Publications by authors named "Chao Li"

2,757 Publications

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Titanium carbide/zeolite imidazole framework-8/polylactic acid electrospun membrane for near-infrared regulated photothermal/photodynamic therapy of drug-resistant bacterial infections.

J Colloid Interface Sci 2021 Apr 24;599:390-403. Epub 2021 Apr 24.

State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, 2 Linggong Road, Dalian, Liaoning 116024, PR China. Electronic address:

Bacteria induced wound infection has become fatal healthcare issues needed to be resolved urgently. It is of vital importance to develop multifunctional therapeutic platforms to fight against increased bacterial antibiotic resistance. Herein, a titanium carbide (MXene)/zeolite imidazole framework-8 (ZIF-8)/polylactic acid (PLA) composite membrane (MZ-8/PLA) was fabricated through in-situ growth of ZIF-8 on MXene and the subsequent electrospinning process. It indicated MZ-8 can generate singlet oxygen and hyperthermia at photothermal (PTT) convention efficiency of 80.5% with bactericidal rate of more than 99.0%. In addition, MZ-8 showed remarkable antitumor efficiency in vitro and in vivo based on the combined photodynamic/photothermal therapy. Theoretical calculation illustrated MZ-8 could improve the laser activation process by acceleration of intermolecular charge transfer, reducing excitation energy, stabilizing excited states and increasing intersystem crossing rate. After incorporated into electrospun scaffolds, MZ-8/PLA exhibited potent PTT and photodynamic therapy (PDT) properties under 808 nm laser irradiation. The antibacterial rates of MZ-8/PLA were up to 99.9% and 99.8% against Escherichia coli and Methicillin-resistant staphylococcus aureus, respectively. In-vivo experimental results further confirmed that MZ-8/PLA can accelerate bacteria infected wound healing without observable resistance. This work opens a new avenue to design promising platforms for fighting against extremely drug resistant bacterial infection.
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http://dx.doi.org/10.1016/j.jcis.2021.04.109DOI Listing
April 2021

SPP1 derived from silica-exposed macrophage exosomes triggers fibroblast transdifferentiation.

Toxicol Appl Pharmacol 2021 May 4;422:115559. Epub 2021 May 4.

Department of Occupational Health and Environmental Health, College of Public Health, Zhengzhou University, Zhengzhou, 450001, Henan, China. Electronic address:

The occurrence and development of silicosis is related to the interaction of multiple cells through signal transmission caused by silica dust. Including inflammatory changes reduced by macrophages and phenotypic transdifferentiation reduced by lung fibroblasts. As a communication medium between cells, exosomes have become a hot research topic. To explore the role of exosomal proteins in the occurrence and development of silicosis and the possible intervention targets, this study conducted proteomic analysis of macrophage-derived exosomes induced by silica, to identify specific proteins for intervention. In this study, we used proteomic analysis to screen exosomal protein profiles from the RAW264.7 macrophages exposed to silica. A total of 291 proteins were differentially expressed, of which 178 were upregulated and 113 were downregulated. By performing functional annotation and analysis of the differentially expressed proteins, we identified proteins SPP1, HMGB3, and HNRNPAB, which were consistent with the proteomics analysis. The involvement of SPP1 protein in fibrosis was studied further. Knocking down the expression of SPP1 in exosomes resulted in a decrease in fibrosis-related indicators. These results help to understand that exosomal protein can mediate cell communication and play a key role in the transition from fibroblasts to myofibroblasts. Further, this study also provided strategies and scientific basis for future studies on the intervention of silicosis.
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http://dx.doi.org/10.1016/j.taap.2021.115559DOI Listing
May 2021

Photocuring Three-Dimensional Printing of Thermoplastic Polymers Enabled by Hydrogen Bonds.

ACS Appl Mater Interfaces 2021 May 7. Epub 2021 May 7.

College of Transportation and Civil Engineering, Fujian Agriculture and Forestry University, Fuzhou 350108, P. R. China.

The advent of 3D printing has led to a new era of highly customized products. Printing reprocessable thermoplastic polymers is limited to slow printing techniques such as fused deposition modeling. Photocuring 3D printing is a high-speed 3D printing technique suitable for photocurable thermosetting resins because the cross-linked 3D network could achieve rapid solid-liquid separation during printing. However, thermoplastics usually cannot be printed via photocuring 3D printers because rapid solid-liquid separation is hard to be achieved due to the diffusion/dissolution of linear molecular chains in their liquid precursor. Herein, we hypothesize that hydrogen bonds (H-bonds) between monomers may accelerate polymerization and reduce solubility of the polymer in liquid precursors to achieve rapid solid-liquid separation. Using this strategy, a series of UV-curable methacrylic and acrylic monomers was selected as inks to demonstrate the role of H-bonds in photocuring 3D printing. The hypothesis was further verified by using blended inks of -vinyl-2-pyrrolidinone (NVP) and acrylic acid (AA) via experimental and molecular dynamic simulation. Oil palm occupies the top position of plantation species in southeastern Asian forests. Palm oil (PO) has the lowest price compared with other plant oils. Thus, a PO-based vinyl monomer was selected as the raw material for 3D printing thermoplastic polymers. Various biobased thermoplastics were successfully printed from the PO-based monomer and commercial monomers. The amide structure in the PO monomer formed H-bonds with polar monomers, including NVP and AA, resulting in printed 3D objects with surprising functionalities such as high stretchability and self-healing ability.
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http://dx.doi.org/10.1021/acsami.1c02513DOI Listing
May 2021

Eshelby untwisting.

Chem Commun (Camb) 2021 May 7. Epub 2021 May 7.

Department of Chemistry and the Molecular Design Institute, New York University, 100 Washington Square East, New York, NY 10003-6688, USA.

The concept of Eshelby untwisting, the effect of an axial screw dislocation driving an intrinsically twisted nanocrystal towards a straighter configuration more consistent with long-range translational symmetry, is introduced here. Force-field simulations of nanorods built from the enantiomorphous (space groups, P3121 and P3221) crystal structures of benzil (C6H5-C(O)-C(O)-C6H5) were previously shown to twist in opposite directions, even in the absence of dislocations. Here, both right- and left-handed screw dislocations were introduced into benzil nanorods in silico. For rods built from the P3221 enantiomorph, dislocations with negative Burgers vectors increased the right-handed twisting already present in the intrinsically twisted structures without dislocations, whereas dislocations with positive Burgers vectors drove the twisted structure back towards a straight configuration, untwisting. In the dynamic simulations, the P3221 helicoid endowed with a positive Burgers vector ultimately twisted back through the straight configuration, until a helicoid of opposite sense from that of the starting structure, was obtained. The bearing of these observations on the propensity of small crystals to adopt non-polyhedral morphologies is discussed.
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http://dx.doi.org/10.1039/d1cc01431eDOI Listing
May 2021

The chromatin remodelling protein LSH/HELLS regulates the amount and distribution of DNA hydroxymethylation in the genome.

Epigenetics 2021 May 7:1-22. Epub 2021 May 7.

Laboratory of Cancer Epigenetics, Faculty of Medicine, ULB-Cancer Research Centre (U-CRC), Université Libre De Bruxelles, Brussels, Belgium.

Ten-Eleven Translocation (TET) proteins convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) leading to a dynamic epigenetic state of DNA that can influence transcription and chromatin organization. While TET proteins interact with complexes involved in transcriptional repression and activation, the overall understanding of the molecular mechanisms involved in TET-mediated regulation of gene expression still remains limited. Here, we show that TET proteins interact with the chromatin remodelling protein lymphoid-specific helicase (LSH/HELLS) and . In mouse embryonic fibroblasts (MEFs) and embryonic stem cells (ESCs) knock out of leads to a significant reduction of 5-hydroxymethylation amount in the DNA. Whole genome sequencing of 5hmC in wild-type versus knock-out MEFs and ESCs showed that in absence of , some regions of the genome gain 5hmC while others lose it, with mild correlation with gene expression changes. We further show that differentially hydroxymethylated regions did not completely overlap with differentially methylated regions indicating that changes in 5hmC distribution upon knock-out are not a direct consequence of 5mC decrease. Altogether, our results suggest that LSH, which interacts with TET proteins, contributes to the regulation of 5hmC levels and distribution in MEFs and ESCs.
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http://dx.doi.org/10.1080/15592294.2021.1917152DOI Listing
May 2021

Bone marrow mesenchymal stromal cells in chronic myelomonocytic leukaemia: overactivated WNT/β-catenin signalling by parallel RNA sequencing and dysfunctional phenotypes.

Br J Haematol 2021 May 6. Epub 2021 May 6.

Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, South China University of Technology, Guangzhou, Guangdong, 510080, P.R. China.

Sophisticated cross-talk between bone marrow mesenchymal stromal cells (BM MSCs) and haematopoietic/leukaemic stem cells in patients with myelodysplastic syndromes (MDS) and myeloid leukaemia have been emphasized in previous reports. However, mesenchymal elements in patients with chronic myelomonocytic leukaemia (CMML) were poorly investigated. By utilizing a parallel RNA-sequencing method, we investigated the transcriptional profile and functional defects of primary BM MSCs from patients with CMML for the first time. Within a 24-patient cohort, transcriptional and functional analysis reveals a prominent enrichment of WNT/β-catenin signalling and multiple biology processes. Deregulated expression of WNT/β-catnin factors CTNNB1, CMYC, LEF1, and FRZB is associated with impaired proliferation, senescence phenotype, and abnormal secretion in CMML MSCs. The impaired ability to support healthy CD34 haematopoietic stem and progenitor cells (HSPCs) correlates with activation of WNT/β-catenin signalling in CMML MSCs. Furthermore, we observed an association between WNT/β-catenin factors and treatment response to hypomethylating agents (HMAs) in a cohort of patients with MDS/myeloproliferative neoplasms (MPNs). Taken together, our study provides evidence for transcriptional and functional abnormalities in CMML MSCs, and suggests potential prognostic value of evaluating WNT/β-catenin signalling in patients with CMML.
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http://dx.doi.org/10.1111/bjh.17425DOI Listing
May 2021

Berberine-Loaded Carboxylmethyl Chitosan Nanoparticles Ameliorate DSS-Induced Colitis and Remodel Gut Microbiota in Mice.

Front Pharmacol 2021 20;12:644387. Epub 2021 Apr 20.

State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, China.

Inflammatory bowel disease (IBD) is a refractory disorder characterized by chronic and recurrent inflammation. The progression and pathogenesis of IBD is closely related to oxidative stress and irregularly high concentrations of reactive oxygen species (ROS). A new oxidation-responsive nano prodrug was constructed from a phenylboronic esters-modified carboxylmethyl chitosan (OC-B) conjugated with berberine (BBR) that degrades selectively in response to ROS. The optimized micelles exhibited well-controlled physiochemical properties and stability in a physiological environment. OC-B-BBR micelles could effectively encapsulate the anti-inflammatory drug berberine and exhibit ideal HO-triggered release behavior as confirmed by drug loading and release studies. The anti-inflammatory effect and regulation of gut microbiota caused by it were explored in mice with colitis induced by dextran sodium sulfate (DSS). The results showed that OC-B-BBR significantly ameliorated colitis symptoms and colon damage by regulating the expression levels of IL-6 and remodeling gut microbiota. In summary, this study exhibited a novel BBR-loaded Carboxylmethyl Chitosan nano delivery system which may represent a promising approach for improving IBD treatment.
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http://dx.doi.org/10.3389/fphar.2021.644387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093821PMC
April 2021

Bioinformatics analysis for the identification of differentially expressed genes and related signaling pathways in CagA transfected gastric cancer cells.

PeerJ 2021 15;9:e11203. Epub 2021 Apr 15.

Key Laboratory of Endemic and Ethnic Diseases , Ministry of Education, Guizhou Medical University, Guiyang, China.

Aim: cytotoxin-associated protein A (CagA) is an important virulence factor known to induce gastric cancer development. However, the cause and the underlying molecular events of CagA induction remain unclear. Here, we applied integrated bioinformatics to identify the key genes involved in the process of CagA-induced gastric epithelial cell inflammation and can ceration to comprehend the potential molecular mechanisms involved.

Materials And Methods: AGS cells were transected with pcDNA3.1 and pcDNA3.1::CagA for 24 h. The transfected cells were subjected to transcriptome sequencing to obtain the expressed genes. Differentially expressed genes (DEG) with adjusted value < 0.05, - logFC -> 2 were screened, and the R package was applied for gene ontology (GO) enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The differential gene protein-protein interaction (PPI) network was constructed using the STRING Cytoscape application, which conducted visual analysis to create the key function networks and identify the key genes. Next, the Kaplan-Meier plotter survival analysis tool was employed to analyze the survival of the key genes derived from the PPI network. Further analysis of the key gene expressions in gastric cancer and normal tissues were performed based on The Cancer Genome Atlas (TCGA) database and RT-qPCR verification.

Results: After transfection of AGS cells, the cell morphology changes in a hummingbird shape and causes the level of CagA phosphorylation to increase. Transcriptomics identified 6882 DEG, of which 4052 were upregulated and 2830 were downregulated, among which q-value < 0.05, FC > 2, and FC under the condition of ≤2. Accordingly, 1062 DEG were screened, of which 594 were upregulated and 468 were downregulated. The DEG participated in a total of 151 biological processes, 56 cell components, and 40 molecular functions. The KEGG pathway analysis revealed that the DEG were involved in 21 pathways. The PPI network analysis revealed three highly interconnected clusters. In addition, 30 DEG with the highest degree were analyzed in the TCGA database. As a result, 12 DEG were found to be highly expressed in gastric cancer, while seven DEG were related to the poor prognosis of gastric cancer. RT-qPCR verification results showed that Helicobacter pylori CagA caused up-regulation of expression.

Conclusion: The current comprehensive analysis provides new insights for exploring the effect of CagA in human gastric cancer, which could help us understand the molecular mechanism underlying the occurrence and development of gastric cancer caused by .
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http://dx.doi.org/10.7717/peerj.11203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053379PMC
April 2021

Prognostic value of tumour microenvironment-related genes by TCGA database in rectal cancer.

J Cell Mol Med 2021 May 5. Epub 2021 May 5.

Department of Endocrinology and Metabolism, The First Hospital of Jilin University, Changchun, China.

Rectal cancer is a common malignant tumour and the progression is highly affected by the tumour microenvironment (TME). This study intended to assess the relationship between TME and prognosis, and explore prognostic genes of rectal cancer. The gene expression profile of rectal cancer was obtained from TCGA and immune/stromal scores were calculated by Estimation of Stromal and Immune cells in Malignant Tumors using Expression data (ESTIMATE) algorithm. The correlation between immune/stromal scores and survival time as well as clinical characteristics were evaluated. Differentially expressed genes (DEGs) were identified according to the stromal/immune scores, and the functional enrichment analyses were conducted to explore functions and pathways of DEGs. The survival analyses were conducted to clarify the DEGs with prognostic value, and the protein-protein interaction (PPI) network was performed to explore the interrelation of prognostic DEGs. Finally, we validated prognostic DEGs using data from the Gene Expression Omnibus (GEO) database by PrognoScan, and we verified these genes at the protein levels using the Human Protein Atlas (HPA) databases. We downloaded gene expression profiles of 83 rectal cancer patients from The Cancer Genome Atlas (TCGA) database. The Kaplan-Meier plot demonstrated that low-immune score was associated with worse clinical outcome (P = .034), metastasis (M1 vs. M0, P = .031) and lymphatic invasion (+ vs. -, P < .001). A total of 540 genes were screened as DEGs with 539 up-regulated genes and 1 down-regulated gene. In addition, 60 DEGs were identified associated with overall survival. Functional enrichment analyses and PPI networks showed that the DEGs are mainly participated in immune process, and cytokine-cytokine receptor interaction. Finally, 19 prognostic genes were verified by GSE17536 and GSE17537 from GEO, and five genes (ADAM23, ARHGAP20, ICOS, IRF4, MMRN1) were significantly different in tumour tissues compared with normal tissues at the protein level. In summary, our study demonstrated the associations between TME and prognosis as well as clinical characteristics of rectal cancer. Moreover, we explored and verified microenvironment-related genes, which may be the potential key prognostic genes of rectal cancer. Further clinical samples and functional studies are needed to validate this finding.
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http://dx.doi.org/10.1111/jcmm.16547DOI Listing
May 2021

The application of venous nerve conduit trap in the immediate repair and reconstruction of facial nerve in parotid gland tumor: an attempt of a new technique.

Eur Arch Otorhinolaryngol 2021 May 4. Epub 2021 May 4.

Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology, Chengdu, China.

Objective: To introduce the application of venous nerve conduit in the immediate repair and reconstruction of facial nerve in parotid gland tumor.

Methods: Three patients with parotid gland tumor in Sichuan Provincial Cancer Hospital were reviewed. All patients were found that the tumor encased and invaded the facial nerve which was difficult to be separated during the operation when all patients were treated with facial nerve repair and reconstruction with the venous nerve conduit trapping technique.

Results: After 1-year follow-up, all patients recovered well in facial nerve function.

Conclusion: The venous nerve conduit trapping technique is an effective attempt in the immediate repair and reconstruction of facial nerve in parotid gland tumor, but it needs to be further confirmed by multiple studies.
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http://dx.doi.org/10.1007/s00405-021-06732-6DOI Listing
May 2021

Image Inpainting by End-to-End Cascaded Refinement With Mask Awareness.

IEEE Trans Image Process 2021 7;30:4855-4866. Epub 2021 May 7.

Inpainting arbitrary missing regions is challenging because learning valid features for various masked regions is nontrivial. Though U-shaped encoder-decoder frameworks have been witnessed to be successful, most of them share a common drawback of mask unawareness in feature extraction because all convolution windows (or regions), including those with various shapes of missing pixels, are treated equally and filtered with fixed learned kernels. To this end, we propose our novel mask-aware inpainting solution. Firstly, a Mask-Aware Dynamic Filtering (MADF) module is designed to effectively learn multi-scale features for missing regions in the encoding phase. Specifically, filters for each convolution window are generated from features of the corresponding region of the mask. The second fold of mask awareness is achieved by adopting Point-wise Normalization (PN) in our decoding phase, considering that statistical natures of features at masked points differentiate from those of unmasked points. The proposed PN can tackle this issue by dynamically assigning point-wise scaling factor and bias. Lastly, our model is designed to be an end-to-end cascaded refinement one. Supervision information such as reconstruction loss, perceptual loss and total variation loss is incrementally leveraged to boost the inpainting results from coarse to fine. Effectiveness of the proposed framework is validated both quantitatively and qualitatively via extensive experiments on three public datasets including Places2, CelebA and Paris StreetView.
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http://dx.doi.org/10.1109/TIP.2021.3076310DOI Listing
May 2021

Sestrin2 as a gatekeeper of cellular homeostasis: Physiological effects for the regulation of hypoxia-related diseases.

J Cell Mol Med 2021 May 4. Epub 2021 May 4.

Tianjin Institute of Environmental and Operational Medicine, Tianjin, China.

Sestrin2 (SESN2) is a conserved stress-inducible protein (also known as hypoxia-inducible gene 95 (HI95)) that is induced under hypoxic conditions. SESN2 represses the production of reactive oxygen species (ROS) and provides cytoprotection against various noxious stimuli, including hypoxia, oxidative stress, endoplasmic reticulum (ER) stress and DNA damage. In recent years, the determination of the regulation and signalling mechanisms of SESN2 has increased our understanding of its role in the hypoxic response. SESN2 has well-documented roles in hypoxia-related diseases, making it a potential target for diagnosis and treatment. This review discusses the regulatory mechanisms of SESN2 and highlights the significance of SESN2 as a biomarker and therapeutic target in hypoxia-related diseases, such as cancer, respiratory-related diseases, cardiovascular diseases and cerebrovascular diseases.
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http://dx.doi.org/10.1111/jcmm.16540DOI Listing
May 2021

Postoperative morbidity adversely impacts long-term oncologic prognosis following hepatectomy for hepatocellular carcinoma: A multicenter observational study.

Eur J Surg Oncol 2021 Apr 26. Epub 2021 Apr 26.

Department of Hepatobiliary Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China; School of Clinical Medicine, Hangzhou Medical College, Hangzhou, Zhejiang, China; Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Navy Medical University, Shanghai, China. Electronic address:

Background & Aims: Postoperative morbidity following hepatectomy for hepatocellular carcinoma (HCC) is common and its impact on long-term oncological outcome remains unclear. This study aimed to investigate if postoperative morbidity impacts long-term survival and recurrence following hepatectomy for HCC.

Methods: The data from a multicenter Chinese database of curative-intent hepatectomy for HCC were analyzed, and independent risks of postoperative 30-day morbidity were identified. After excluding patients with postoperative early deaths (≤90 days), early (≤2 years) and late (>2 years) recurrence rates, overall survival (OS), and time-to-recurrence (TTR) were compared between patients with and without postoperative morbidity.

Results: Among 2,161 patients eligible for the study, 758 (35.1%) had postoperative 30-day morbidity. Multivariable logistic regression analysis showed that diabetes mellitus, obesity, Child-Pugh grade B, cirrhosis, and intraoperative blood transfusion were independent risks of postoperative morbidity. The rates of early and late recurrence among patients with postoperative morbidity were higher than those without (50.7% vs. 38.8%, P < 0.001; and 41.7% vs. 34.1%, P = 0.017). Postoperative morbidity was associated with decreased OS (median: 48.1 vs. 91.6 months, P < 0.001) and TTR (median: 19.8 vs. 46.1 months; P < 0.001). After adjustment of confounding factors, multivariable Cox-regression analyses revealed that postoperative morbidity was associated with a 27.8% and 18.7% greater likelihood of mortality (hazard ratio 1.278; 95% confidence interval: 1.126-1.451; P < 0.001) and recurrence (1.187; 1.058-1.331; P = 0.004).

Conclusion: This large multicenter study provides strong evidence that postoperative morbidity adversely impacts long-term oncologic prognosis after hepatectomy for HCC. The prevention and management of postoperative morbidity may be oncologically important.
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http://dx.doi.org/10.1016/j.ejso.2021.04.027DOI Listing
April 2021

Complement genes in black rockfish (Sebastods schlegelii): genome-wide identification, evolution and their potential functions in response to Vibrio anguillarum infection.

Fish Shellfish Immunol 2021 Apr 28;114:119-131. Epub 2021 Apr 28.

School of Marine Science and Engineering, Qingdao Agricultural University, Qingdao, 266109, China. Electronic address:

As complex components of innate immune system, members of complement system play crucial roles during the process of defensing against pathogens. Black rockfish (Sebastes schlegelii) is one of the important aquaculture species in East Asian. However, studies of complement genes in black rockfish and its related immune activities are still lacking. Therefore, a total of 112 members of the complement genes were identified from the genome of black rockfish and were classified into five subgroups. According to their functional annotations, 30 genes belonged to pattern recognition, 6 genes belonged to proteases, 14 genes belonged to complement components, 36 genes belonged to receptors, and 26 genes belonged to regulators. It can be found that many complement genes evolved into multi-copies, especially in teleost, which may be influenced by whole-genome duplication or tandem duplication events. Complement genes were randomly distributed on 22 chromosomes. The number of introns of complement genes varied from 1 to 70. Results of the expression patterns of 10 randomly selected genes from 5 subtypes response to Vibrio anguillarum infection revealed that most of the members of the complement genes were induced in gill and skin. In contrast, most genes in intestine showed downregulation. This study systematically characterized and analyzed the complement genes in black rockfish and provided new insights into their functions responding to bacterial infection.
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http://dx.doi.org/10.1016/j.fsi.2021.04.020DOI Listing
April 2021

Risk Factors of Fluoropyrimidine Induced Cardiotoxicity among Cancer Patients: A Systematic Review and Meta-analysis.

Crit Rev Oncol Hematol 2021 Apr 27;162:103346. Epub 2021 Apr 27.

Department of Health Outcomes Research and Policy, Auburn University, Auburn, AL, USA. Electronic address:

Cancer patients experienced an increased risk of cardiotoxicity during fluoropyrimidine-based chemotherapy (5-fluorouracil or capecitabine). We searched PubMed, PsycINFO, IPA, CINAHL, Web of Science, and ClinicalTrials.gov for studies published between January 1, 1990 and December 31, 2019, in English, examining risk factors for cardiotoxicity induced by fluoropyrimidine. Included study-level data were converted to risk ratios (RRs) and pooled RRs were calculated for meta-analyses using a random-effects method. Among 690 publications identified for abstract and title screening, 22 unique studies were included in the review, and 20 had sufficient data for meta-analyses. Results indicated that patients undergoing capecitabine-based combination therapy had a higher risk than those with monotherapy (pooled RR = 1.61). Patients with pre-existing cardiac disease (pooled RR = 3.26), hypertension (pooled RR = 1.52) or smoking (pooled RR = 2.22) also had higher risks than their counterparts. Developing risk assessment tools to mitigate the risk could be a viable strategy to improve outcomes for cancer patients undergoing fluoropyrimidine-based treatments.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103346DOI Listing
April 2021

The Effect of Combined Guidance of Botulinum Toxin Injection with Ultrasound, Catheter Balloon, and Electromyography on Neurogenic Cricopharyngeal Dysfunction: A Prospective Study.

Dysphagia 2021 Apr 29. Epub 2021 Apr 29.

Department of Rehabilitation Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, 600 Tianhe Road, Guangzhou, 510630, Guangdong Province, China.

Background: Cricopharyngeal botulinum toxin (BTX) injection is one of the treatments for neurogenic cricopharyngeal dysfunction (CPD). We conducted this prospective study to investigate the effect and safety of BTX injection for neurogenic CPD with a novel guidance.

Methods: Twenty-one patients with neurogenic CPD whose symptoms did not reduce after conventional swallowing therapy were included in this study. The impact of BTX injection on the swallowing function of the patients was evaluated.

Key Results: After the injection, the Functional Oral Intake Scale (FOIS) score increased in 17 of 21 patients (80.9%), which ranged from 1 to 3 (P < 0.001). Moreover, there was a significant reduction in the UES opening impairment (P < 0.01), UES residual pressure (P < 0.05), duration of UES relaxation, penetration-aspiration scale score (P < 0.05), secretion (P < 0.05), vallecular residue (P < 0.01), and left (P < 0.05) and right (P < 0.05) pyriform sinus residue. With at least 6 months of follow-up, we found that FOIS continued to increase in patients who showed improvement after the injection (i.e., FOIS 5-7 points), while it remained unchanged in patients without improvement after the injection. There were no side effects reported in this study.

Conclusion & Inferences: BTX injection into the cricopharyngeal muscle guided by ultrasound, catheter balloon, and electromyography possibly has a long-lasting effect that can effectively and safely improve the swallowing function of patients with neurogenic CPD.
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http://dx.doi.org/10.1007/s00455-021-10310-7DOI Listing
April 2021

Preparation and characterization of chitosan-based edible active films incorporated with Sargassum pallidum polysaccharides by ultrasound treatment.

Int J Biol Macromol 2021 Apr 26;183:473-480. Epub 2021 Apr 26.

School of Food Science and Engineering, Guangdong Province Key Laboratory for Green Processing of Natural Products and Product Safety, South China University of Technology, Guangzhou 510640, China; SCUT-Zhuhai Institute of Modern Industrial Innovation, Zhuhai 519715, China. Electronic address:

In this study, Sargassum pallidum polysaccharides (SPPs) were incorporated into chitosan (CH) to develop a novel edible active film (CH/SPPs-US) via ultrasonication. The mechanical, water vapor permeability, surface morphology, crystallinity, antioxidant, and fruit preservation properties of CH/SPPs-US films prepared under sequences of matrix ratios and ultrasound treatment were investigated. The results revealed that the addition of SPPs combined with ultrasonic treatment could significantly enhance the transparency, elongation and tensile strength of the films whereas the water vapor permeability was decreased. Tensile strength and elongation at break of the C2/SP1.2-US film were 12.07 N and 54.18%, respectively, which were significantly higher than those for CH film. Meanwhile, the water vapor permeability value of C2/SP1.2-US was reduced by as high as 40.2% compared with that of chitosan film. In addition, antioxidant effect evaluation showed that the CH-based films added with SPPs exhibited better antioxidant activity than CH film, and ultrasonic treatment could further strengthen the antioxidant activity of the film. The CH/SPPs-US films could effectively extend the shelf life and inhibit the deterioration of the strawberry at room temperature (25 ± 1 °C) and 70% ± 5% relative humidity for 7 days. These results indicated that the CH/SPPs edible films via ultrasonication could be developed as edible packaging films for the preservation of fresh fruits.
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http://dx.doi.org/10.1016/j.ijbiomac.2021.04.147DOI Listing
April 2021

Acetylcholinesterase target sites for developing environmentally friendly insecticides against Tetranychus urticae (Acari: Tetranychidae).

Exp Appl Acarol 2021 Apr 29. Epub 2021 Apr 29.

Key Laboratory of Northern Urban Agriculture of Ministry of Agriculture and Rural Affairs, College of Bioscience and Resource Environment, Beijing University of Agriculture, Beijing, 102206, China.

The non-target toxicity and resistance problems of acetylcholinesterase (AChE) insecticides, such as organophosphates and carbamates, are of growing concern. To explore the potential targets for achieving inhibitor selectivity, the AChE structures at or near the catalytic pocket of Tetranychus urticae (TuAChE), honey bees, and humans were compared. The entrances to the AChE catalytic pocket differ significantly because of their different peripheral sites. The role of these potential mite-specific sites in AChE function was further elucidated by site-directed mutagenesis of these sites and then examining the catalytic activities of TuAChE mutants. The spider mite E, H, and V active sites are important for AChE function. By further analyzing their physostigmine inhibitory properties and the detailed interaction between physostigmine and TuAChE, the peripheral site H locating near the gorge entrance, and S at the oxyanion hole, affects substrate and inhibitor trafficking. The discovery of conserved mite-specific residues in Tetranychus will enable the development of safer, effective pesticides that target residues present only in mite AChEs, potentially offering effective control against this important agricultural pest.
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http://dx.doi.org/10.1007/s10493-021-00624-4DOI Listing
April 2021

Functional soil organic matter fraction in response to short-term tillage management under the double-cropping rice paddy field in southern of China.

Environ Sci Pollut Res Int 2021 Apr 28. Epub 2021 Apr 28.

Hunan Soil and Fertilizer Institute, Changsha, 410125, China.

Soil organic matter (SOM) and its fraction play an important role in maintaining and improving soil fertility of paddy field. However, there is still limited information about how SOM fraction response to carbon (C) sequestration with different short-term tillage practices under the double-cropping rice paddy field in southern of China. Therefore, the effects of 5-year short-term tillage treatments on different SOM fractions (physically protected, physico-chemically protected, physico-biochemically protected, chemically protected, biochemically protected, and unprotected) under the double-cropping rice paddy field in southern of China were studied in this paper. The field experiment included four different tillage treatments: rotary tillage with crop residue removed as a control (RTO), conventional tillage with crop residue incorporation (CT), rotary tillage with crop residue incorporation (RT), and no-tillage with crop residue retention (NT). The results showed that soil unprotected (cPOM), biochemically (NH-dSilt), physically-biochemically (NH-μSilt), and chemically protected (H-dSilt) fractions with different tillage treatments were the mainly C storage fraction in paddy field. The soil organic carbon (SOC) content in unprotected (cPOM and fPOM), physically protected (iPOM), and physico-chemically protected (H-μClay) fractions with CT treatment was increased by 1.45, 2.13, 1.91, and 1.42 times higher than that of RTO treatment, respectively. The results showed that largest proportion of fraction to SOC content was biochemically protected, followed by unprotected and physically-biochemically protected, and physically protected was the lowest. These results indicated that soil physically protected, physically-chemically protected, and physically-biochemically protected fractions with CT and RT treatments were higher than that of NT and RTO treatments. In summary, it was a benefit practice for increasing SOM fraction under the double-cropping rice paddy field in southern of China by combined application of conventional tillage and rotary tillage with crop residue incorporation management.
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http://dx.doi.org/10.1007/s11356-021-14173-1DOI Listing
April 2021

Single-cell transcriptome and genome analyses of pituitary neuroendocrine tumors.

Neuro Oncol 2021 Apr 28. Epub 2021 Apr 28.

Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China.

Background: Pituitary neuroendocrine tumors (PitNETs) are the second most common intracranial tumor. We lacked a comprehensive understanding of the pathogenesis and heterogeneity of these tumors.

Methods: We performed high-precision single-cell RNA sequencing for 2,679 individual cells obtained from 23 surgically resected samples of the major subtypes of PitNETs from 21 patients. We also performed single-cell multi-omics sequencing for 238 cells from 5 patients.

Results: Unsupervised clustering analysis distinguished all tumor subtypes, which was in accordance with the classification based on immunohistochemistry and provided additional information. We identified three normal endocrine cell types: somatotrophs, lactotrophs and gonadotrophs. Comparisons of tumor and matched normal cells showed that differentially expressed genes of gonadotroph tumors were predominantly downregulated, while those of somatotroph and lactrotroph tumors were mainly upregulated. We identified novel tumor-related genes, such as AMIGO2, ZFP36, BTG1 and DLG5. Tumors expressing multiple hormone genes showed little transcriptomic heterogeneity. Furthermore, single-cell multi-omics analysis demonstrated that the tumor shad a relatively uniform pattern of genome with slight heterogeneity in copy number variations.

Conclusions: Our single-cell transcriptome and single-cell multi-omics analyses provide novel insights into the characteristics and heterogeneity of these complex neoplasms for the identification of biomarkers and therapeutic targets.
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http://dx.doi.org/10.1093/neuonc/noab102DOI Listing
April 2021

Photo-induced mitochondrial DNA damage and NADH depletion by -NO modified Ru(II) complexes.

Chem Commun (Camb) 2021 Apr;57(34):4162-4165

Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China.

Two mitochondria-localized Ru(ii) complexes with photo-labile ligands were reported to exert one- and two-photon activatable anticancer activity through a dual-function mechanism, i.e. mitochondrial DNA covalent binding after photo-induced ligand dissociation and photo-catalyzed NADH depletion, thus displaying good activity towards cisplatin-resistant cancer cells under both normoxic and hypoxic conditions.
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http://dx.doi.org/10.1039/d1cc00258aDOI Listing
April 2021

Efficient generation of mouse models with the prime editing system.

Cell Discov 2020 Apr 28;6(1):27. Epub 2020 Apr 28.

Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, 712100, Shaanxi, China.

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http://dx.doi.org/10.1038/s41421-020-0165-zDOI Listing
April 2020

Sevoflurane represses the migration and invasion of gastric cancer cells by regulating forkhead box protein 3.

J Int Med Res 2021 Apr;49(4):3000605211005936

Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei Province, China.

Objective: Previous studies suggested that sevoflurane exerts anti-proliferative, anti-migratory, and anti-invasive effects on cancer cells. To determine the role of sevoflurane on gastric cancer (GC) progression, we evaluated its effects on the proliferation, migration, and invasion of SGC7901, AGS, and MGC803 GC cells.

Methods: GC cells were exposed to different concentrations of sevoflurane (1.7, 3.4, or 5.1% v/v). Cell viability, migration, and invasion were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays. Immunohistochemical staining and immunoblotting were performed to analyze forkhead box protein 3 (FOXP3) protein expression in tissue specimens and cell lines, respectively.

Results: FOXP3 was downregulated in human GC specimens and cell lines. Functionally, FOXP3 overexpression significantly inhibited the proliferation, migration, and invasion of GC cells and accelerated their apoptosis. Moreover, sevoflurane significantly blocked GC cell migration and invasion compared with the findings in the control group. However, FOXP3 silencing neutralized sevoflurane-induced apoptosis and the inhibition of GC cell migration and invasion. Sevoflurane-induced apoptosis and the suppression of migration and invasion might be associated with FOXP3 overactivation in GC cells.

Conclusions: Sevoflurane activated FOXP3 and prevented GC progression via inhibiting cell migration and invasion .
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http://dx.doi.org/10.1177/03000605211005936DOI Listing
April 2021

The effect of different drinking water in culture medium on feces microbiota diversity.

J Water Health 2021 Apr;19(2):267-277

Tianjin Institute of Environmental and Operational Medicine, Tianjin 300050, China E-mail:

The human gut harbors trillions of microbes, which are extremely important to the health of the host. However, the effect of drinking water on gut microbiota has been poorly understood. In this study, we explored the response of BALB/c mice gut bacterial community (feces) to the different types of drinking water, including commercial bottled mineral water (MW), natural water (NW), purified water (PW) and tap water (TW). Feces were cultured with brain heart infusion broth dissolved in four types of drinking water. 16S rRNA gene analysis was performed. Our results reveal that the microbiota composition is different among culturing with four types of drinking water. As the culture time increases, the number of OTUs significantly decreased, except under the aerobic condition of MW. Under aerobic conditions on the 5th day, the considerable differences of alpha diversity index are found between MW and three others, and these are the most unique taxa in the MW group. Importantly, the LEfSe analysis discovers that the Bacteroidetes taxa dominate the differences between MW and the other water types. Our findings demonstrate that the mineral water as a culture medium may lead to a progressive increase of the gut microbiota diversity by providing the growth convenience to Bacteroidetes.
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http://dx.doi.org/10.2166/wh.2020.075DOI Listing
April 2021

TRIM29 alters bioenergetics of pancreatic cancer cells via cooperation of miR-2355-3p and DDX3X recruitment to AK4 transcript.

Mol Ther Nucleic Acids 2021 Jun 3;24:579-590. Epub 2021 Feb 3.

Department of Biochemistry and Molecular Biology, China Medical University, Shenyang 110026, China.

TRIM29 is dysregulated in pancreatic cancer and implicated in maintenance of stem-cell-like characters of pancreatic cancer cells. However, the exact mechanisms underlying oncogenic function of TRIM29 in pancreatic cancer cells remain largely unclarified. Using a global screening procedure, the current study found that adenylate kinase 4 (AK4) was profoundly reduced by TRIM29 knockdown. In addition, our data demonstrated that TRIM29 knockdown altered bioenergetics and suppressed proliferation and invasion of pancreatic cancer cells via downregulation of AK4 at the posttranscriptional level. The current study demonstrated that upregulation of microRNA-2355-3p (miR-2355-3p) upregulated AK4 expression via facilitating DDX3X recruitment to the AK4 transcript, and TRIM29 knockdown thereby destabilized the AK4 transcript via miR-2355-3p downregulation. Collectively, our study uncovers posttranscriptional stabilization of the AK4 transcript by miR-2355-3p interaction to facilitate DDX3X recruitment. Regulation of AK4 by TRIM29 via miR-2355-3p thereby provides additional information for further identification of attractive targets for therapy with pancreatic cancer.
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http://dx.doi.org/10.1016/j.omtn.2021.01.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054099PMC
June 2021

Two-step biosynthesis of d-allulose via a multienzyme cascade for the bioconversion of fruit juices.

Food Chem 2021 Apr 5;357:129746. Epub 2021 Apr 5.

Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, Tianjin Key Laboratory of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, National Engineering Laboratory for Industrial Enzymes, Tianjin 300457, PR China. Electronic address:

d-Allulose, a low-calorie rare sugar with potential as sucrose substitute for diabetics, can be produced using d-allulose 3-epimerase (DAE). Here, we characterized a putative thermostable DAE from Pirellula sp. SH-Sr6A (PsDAE), with a half-life of 6 h at 60 °C. Bioconversion of 500 g/L d-fructose using immobilized PsDAE on epoxy support yielded 152.7 g/L d-allulose, which maintained 80% of the initial activity after 11 reuse cycles. A multienzyme cascade system was developed to convert sucrose to d-allulose comprising sucrose invertase, d-glucose isomerase and PsDAE. Fruit juices were treated using this system to convert the high-calorie sugars, such as sucrose, d-glucose, and d-fructose, into d-allulose. The content of d-allulose among total monosaccharides in the treated fruit juice remained between 16 and 19% during 15 reaction cycles. This study provides an efficient strategy for the development of functional fruit juices containing d-allulose for diabetics and other special consumer categories.
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http://dx.doi.org/10.1016/j.foodchem.2021.129746DOI Listing
April 2021

Impact of Subthalamic Deep Brain Stimulation on Hyposmia in Patients With Parkinson's Disease Is Influenced by Constipation and Dysbiosis of Microbiota.

Front Neurol 2021 6;12:653833. Epub 2021 Apr 6.

Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, China.

Non-motor symptoms in PD usually arise at very early stage and vary during the whole disease progression. Deep brain stimulation (DBS) is considered as a highly efficient treatment option for PD's motor function. However, the effect of DBS on NMS, especially hyposmia, has not been fully understood and the deep connection between different NMS such as hyposmia and constipation is still unknown. The objective of this study was to evaluate the therapeutic effect of DBS on hyposmia in PD patients with or without constipation and find potential factors which might influence the efficacy. A retrospective analysis of 65 PD patients accepted STN-DBS operation in Qilu Hospital during 2019-2020 were conducted to evaluate the exact therapeutic effect of DBS on hyposmia in PD. Sub-group analyses about the relationship between hyposmia and constipation were carried out. Analysis of flora in nasal mucosa was also conducted to evaluate the abundance and variety in different PD groups. Our study showed that DBS had clearly improved olfactory function in Parkinson patients ( = 0.012) and subgroup analysis found that PD patients with constipation have lower olfactory function scores (25.27 ± 3.44 vs. 33.90 ± 6.633, = 0.014) and worse improvement after DBS operation (ΔTDI 12.11 ± 3.2 vs. 8.78 ± 2.91, = 0.0072). Analysis of flora indicated the obvious discrepancy on olfactory function scores and degree of improvement might be related to the abundance and dysbiosis of microbiota. In summary, this article presents a study on PD with hyposmia and constipation after DBS operation, explored the relationship between different NMS and offer a potential explanation on why PD patients with constipation usually have worse olfactory function for the less abundance and variety of microbiota.
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http://dx.doi.org/10.3389/fneur.2021.653833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056012PMC
April 2021

Combining Mechanical High-Intensity Focused Ultrasound Ablation with Chemotherapy for Augmentation of Anticancer Immune Responses.

Mol Pharm 2021 05 22;18(5):2091-2103. Epub 2021 Apr 22.

School of Biomedical Engineering, Sun Yat-sen University, Guangzhou, Guangdong 510006, China.

As a noninvasive therapy, high-intensity focused ultrasound (HIFU) shows great potential in inducing anticancer immune responses. However, the overall anticancer efficacy of HIFU is still limited due to the rapid attenuation of ultrasound waves and inadequacy of ultrasound waves to spread to the whole tumor. Here, we combined HIFU with the ultrasound contrast agent/chemotherapeutic drug co-delivery nanodroplets to achieve synergistic enhancement of anticancer efficacy. Different from the widely used thermal HIFU irradiation, by which excessive heating would result in inactivation of immune stimulatory molecules, we used short acoustic pulses to trigger HIFU (mechanical HIFU, mHIFU) to improve anticancer immune responses. The nanodroplets displayed a mHIFU/glutathione (GSH)-dual responsive drug release property, and their cellular uptake efficacy and toxicity against cancer cells increased upon mHIFU irradiation. The generated immunogenic debris successfully induced the exposure of damage-associated molecular patterns on the cell surface for dendritic cells (DCs) maturation. In vivo experiments with tumor-bearing mice showed that the co-delivery nanodroplets in combination with mHIFU could effectively inhibit tumor growth by inducing immunogenic cell death, activating DCs maturation, and enhancing the effector T-cell infiltration within tumors. This work reveals that combined treatment with nanodroplets and mHIFU is a promising approach to eradicate tumors.
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http://dx.doi.org/10.1021/acs.molpharmaceut.1c00229DOI Listing
May 2021

Proteomics analysis in the kidney of mice following oral feeding Realgar.

J Ethnopharmacol 2021 Apr 18;275:114118. Epub 2021 Apr 18.

Tianjin University of Traditional Chinese Medicine, Tianjin, 300139, China; NMPA Key Laboratory for Quality Control of Traditional Chinese Medicine, Shanghai Institute for Food and Drug Control, Shanghai, 201203, China. Electronic address:

Ethnopharmacological Relevance: Realgar, a famous traditional Chinese mineral medicine, has been toxic to the renal system. However, the underlying mechanism of Realgar nephrotoxicity is still unclear.

Aim Of The Study: This study aimed to investigate the potential mechanism of Realgar-induced nephrotoxicity by using a label-free quantitative proteomic method.

Materials And Methods: 36 mice were randomly divided into four groups: Control group, 0.5-, 1.0, and 2.0 g/kg Realgar group. After one week, serum biochemical parameters and renal histopathological examination were performed. Label-free quantitative proteomics was used to identify differentially expressed proteins which were subsequently analyzed with bioinformatics methods. Western blot was utilized to verify the six representative protein expressions.

Results: The results showed that 2.0 g/kg Realgar significantly increased blood urea nitrogen and induced the formation of tube cast of renal tubules, while the lower-dose of 0.5 g/kg and 1.0 g/kg Realgar showed no changes. Label-free proteomic analysis identified 3138 proteins, and 272 of those proteins were screened for significant changes in a dose-dependent manner. Functional enrichment analysis suggested that these proteins could affect the apoptotic process and oxidative stress. Representative proteins in the 2.0 g/kg Realgar group, including Cat, Bad, Cycs, Nqo1, Podxl, and Hmox1, were verified by western blot.

Conclusions: The results in this study suggest that apoptosis and oxidative stress might be related to the Realgar-induced nephrotoxicity in mice. Moreover, the strategy of proteomics could contribute to the understanding of the mechanisms of nephrotoxicity in mice exposed to Realgar.
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http://dx.doi.org/10.1016/j.jep.2021.114118DOI Listing
April 2021

Decitabine With or Without Micro-Transplantation for the Treatment of Intermediate or High-Risk Myelodysplastic Syndrome: A Chinese Single-Center Retrospective Study of 22 Patients.

Front Oncol 2021 31;11:628127. Epub 2021 Mar 31.

Department of Hematology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.

The treatment outcomes of intermediate or high-risk myelodysplastic syndrome (MDS) remain unsatisfactory. This study was designed to evaluate the safety and efficacy of human leukocyte antigen (HLA)-mismatched hematopoietic stem cell micro-transplantation (MST) in patients with MDS. A total of 22 patients with MDS, ranging between the ages of 39 and 74, were enrolled in this study. Eleven patients were given decitabine (DAC), a DNA methyltransferase inhibitor, combined with HLA-mismatched MST (MST-DAC group), and the remaining patients were given decitabine only (DAC group). The median overall survival (OS) of the MST-DAC group was higher than that of the DAC group (24 vs. 14.3 months; HR 0.32; 95% CI: 0.11-0.96; = 0.04), although it is a study with small samples. The overall response rate (ORR), marrow complete remission (mCR), plus hematological improvement (HI) rates of the MST-DAC group were higher than that of the DAC group (81.8 vs. 54.5%, = 0.36; 63.6 vs. 27.3%, = 0.09, respectively); however, there were no statistical differences between the two groups, which may be attributed to the limited number of cases evaluated in this study. No graft-vs.-host disease was observed in the MST-DAC group. Patients in the MST-DAC group demonstrated a slightly lower incidence of hematological and non-hematological adverse events (AEs). DAC combined with HLA-mismatched MST may provide a novel, effective, and safe treatment for use in intermediate or high-risk MDS pathologies.
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http://dx.doi.org/10.3389/fonc.2021.628127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044401PMC
March 2021