dysfunction, all of which were effectively improved by SFN treatment, coupled with an up-regulation of Nrf2 and downstream genes. Bisulfite genome sequencing and chromatin immunoprecipitation (ChIP) were performed to detect the methylation level of the first 15 CpGs and histone H3 acetylation (Ac-H3) status in the Nrf2 promoter region, respectively. The results showed that SFN reduced Ang II-induced CpG hypermethylation and promoted Ac-H3 accumulation in the Nrf2 promoter region, accompanied by the inhibition of global DNMT and HDAC activity, and a decreased protein expression of key DNMT and HDAC enzymes. Taken together, SFN exerts its cardioprotective effect through epigenetic modification of Nrf2, which may partially contribute to long-term activation of cardiac Nrf2.
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http://dx.doi.org/10.1111/jcmm.16504DOI Listing
April 2021

A combination of epigenetic BET and CDK9 inhibitors for treatment of human melanoma.

J Invest Dermatol 2021 Mar 26. Epub 2021 Mar 26.

Melanoma Immunology and Oncology Program, The Centenary Institute, University of Sydney, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia; Melanoma Institute Australia, The University of Sydney, Sydney, NSW, Australia. Electronic address:

Dysregulation of epigenetic modifiers is a frequent event in melanoma and underlies many aspects of melanoma biology including resistance to targeted and immunotherapies. Here we report that dual targeting of BET and CDK9 proteins have synergistic effects against melanoma cells in vitro and in vivo. The BET inhibitor (IBET151) and CDK9 inhibitor (CDKI73) synergistically killed melanoma cells in vitro independent of their BRAF or NRAS mutation status. The combination of drugs markedly inhibited the growth of human melanoma C002M cells in vitro in 3D spheroids and in vivo in NSG mice compared to vehicle control and the individual drugs (p<0.05). Cell death was associated with mitochondrial depolarisation and caspase dependent apoptosis with cleavage of PARP1 as well as downregulation of anti-apoptotic proteins BCL2, BCLXL and MCL1. GSEA revealed downregulation of hallmark gene-sets associated with E2F, G2M checkpoint and c-MYC. Survival analysis showed worse prognosis with high G2M, E2F or c-MYC gene signatures suggesting biomarkers of response of BET and CDK9 inhibitors in melanoma. This combination of epigenetic inhibitors targets multiple downstream genes leading to cell death of melanoma cells in vitro and in vivo and warrant further investigation for treatment of melanoma in patients not responding to current therapies.
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http://dx.doi.org/10.1016/j.jid.2020.12.038DOI Listing
March 2021

SE-OnionNet: A Convolution Neural Network for Protein-Ligand Binding Affinity Prediction.

Front Genet 2020 19;11:607824. Epub 2021 Feb 19.

Trinity Earth Technology Co. Ltd, Beijing, China.

Deep learning methods, which can predict the binding affinity of a drug-target protein interaction, reduce the time and cost of drug discovery. In this study, we propose a novel deep convolutional neural network called SE-OnionNet, with two squeeze-and-excitation (SE) modules, to computationally predict the binding affinity of a protein-ligand complex. The OnionNet is used to extract a feature map from the three-dimensional structure of a protein-drug molecular complex. The SE module is added to the second and third convolutional layers to improve the non-linear expression of the network to improve model performance. Three different optimizers, stochastic gradient descent (SGD), Adam, and Adagrad, were also used to improve the performance of the model. A majority of protein-molecule complexes were used for training, and the comparative assessment of scoring functions (CASF-2016) was used as the benchmark. Experimental results show that our model performs better than OnionNet, Pafnucy, and AutoDock Vina. Finally, we chose the macrophage migration inhibitor factor (PDB ID: 6cbg) to test the stability and robustness of the model. We found that the prediction results were not affected by the docking position, and thus, our model is of acceptable robustness.
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http://dx.doi.org/10.3389/fgene.2020.607824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962986PMC
February 2021

Ventricular fibrillation storm after revascularization of chronic total occlusion of the left anterior descending artery: is this reperfusion arrhythmia?

J Int Med Res 2021 Mar;49(3):300060521997618

Department of Cardiology, the First Hospital of Jilin University, Changchun, Jilin Province, China.

Electrical storm is a life-threatening emergency condition defined as three or more episodes of ventricular tachycardia or ventricular fibrillation (VF) within 24 hours requiring anti-tachycardia therapy, electrical cardioversion, or defibrillation. However, studies of the incidence of electrical storm after chronic total occlusion-percutaneous coronary intervention (CTO-PCI) are limited, and post-procedural VF after revascularization of CTO has not been described. The purpose of this article was to present a case of post-operative VF electrical storm after revascularization of CTO of the left anterior descending (LAD) artery to determine whether the electrical storm was caused by reperfusion arrhythmia or compromise of either branch vessels or the collateral circulation during intervention.
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http://dx.doi.org/10.1177/0300060521997618DOI Listing
March 2021

DL-SMILES#: A Novel Encoding Scheme for Predicting Compound Protein Affinity by Deep Learning.

Comb Chem High Throughput Screen 2021 Feb 18. Epub 2021 Feb 18.

School of Economics, Beijing Technology and Business University, Beijing, 100048. China.

Introduction: Drug repositioning aims to screen drugs and therapeutic goals from approved drugs and abandoned compounds that have been identified as safe. This trend is changing the landscape of drug development and creating a model of drug repositioning for new drug development. In recent decade, machine learning methods have been applied to predict the binding affinity of compound proteins, while deep learning is recently becoming hot and achieving significant performances. Among the models, the way of representing the compounds is usually simple, which is the molecular fingerprints, i.e., a single SMILES string.

Methods: In this work, we improve it by proposing a novel representing manner, named SMILES#, to recode the SMILES string. This approach takes into account the properties of compounds and achieves well performance. After that, we propose a deep learning model that combines recurrent neural networks with a convolutional neural network with an attentional mechanism, using unlabeled data and labeled data to jointly encode molecular and predict binding affinity.

Results: Experimental results show that SMILES# with compound properties can effectively improve the accuracy of the model and reduce the RMS error on most data sets.

Conclusion: Then, we used the method to verify the related and unrelated compounds with the same target, and the experimental results show the effectiveness of the method.
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http://dx.doi.org/10.2174/1386207324666210219102728DOI Listing
February 2021

Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents.

Eur J Med Chem 2021 Mar 2;214:113244. Epub 2021 Feb 2.

School of Pharmacy and Biodiscovery Institute, University of Nottingham, University Park, Nottingham, NG7 2RD, UK; Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia. Electronic address:

Cyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the conserved ATP binding site, designing selective CDK9 inhibitors has been challenging. Here we report our continued efforts in the optimization of 2,4,5-tri-substituted pyrimidine compounds as potent and selective CDK9 inhibitors. The most selective compound 30m was >100-fold selective for CDK9 over CDK1 and CDK2. These compounds showed broad anti-proliferative activities in various solid tumour cell lines and patient-derived chronic lymphocytic leukaemia (CLL) cells. Decreased phosphorylation of the carboxyl terminal domain (CTD) of RNAPII at Ser-2 and down-regulation of anti-apoptotic protein Mcl-1 were confirmed in both the ovarian cancer model A2780 and patient-derived CLL cells.
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http://dx.doi.org/10.1016/j.ejmech.2021.113244DOI Listing
March 2021

Potent and orally bioavailable CDK8 inhibitors: Design, synthesis, structure-activity relationship analysis and biological evaluation.

Eur J Med Chem 2021 Mar 3;214:113248. Epub 2021 Feb 3.

Drug Discovery and Development, Cancer Research Institute, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5000, Australia. Electronic address:

CDK8 regulates transcription either by phosphorylation of transcription factors or, as part of a four-subunit kinase module, through a reversible association of the kinase module with the Mediator complex, a highly conserved transcriptional coactivator. Deregulation of CDK8 has been found in various types of human cancer, while the role of CDK8 in supressing anti-cancer response of natural killer cells is being understood. Currently, CDK8-targeting cancer drugs are highly sought-after. Herein we detail the discovery of a series of novel pyridine-derived CDK8 inhibitors. Medicinal chemistry optimisation gave rise to 38 (AU1-100), a potent CDK8 inhibitor with oral bioavailability. The compound inhibited the proliferation of MV4-11 acute myeloid leukaemia cells with the kinase activity of cellular CDK8 dampened. No systemic toxicology was observed in the mice treated with 38. These results warrant further pre-clinical studies of 38 as an anti-cancer agent.
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http://dx.doi.org/10.1016/j.ejmech.2021.113248DOI Listing
March 2021

3D Multiple-Antenna Channel Modeling and Propagation Characteristics Analysis for Mobile Internet of Things.

Sensors (Basel) 2021 Feb 2;21(3). Epub 2021 Feb 2.

School of Electrical and Automation Engineering, Hefei University of Technology, Hefei 230009, China.

The demand for optimization design and performance evaluation of wireless communication links in a mobile Internet of Things (IoT) motivates the exploitation of realistic and tractable channel models. In this paper, we develop a novel three-dimensional (3D) multiple-antenna channel model to adequately characterize the scattering environment for mobile IoT scenarios. Specifically, taking into consideration both accuracy and mathematical tractability, a 3D double-spheres model and ellipsoid model are introduced to describe the distribution region of the local scatterers and remote scatterers, respectively. Based on the explicit geometry relationships between transmitter, receiver, and scatterers, we derive the complex channel gains by adopting the radio-wave propagation model. Subsequently, the correlation-based approach for theoretical analysis is performed, and the detailed impacts with respect to the antenna deployment, scatterer distribution, and scatterer density on the vital statistical properties are investigated. Numerical simulation results have shown that the statistical channel characteristics in the developed simulation model nicely match those of the corresponding theoretical results, which demonstrates the utility of our model.
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http://dx.doi.org/10.3390/s21030989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867299PMC
February 2021

Epigenetic Regulation Associated With Sirtuin 1 in Complications of Diabetes Mellitus.

Front Endocrinol (Lausanne) 2020 18;11:598012. Epub 2021 Jan 18.

School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, China.

Diabetes mellitus (DM) has been one of the largest health concerns of the 21st century due to the serious complications associated with the disease. Therefore, it is essential to investigate the pathogenesis of DM and develop novel strategies to reduce the burden of diabetic complications. Sirtuin 1 (SIRT1), a nicotinamide adenosine dinucleotide (NAD)-dependent deacetylase, has been reported to not only deacetylate histones to modulate chromatin function but also deacetylate numerous transcription factors to regulate the expression of target genes, both positively and negatively. SIRT1 also plays a crucial role in regulating histone and DNA methylation through the recruitment of other nuclear enzymes to the chromatin. Furthermore, SIRT1 has been verified as a direct target of many microRNAs (miRNAs). Recently, numerous studies have explored the key roles of SIRT1 and other related epigenetic mechanisms in diabetic complications. Thus, this review aims to present a summary of the rapidly growing field of epigenetic regulatory mechanisms, as well as the epigenetic influence of SIRT1 on the development and progression of diabetic complications, including cardiomyopathy, nephropathy, and retinopathy.
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http://dx.doi.org/10.3389/fendo.2020.598012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848207PMC
January 2021

Discovery of novel 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors for acute myeloid leukaemia with FLT3 mutations.

Eur J Med Chem 2021 Mar 22;213:113215. Epub 2021 Jan 22.

Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, SA, 5001, Australia. Electronic address:

Feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) is one of the most pursued targets in the treatment of acute myeloid leukaemia (AML) as its gene amplification and mutations, particularly internal tandem duplication (ITD), contribute to the pathogenesis of AML and the resistance to known FLT3 inhibitors. To conquer this challenge, there is a quest for structurally novel FLT3 inhibitors. Herein, we report the discovery of a new series of 4-azaaryl-N-phenylpyrimidin-2-amine derivatives as potent and selective FLT3 inhibitors. Compounds 12b and 12r were capable of suppressing a wide range of mutated FLT3 kinases including ITD and D835Y mutants; the latter isoform is closely associated with acquired drug resistance. In addition, both compounds displayed an anti-proliferative specificity for FLT3-ITD-harbouring cell lines (i.e., MV4-11 and MOLM-13 cells) over those with expression of the wild-type kinase or even without FLT3 expression. In mechanistic studies using MV4-11 cells, 12b was found to diminish the phosphorylation of key downstream effectors of FLT3 and induce apoptosis, supporting an FLT3-ITD-targeted mechanism of its anti-proliferative action.
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http://dx.doi.org/10.1016/j.ejmech.2021.113215DOI Listing
March 2021

Insights into the Reactive and Deactivation Mechanisms of Manganese Oxides for Ozone Elimination: The Roles of Surface Oxygen Species.

Langmuir 2021 Feb 24;37(4):1410-1419. Epub 2021 Jan 24.

Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. China.

Manganese oxides with varied Mn valance states but identical morphologies were synthesized via a facile thermal treatment of γ-MnOOH. Also, their catalytic performance on ozone decomposition was investigated following the order of MnO < MnO < MnO < MnO-H-200. In combination with X-ray diffraction (XRD), scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET), transmission electron microscopy (TEM), H-temperature-programmed reduction (TPR), O-temperature-programmed desorption (TPD), and X-ray photoelectron spectroscopy (XPS) characterization, it was deduced that the superior O decomposition capacity for MnO-H-200 was strongly associated with abundant oxygen vacancies on its surface. Among MnO, MnO, and MnO, the difference in O decomposition efficiency was dependent on the divergent nature of oxygen vacancy. Density functional theory (DFT) calculation revealed that MnO and MnO possessed lower formation energy of oxygen vacancy, while MnO had the minimum desorption energy of peroxide species (O*). It was deduced that the promotion of the O decomposition capability was attributed to the easier O* desorption. Insights into the deactivation mechanism for MnO-H-200 further validated the assumptions. As the reaction proceeded, adsorbed oxygen species accumulated on the catalyst surface, and a portion of them were transformed to lattice oxygen. The consumption of oxygen vacancy led to the deactivation of the catalyst.
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http://dx.doi.org/10.1021/acs.langmuir.0c02841DOI Listing
February 2021

Mnk inhibitors: a patent review.

Pharm Pat Anal 2021 Jan 14;10(1):25-35. Epub 2021 Jan 14.

Drug Discovery & Development, Cancer Research Institute, Clinical & Health Sciences, University of South Australia, Adelaide, South Australia 5001, Australia.

The alteration of mRNA translation has a crucial role in defining the changes in cellular proteome. The phosphorylation of eukaryotic initiation factor 4E by mitogen-activated protein kinase-interacting kinases (Mnks) leads to the release and translation of mRNAs of specific oncogenic proteins. In recent years, the efforts made by the pharmaceutical industry to develop novel chemical skeletons to create potent and selective Mnk inhibitors have been fruitful. The pyridone-aminal scaffold has been utilized to generate several series of Mnk inhibitors presented in multiple patent applications and research articles. Tomivosertib (eFT508) is one of the molecules with such scaffold. It is one of the first two Mnk inhibitors that entered clinical trials, and has displayed momentous activity against several solid and hematological cancers. The present compilation provides a succinct review of the current state of development of pyridone-aminal-derived Mnk inhibitors through the analysis of relevant patent applications filed in the last 5 years.
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http://dx.doi.org/10.4155/ppa-2020-0028DOI Listing
January 2021

Molecular mechanisms of doxorubicin-induced cardiotoxicity: novel roles of sirtuin 1-mediated signaling pathways.

Cell Mol Life Sci 2021 Apr 13;78(7):3105-3125. Epub 2021 Jan 13.

School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.

Doxorubicin (DOX) is an anthracycline chemotherapy drug used in the treatment of various types of cancer. However, short-term and long-term cardiotoxicity limits the clinical application of DOX. Currently, dexrazoxane is the only approved treatment by the United States Food and Drug Administration to prevent DOX-induced cardiotoxicity. However, a recent study found that pre-treatment with dexrazoxane could not fully improve myocardial toxicity of DOX. Therefore, further targeted cardioprotective prophylaxis and treatment strategies are an urgent requirement for cancer patients receiving DOX treatment to reduce the occurrence of cardiotoxicity. Accumulating evidence manifested that Sirtuin 1 (SIRT1) could play a crucially protective role in heart diseases. Recently, numerous studies have concentrated on the role of SIRT1 in DOX-induced cardiotoxicity, which might be related to the activity and deacetylation of SIRT1 downstream targets. Therefore, the aim of this review was to summarize the recent advances related to the protective effects, mechanisms, and deficiencies in clinical application of SIRT1 in DOX-induced cardiotoxicity. Also, the pharmaceutical preparations that activate SIRT1 and affect DOX-induced cardiotoxicity have been listed in this review.
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http://dx.doi.org/10.1007/s00018-020-03729-yDOI Listing
April 2021

A Novel XGBoost Method to Identify Cancer Tissue-of-Origin Based on Copy Number Variations.

Front Genet 2020 20;11:585029. Epub 2020 Nov 20.

Geneis (Beijing) Co., Ltd., Beijing, China.

The discovery of cancer of unknown primary (CUP) is of great significance in designing more effective treatments and improving the diagnostic efficiency in cancer patients. In the study, we develop an appropriate machine learning model for tracing the tissue of origin of CUP with high accuracy after feature engineering and model evaluation. Based on a copy number variation data consisting of 4,566 training cases and 1,262 independent validation cases, an XGBoost classifier is applied to 10 types of cancer. Extremely randomized tree (Extra tree) is used for dimension reduction so that fewer variables replace the original high-dimensional variables. Features with top 300 weights are selected and principal component analysis is applied to eliminate noise. We find that XGBoost classifier achieves the highest overall accuracy of 0.8913 in the 10-fold cross-validation for training samples and 0.7421 on independent validation datasets for predicting tumor tissue of origin. Furthermore, by contrasting various performance indices, such as precision and recall rate, the experimental results show that XGBoost classifier significantly improves the classification performance of various tumors with less prediction error, as compared to other classifiers, such as K-nearest neighbors (KNN), Bayes, support vector machine (SVM), and Adaboost. Our method can infer tissue of origin for the 10 cancer types with acceptable accuracy in both cross-validation and independent validation data. It may be used as an auxiliary diagnostic method to determine the actual clinicopathological status of specific cancer.
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http://dx.doi.org/10.3389/fgene.2020.585029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716814PMC
November 2020

Mechanistic insights into the contribution of Lewis acidity to brominated VOCs combustion over titanium oxide supported Ru catalyst.

Chemosphere 2021 Jan 29;263:128112. Epub 2020 Aug 29.

Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, PR China.

CHBr catalytic oxidation as the probe reaction was investigated over Ru supported on TiO with different crystalline phases. 1% Ru/anatase TiO (a-TiO) exhibited superior stability at 240 °C after a 180 h time-on-stream run. And there was an induced activation for 1% Ru/a-TiO during the initial 60 h reaction. Then the activity sustained stable. To elucidate the intrinsic mechanism, a series of characterizations were performed such as XRD, CO-Pulse, H-TPR, XPS and NH-TPD etc. Results showed that the Ru particle size increased and the Ru content decreased as the reaction proceeded, which were not conductive to the reaction. It was assumed that the catalytic activity was strongly dependent on other factors. In combination with NH-TPD and Py-FTIR measurements, it was confirmed that the enhanced activity and stability was strongly associated with the surface acidity, especially moderate strong Lewis acid (L acid). The increase of the acid amount and acidity strength was led by the generation and adsorption of HBr, Br and RuOBr during the reaction, among which HBr and Br was easier to desorb at 250 °C. While moderate strong L acid was sourced from the formation of RuOBr. The addition of transition metal (Ce, Co, Mn, Nb and Ni) further validated that the moderate strong L acid played a decisive role in the CHBr catalytic oxidation.
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http://dx.doi.org/10.1016/j.chemosphere.2020.128112DOI Listing
January 2021

Regulatory mechanisms of Sesn2 and its role in multi-organ diseases.

Pharmacol Res 2021 Feb 4;164:105331. Epub 2020 Dec 4.

School of Nursing, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address:

Sestrin2 (Sesn2) is a powerful anti-oxidant that can prevent acute and chronic diseases. The role of Sesn2 has been thoroughly reviewed in liver, nervous system, and immune system diseases. However, there is a limited number of reviews that have summarized the effects of Sesn2 in heart and vascular diseases, and very less literature-based information is available on involvement of Sesn2 in renal and respiratory pathologies. This review summarizes the latest research on Sesn2 in multi-organ stress responses, with a particular focus on the protective role of Sesn2 in cardiovascular, respiratory, and renal diseases, emphasizing the potential therapeutic benefit of targeting Sesn2 in stress-related diseases.
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http://dx.doi.org/10.1016/j.phrs.2020.105331DOI Listing
February 2021

Elabela may regulate SIRT3-mediated inhibition of oxidative stress through Foxo3a deacetylation preventing diabetic-induced myocardial injury.

J Cell Mol Med 2021 Jan 26;25(1):323-332. Epub 2020 Nov 26.

Department of Cardiovascular Center, The First Hospital of Jilin University, Changchun, Jilin, China.

Diabetic cardiomyopathy-pathophysiological heart remodelling and dysfunction that occurs in absence of coronary artery disease, hypertension and/or valvular heart disease-is a common diabetic complication. Elabela, a new peptide that acts via Apelin receptor, has similar functions as Apelin, providing beneficial effects on body fluid homeostasis, cardiovascular health and renal insufficiency, as well as potentially beneficial effects on metabolism and diabetes. In this study, Elabela treatment was found to have profound protective effects against diabetes-induced cardiac oxidative stress, inflammation, fibrosis and apoptosis; these protective effects may depend heavily upon SIRT3-mediated Foxo3a deacetylation. Our findings provide evidence that Elabela has cardioprotective effects for the first time in the diabetic model.
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http://dx.doi.org/10.1111/jcmm.16052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810951PMC
January 2021

Cardiac injury prediction and lymphocyte immunity and inflammation analysis in hospitalized patients with coronavirus disease 2019 (COVID-19).

Int J Cardiol 2021 03 22;326:237-242. Epub 2020 Oct 22.

The Center of Cardiovascular Diseases, the First Hospital of Jilin University, Changchun 130021, China. Electronic address:

Background: Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic. The ability to predict cardiac injury and analyze lymphocyte immunity and inflammation of cardiac damage in patients with COVID-19 is limited. We aimed to determine the risk factors and predictive markers of cardiac injury in these patients.

Methods: Data from 124 consecutive hospitalized patients with confirmed COVID-19 were collected. We compared the proportion of cardiovascular disease history in moderate, severe, and critical cases. We obtained high-sensitivity cardiac troponin I (hs-cTn I) results from 68 patients. Patients were divided into two groups based on positive hs-cTn I result: those with cardiac injury (n = 19) and those without cardiac injury (n = 49).

Results: Compared with the group with moderate disease, hypertension, coronary heart disease, and smoking were more common in severe and critical cases. Diabetes mellitus was most common in the critical group. Age older than 65 years, presence of chronic kidney disease, and lower blood lymphocyte percentage were independent risk factors of cardiac injury. The total T- and B-lymphocyte counts and CD4+ and CD8+ T-cell counts were significantly lower in those with cardiac injury. A minimal lymphocyte percentage < 7.8% may predict cardiac injury. The interleukin (IL) 6 level in plasma was elevated in the group with cardiac injury.

Conclusions: The lymphocyte percentage in blood may become a predictive marker of cardiac injury in COVID-19 patients. The total T and B cells and CD4+ and CD8+ cell counts decreased and the IL-6 level increased in COVID-19 patients with cardiac injury.
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http://dx.doi.org/10.1016/j.ijcard.2020.10.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577874PMC
March 2021

CDK12: a potential therapeutic target in cancer.

Drug Discov Today 2020 12 7;25(12):2257-2267. Epub 2020 Oct 7.

Drug Discovery and Development, University of South Australia, UniSA Clinical and Health Sciences, Adelaide, SA, 5000, Australia. Electronic address:

Cyclin-dependent kinase (CDK) 12 engages in diversified biological functions, from transcription, post-transcriptional modification, cell cycle, and translation to cellular proliferation. Moreover, it regulates the expression of cancer-related genes involved in DNA damage response (DDR) and replication, which are responsible for maintaining genomic stability. CDK12 emerges as an oncogene or tumor suppressor in different cellular contexts, where its dysregulation results in tumorigenesis. Current CDK12 inhibitors are nonselective, which impedes the process of pharmacological target validation and drug development. Herein, we discuss the latest understanding of the biological roles of CDK12 in cancers and provide molecular analyses of CDK12 inhibitors to guide the rational design of selective inhibitors.
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http://dx.doi.org/10.1016/j.drudis.2020.09.035DOI Listing
December 2020

Green chemical mechanical polishing of sapphire wafers using a novel slurry.

Nanoscale 2020 Nov;12(44):22518-22526

Key Laboratory for Precision and Non-Traditional Machining Technology of Ministry of Education, Dalian University of Technology, Dalian 116024, China.

Toxic and corrosive solutions are widely used in the preparation of abrasives and chemical mechanical polishing (CMP) of sapphire wafers, resulting in potential environmental pollution. Developing a novel green CMP technique to achieve light-emitting diode sapphire wafers is a significant challenge. In this study, a novel green CMP slurry, consisting of silica, sorbitol, aminomethyl propanol, and deionized water was developed for sapphire wafers. After CMP, the sapphire wafers were cleaned with deionized water and dried with compressed air, which is a green process. After CMP, the surface roughness Ra of the sapphire wafer surface with an area of 5 × 5 μm2 was 0.098 nm, which is the lowest surface roughness reported to date for sapphire wafers. Tetrahydroxy-coordinated Al(OH)4- ions were produced in the alkaline CMP slurry, and chelation occurred between sorbitol and these ions. The proposed green CMP has potential applications in the semiconductor and microelectronics industries.
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http://dx.doi.org/10.1039/d0nr04705hDOI Listing
November 2020

A first-in-class CDK4 inhibitor demonstrates in vitro, ex-vivo and in vivo efficacy against ovarian cancer.

Gynecol Oncol 2020 12 18;159(3):827-838. Epub 2020 Sep 18.

Drug Discovery and Development, Cancer Research Institute and Clinical and Health Sciences, University of South Australia, Australia. Electronic address:

Introduction: Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are involved in the initiation and progression of various cancers. Deregulation of the CDK4/6-cyclin D-retinoblastoma (Rb) pathway is common in ovarian cancer and is associated with an aggressive phenotype and poor prognosis. Patients with advanced ovarian cancer whose tumor demonstrates Rb-positivity, a low expression of p16 and overexpression of cyclin D1 are most likely to benefit from CDK4/6 inhibition.

Materials And Method: Anti-proliferative activity and mechanistic investigations for CDDD2-94, employing palbociclib as comparator, were evaluated by MTT assay, cell cycle and apoptosis analysis, western blotting as well as senescence and colony formation assay. In vivo safety and efficacy studies were done in A2780 tumor-bearing nude mice. Combinations of CDDD2-94 with mTOR, MEK, PI3K or PARP inhibitors were evaluated in A2780 and OVCAR5 ovarian cancer cells.

Results: Consistent with a CDK4-targeted mechanism, CDDD2-94 arrested the G1/G0 cell cycle, induced senescence and inhibited the proliferation of Rb-proficient ovarian cancer cells. CDDD2-94 exhibited synergistic anti-proliferative activities with mTOR, MEK, PI3K or PARP inhibitors. Importantly, unlike palbociclib which caused significant reductions in the number of lymphocytes and neutrophils, CDDD2-94 had little effect. CDDD2-94, as single agent and in combination with everolimus, delayed tumor growth and significantly increased survival of mice.

Conclusion: Given its high specificity in targeting CDK4 and excellent anti-tumor efficacy with low toxicity, CDDD2-94 has potential to be developed as a standalone agent or in combination with targeted therapeutics for the treatment of ovarian cancer.
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http://dx.doi.org/10.1016/j.ygyno.2020.09.012DOI Listing
December 2020

Prominent vegetation greening and its correlation with climatic variables in northern China.

Environ Monit Assess 2020 Sep 12;192(10):636. Epub 2020 Sep 12.

Ministry of Ecology and Environment Center for Satellite Application on Ecology and Environment, Beijing, 100094, China.

Global vegetation has been reported to be turning greener, especially in China and India. The Yellow River Basin is one of the most prominent greening areas in China. While some studies have attributed vegetation greening to large-scale ecological restoration efforts, our study focuses on the role of climate change in vegetation greening. We selected a time series of annual vegetation net primary productivity (NPP) and vegetation coverage from satellite data to quantify the vegetation greening trend. Annual temperature and precipitation were selected to examine the climate trend from 2000 to 2019. The results showed that the Yellow River Basin experienced a rapid increase in temperature and precipitation during this period. Annual temperature increased with an average speed of 0.905 °C per decade, approximately 4.5 times larger than that of global warming. Annual precipitation increased by 82.8%, with an average speed of 9.17 mm per year. There was widespread vegetation greening in the Yellow River Basin during 2000-2019. This was demonstrated by an increase in vegetation NPP and vegetation coverage in the Yellow River Basin. The increase of annual NPP and coverage from 2000 to 1019 was 26.6% and 30.8%, respectively. Even while considering the effects of conservation and restoration efforts, the rapid increases in temperature and precipitation allowed vegetation to flourish, as evidenced by significant positive correlations between climate variables and vegetation variables. Therefore, climate change played an important positive role in vegetation greening, rather than an undesirable disturbance.
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http://dx.doi.org/10.1007/s10661-020-08593-8DOI Listing
September 2020

Genetic deficiency of Phactr1 promotes atherosclerosis development via facilitating M1 macrophage polarization and foam cell formation.

Clin Sci (Lond) 2020 09;134(17):2353-2368

Department of Geriatrics, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

Genetic variants in phosphatase and actin regulator-1 (Phactr1) are reported to be associated with arteriosclerotic cardiovascular disease (ASCVD). However, the function of Phactr1 in atherosclerosis remains unclear. Patients with acute coronary syndrome (ACS) who underwent coronary angiography and optical coherence tomography (OCT) were enrolled and divided into non-ST segment elevation (NST-ACS) group and ST-ACS group. The expression of Phactr1 on monocytes was higher in NST-ACS and ST-ACS groups as compared with control group. Furthermore, NST-ACS patients who have more vulnerable features including thin-cap fibroatheroma (TCFA) and large lipid area showed higher levels of Phactr1 on monocytes than those with stable plaques. Through mouse models of atherosclerosis, Phactr1-/-Apoe-/- mice (double knockout mice, DKO) developed more severe atherosclerotic plaques, recruiting more macrophages into subendothelium and having elevated levels of proinflammatory cytokines in plaques. Similarly, Apoe knockout mice (Apoe-/-) receiving DKO bone marrow (BM) exhibited elevated plaque burden compared with Apoe-/- mice receiving Apoe-/- BM, indicating the protective effect of Phactr1 in hematopoietic cells. We found that depletion of Phactr1 in BM-derived macrophages (BMDMs) tended to differentiate into M1 phenotype, produced more proatherogenic cytokines and eventually converted into foam cells driven by oxidized low-density lipoprotein (ox-LDL). Mechanistically, Phactr1 activated CREB signaling via directly binding to CREB, up-regulating CREB phosphorylation and inducing KLF4 expression. Finally, overexpression of KLF4 partly rescued the excessive inflammation response and foam cell formation induced by deficiency of Phactr1. In conclusion, our study demonstrates that elevated Phactr1 in monocytes is a promising biomarker for vulnerable plaques, while increased Phactr1 attenuates atherosclerotic development via activation of CREB and M2 macrophage differentiation.
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http://dx.doi.org/10.1042/CS20191241DOI Listing
September 2020

PESM: A novel approach of tumor purity estimation based on sample specific methylation sites.

J Bioinform Comput Biol 2020 10 6;18(5):2050027. Epub 2020 Aug 6.

College of Mathematics and Systems Science, Shandong University of Science and Technology, Qingdao, Shandong, P. R. China.

Tumor purity is of great significance for the study of tumor genotyping and the prediction of recurrence, which is significantly affected by tumor heterogeneity. Tumor heterogeneity is the basis of drug resistance in various cancer treatments, and DNA methylation plays a core role in the generation of tumor heterogeneity. Almost all types of cancer cells are associated with abnormal DNA methylation in certain regions of the genome. The selection of tumor-related differential methylation sites, which can be used as an indicator of tumor purity, has important implications for purity assessment. At present, the selection of information sites mostly focuses on inter-tumor heterogeneity and ignores the heterogeneity of tumor growth space that is sample specificity. Considering the specificity of tumor samples and the information gain of individual tumor sample relative to the normal samples, we present an approach, PESM, to evaluate the tumor purity through the specificity difference methylation sites of tumor samples. Applied to more than 200 tumor samples of Prostate adenocarcinoma (PRAD) and Kidney renal clear cell carcinoma (KIRC), it shows that the tumor purity estimated by PESM is highly consistent with other existing methods. In addition, PESM performs better than the method that uses the integrated signal of methylation sites to estimate purity. Therefore, different information sites selection methods have an important impact on the estimation of tumor purity, and the selection of sample specific information sites has a certain significance for accurate identification of tumor purity of samples.
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http://dx.doi.org/10.1142/S0219720020500274DOI Listing
October 2020

Deactivation mechanism and anti-deactivation modification of Ru/TiO catalysts for CHBr oxidation.

Chemosphere 2020 10 3;257:127249. Epub 2020 Jun 3.

Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, PR China.

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http://dx.doi.org/10.1016/j.chemosphere.2020.127249DOI Listing
October 2020

Remote sensing assessment and spatiotemporal variations analysis of ecological carrying capacity in the Aral Sea Basin.

Sci Total Environ 2020 Sep 21;735:139562. Epub 2020 May 21.

School of Earth Sciences and Engineering, Hohai University, 210098 Nanjing, China.

The severe shrinkage of Aral Sea and water resources coordination issues in upstream and downstream regions lead to the serious ecological crisis in the Aral Sea Basin (ASB). Comprehensive ecological carrying capacity (ECC) assessment is of great significance for the ecological restoration and sustainable development. Based on the Analytic Hierarchy Process (AHP) and Experts Mark, this paper established the index evaluation system according to the specific ecological situation of the ASB. Combining remote sensing (RS) data and geographic information systems (GIS) technology, the paper assessed the ECC from 2001 to 2018 and explained the variations of the ECC by various data. The results indicate that the ECC is getting better in eighteen years. In 2009, the ECC condition is the best. ECC of the upstream region is better than that of the downstream region. The cause analysis that highlights the precipitation and enforcement of ecological policy has a positive impact on the ECC change. And the disparity of water body in upstream and downstream watercourses contributes to the regional difference of ECC. The paper provides an evaluation system of the ECC in the ASB. The analysis of the ECC variations is instructive to the sustainable development and ecological restoration in the ASB and other similar areas.
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http://dx.doi.org/10.1016/j.scitotenv.2020.139562DOI Listing
September 2020

Ag NPs-Assisted Synthesis of Stable Cu NPs on PET Fabrics for Antibacterial and Electromagnetic Shielding Performance.

Polymers (Basel) 2020 Apr 2;12(4). Epub 2020 Apr 2.

State Key Laboratory of Bio-Fibers and Eco-Textiles, College of Textile & Clothing, Qingdao University, Qingdao 266071, China.

In this study, Cu/Ag/polydopamine (PDA)/polyester (PET) fabrics were fabricated for multi-functional textiles. The PET fabrics were firstly modified by dopamine to form a polydopamine (PDA) layer on the fiber surface, then Ag nanoparticles (Ag NPs) were anchored on fiber surface through chelation between PDA and Ag ions, and the Ag NPs were further used as catalytic seeds for in situ reduction of Cu nanoparticles (Cu NPs). The surface morphology, chemistry, and crystalline structure of the prepared PET fabrics were characterized by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), and X-ray diffraction (XRD). As expected, Cu NPs were evenly dispersed on the surface of fibers. The Cu/Ag/PDA/PET fabrics showed good antibacterial property against and exhibited excellent electromagnetic interference (EMI) shielding ability. The Cu/Ag/PDA/PET fabrics with high performance antibacterial and EMI shielding properties can be applied as functional protective textiles.
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http://dx.doi.org/10.3390/polym12040783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240618PMC
April 2020

Mechanistic insights on the reaction behaviors of the acrylonitrile selective catalytic combustion over Cu-based UZM-9.

J Hazard Mater 2020 06 10;392:122497. Epub 2020 Mar 10.

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, PR China. Electronic address:

In this paper, a series of Cu-based UZM-9 catalysts were prepared via modified aqueous ion exchange and the performance of acrylonitrile (AN) selective catalytic combustion (SCC) over these catalysts were investigated, and further characterized by Ar adsorption-desorption, ICP, XRD, H-TPR and XPS. Among which, Cu-11.5 catalyst exhibited a complete AN conversion at 270 °C together with N selectivity higher than 98% during the whole temperature range when water was present. Meantime, the isolated Cu was the main active sites, which could be reduced to Cu during -CN oxidation, then reoxidized to Cu by O. Besides, the mechanism of AN SCC over Cu-11.5 was systematically investigated by in situ DRIFTS, which revealed that both the temperature and HO contents could influence the main N-containing intermediate and the reaction mechanism. In low and high temperature region, the reaction followed hydrolysis mechanism. Within medium temperature range, the reaction mechanism of AN oxidation was strongly associated with the water content. Oxidation was dominant at water-free condition, while oxidation and hydrolysis coexisted at relatively low water content (0.3%). When water content reached up to 0.9% or more, hydrolysis was the principal reaction. Finally, the hydrothermal stability of Cu-based UZM-9 catalysts were illustrated.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122497DOI Listing
June 2020

Classification of Pathological Types of Lung Cancer from CT Images by Deep Residual Neural Networks with Transfer Learning Strategy.

Open Med (Wars) 2020 8;15:190-197. Epub 2020 Mar 8.

Department of Respiratory Medicine, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong, China.

Lung cancer is one of the most harmful malignant tumors to human health. The accurate judgment of the pathological type of lung cancer is vital for treatment. Traditionally, the pathological type of lung cancer requires a histopathological examination to determine, which is invasive and time consuming. In this work, a novel residual neural network is proposed to identify the pathological type of lung cancer via CT images. Due to the low amount of CT images in practice, we explored a medical-to-medical transfer learning strategy. Specifically, a residual neural network is pre-trained on public medical images dataset luna16, and then fine-tuned on our intellectual property lung cancer dataset collected in Shandong Provincial Hospital. Data experiments show that our method achieves 85.71% accuracy in identifying pathological types of lung cancer from CT images and outperforming other models trained with 2054 labels. Our method performs better than AlexNet, VGG16 and DenseNet, which provides an efficient, non-invasive detection tool for pathological diagnosis.
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http://dx.doi.org/10.1515/med-2020-0028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065426PMC
March 2020