Publications by authors named "Yujue Wang"

189 Publications

Proteomic Investigation of Molecular Mechanisms in Response to PEG-Induced Drought Stress in Soybean Roots.

Plants (Basel) 2022 Apr 26;11(9). Epub 2022 Apr 26.

College of Life Sciences, Jilin Agricultural University, Changchun 130118, China.

Roots are generally the critical drought sensors, but little is known about their molecular response to drought stress. We used the drought-tolerant soybean variety 'Jiyu 47' to investigate the differentially expressed proteins (DEPs) in soybean roots during the seedling stage based on the tandem mass tag (TMT) proteomics analysis. Various expression patterns were observed in a total of six physiological parameters. A total of 468 DEPs (144 up-regulated and 324 down-regulated) among a total of 8687 proteins were identified in response to drought stress in 24 h. The expression of DEPs was further validated based on quantitative real-time PCR of a total of five genes (i.e., , , k , and ) involved in the glutathione biosynthesis. Results of enrichment analyses revealed a coordinated expression pattern of proteins involved in various cellular metabolisms responding to drought stress in soybean roots. Our results showed that drought stress caused significant alterations in the expression of proteins involved in several metabolic pathways in soybean roots, including carbohydrate metabolism, metabolism of the osmotic regulation substances, and antioxidant defense system (i.e., the glutathione metabolism). Increased production of reduced glutathione (GSH) enhanced the prevention of the damage caused by reactive oxygen species and the tolerance of the abiotic stress. The glutathione metabolism played a key role in modifying the antioxidant defense system in response to drought stress in soybean roots. Our proteomic study suggested that the soybean plants responded to drought stress by coordinating their protein expression during the vegetative stage, providing novel insights into the molecular mechanisms regulating the response to abiotic stress in plants.
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http://dx.doi.org/10.3390/plants11091173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100407PMC
April 2022

Glycerol's contribution to lactate production outside of a glucose intermediate in fasting humans.

Metabolism 2022 May 11;132:155214. Epub 2022 May 11.

Division of Endocrinology, Metabolism and Nutrition, Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA. Electronic address:

Background: Glycerol is a well-recognized substrate for new glucose production via gluconeogenesis in the liver. However, its carbon contribution to the glycolytic intermediate lactate is not known in humans.

Methods: Here we infused stable isotope tracers C-glycerol and 6,6-D-glucose into six metabolically healthy individuals after an overnight fast to study glycerol metabolism and measure glucose rate of appearance. Serum samples underwent liquid chromatography-mass spectrometry analysis.

Results: Glycerol and glucose rates of appearance were 2.21 ± 1.42 μmol/kg/min and 7.81 ± 1.15 μmol/kg/min, respectively. Under steady-state conditions, the C enrichment for lactate was significantly higher than that of glucose (2.90 ± 0.52% versus 1.53 ± 0.78%, p = 0.017), suggesting direct glycerol to lactate metabolism. The percentage of lactate derived from glycerol was also significantly higher than the percentage of glucose (13.88 ± 2.69% versus 6.50 ± 2.59%, p = 0.005).

Conclusion: Given that lactate itself is a carbon source for gluconeogenesis and tricycarboxylic cycle intermediates, glycerol's ability to donate carbons to lactate may make it quantitatively more important to intermediary metabolism than currently appreciated.
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http://dx.doi.org/10.1016/j.metabol.2022.155214DOI Listing
May 2022

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells.

Mol Nutr Food Res 2022 Apr 15:e2200028. Epub 2022 Apr 15.

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA.

Scope: Butyrate (B) is a short-chain fatty acid produced by dietary fiber, known to inhibit histone deacetylases (HDACs) and possess cancer-preventive/anticancer effects. However, the role of B in metabolic rewiring, epigenomic reprogramming, transcriptomic network, NRF2 signaling, and eliciting cancer-preventive effects in colorectal cancer (CRC) HCT116 cell remains unclear.

Methods And Results: Sodium butyrate (NaB) dose-dependently inhibits the growth of CRC HCT116 cells. NaB inhibits NRF2/NRF2-target genes and blocks NRF2-ARE signaling. NaB increases NRF2 negative regulator KEAP1 expression through inhibiting its promoter methylation. Associative analysis of DEGs (differentially expressed genes) from RNA-seq and DMRs (differentially methylated regions) from CpG methyl-seq identified the tumor suppressor gene ABCA1 and tumor promote gene EGR3 are correlated with their promoters' CpG methylation indicating NaB regulates cancer markers through modulating their promoter methylation. NaB activated the mitochondrial tricarboxylic acid (TCA) cycle while inhibited the methionine metabolism which are both tightly coupled to the epigenetic machinery. NaB regulates the epigenetic enzymes/genes including DNMT1, HAT1, KDM1A, KDM1B, and TET1. Altogether, B's regulation of metabolites coupled to the epigenetic enzymes illustrates the potential underlying biological connectivity between metabolomics and epigenomics.

Conclusion: B regulates KEAP1/NRF2 signaling, drives metabolic rewiring, CpG methylomic, and transcriptomic reprogramming contributing to the overall cancer-prevention/anticancer effect in the CRC cell model.
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http://dx.doi.org/10.1002/mnfr.202200028DOI Listing
April 2022

Can the commonly used quenching method really evaluate the role of reactive oxygen species in pollutant abatement during catalytic ozonation?

Water Res 2022 May 10;215:118275. Epub 2022 Mar 10.

School of Environment, Beijing Key Laboratory for Emerging Organic Contaminants Control, State Key Joint Laboratory of Environmental Simulation and Pollution Control, Tsinghua University, Beijing 100084 China. Electronic address:

Reactive oxygen species (ROS) such as hydroxyl radicals (•OH), superoxide radicals (O), and singlet oxygen (O) have often been suggested to play a role in ozone-resistant pollutant abatement during catalytic ozonation. However, there are significant controversies regarding their relative importance in literature. Currently, the role of ROS in pollutant abatement is commonly evaluated by the quenching method based on the assumption that the added ROS quenchers (e.g., tert-butanol (TBA) and para-benzoquinone (pBQ)) quench only the target ROS, but do not considerably influence other reaction mechanisms of catalytic ozonation. However, we hypothesized that this assumption is possibly unrealistic and a main cause for the controversies reported in literature. To test this hypothesis, this study evaluated the effects of six commonly used ROS quenchers (TBA, pBQ, methanol (MeOH), 4-chloro-7-nitrobenzo-2-oxa-1,3-dizole (NBD-Cl), furfuryl alcohol (FFA), and sodium azide (NaN)) on the mechanism of catalytic ozonation with manganese dioxide. The results show that rather than only quenching their target ROS, these quenchers can profoundly change the catalytic ozonation system through various mechanisms, e.g., interrupting the radical chain reaction of O decomposition, blocking the active sites of catalysts, and consuming O in the system. Due to the significant confounding effects of ROS quenchers on the reaction mechanism, the quenching method actually cannot reveal the role of ROS in pollutant abatement and often misinterpreted the catalytic ozonation mechanism. The results indicate that the commonly used quenching method is probably not an appropriate way to investigate the role of ROS in pollutant abatement during catalytic ozonation, and many previously reported mechanisms obtained with the quenching method may need a revisit.
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http://dx.doi.org/10.1016/j.watres.2022.118275DOI Listing
May 2022

Clinical utility of PDX cohorts to reveal biomarkers of intrinsic resistance and clonal architecture changes underlying acquired resistance to cetuximab in HNSCC.

Signal Transduct Target Ther 2022 03 8;7(1):73. Epub 2022 Mar 8.

Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Cetuximab is a widely used drug for treating head and neck squamous cell carcinomas (HNSCCs); however, it provides restricted clinical benefits, and its response duration is limited by drug resistance. Here, we conducted randomized "Phase II-like clinical trials" of 49 HNSCC PDX models and reveal multiple informative biomarkers for intrinsic resistance to cetuximab (e.g., amplification of ANKH, up-regulation of PARP3). After validating these intrinsic resistance biomarkers in another HNSCC PDX cohort (61 PDX models), we generated acquired cetuximab resistance PDX models and analyzed them to uncover resistance mechanisms. Whole exome sequencing and transcriptome sequencing revealed diverse patterns of clonal selection in acquired resistant PDXs, including the emergence of subclones with strongly activated RAS/MAPK. Extending these insights, we show that a combination of a RAC1/RAC3 dual-target inhibitor and cetuximab could overcome acquired cetuximab resistance in vitro and in vivo. Beyond revealing intrinsic resistance biomarkers, our PDX-based study shows how clonal architecture changes underlying acquired resistance can be targeted to expand the therapeutic utility of this important drug to more HNSCC patients.
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http://dx.doi.org/10.1038/s41392-022-00908-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8904860PMC
March 2022

Convolutional neural network-based automatic classification for incomplete antibody reaction intensity in solid phase anti-human globulin test image.

Med Biol Eng Comput 2022 Apr 7;60(4):1211-1222. Epub 2022 Mar 7.

Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Science, Suzhou, 215163, China.

The precise classification of incomplete antibody reaction intensity (IARI) in hydrogel chromatography medium high density medium solid-phase Coombs test is essential for haemolytic disease screening. However, an automatic and contactless method is required for accurate classification of IARI. Here, we present a deep ensemble learning model that integrates five different convolutional neural networks into a single model for IARI classification. A dataset, including 1628 IARI images and corresponding labels of IARI categories ((-), (1 +), (2 +), (3 +), and (4 +)), was used. We trained our model using 1302 IARIs and validated its performance using 326 IARIs. The proposed model achieved 100%, 99.4%, 99.4%, 100%, and 100% accuracies in the ( -), (1 +), (2 +), (3 +), and (4 +) categories, respectively. The results were compared with those of manual classification by immunologists (average accuracy: 99.8% vs. 88.3%, p < 0.01). Following model assistance, all three immunologists achieved increased accuracy (average accuracy: + 6.1%), with the average accuracy of junior immunologists maximum increasing by 11.3%. The time required for model classification was 0.094 s·image, whereas that required manually was 5.528 s·image. The proposed model can thus substantially improve the accuracy and efficiency of IARI classification and facilitate the automation of haemolytic disease screening equipment.
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http://dx.doi.org/10.1007/s11517-022-02523-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8901095PMC
April 2022

Application of Unsupervised Migration Method Based on Deep Learning Model in Basketball Training.

Comput Intell Neurosci 2022 23;2022:6711331. Epub 2022 Feb 23.

School of Physical Education & Sports Science, South China Normal University, Guangzhou 510006, Guangdong, China.

Nowadays, China's sports industry has attained effective development, but the athlete's efficiency in the training process is too complex to have a scientific guarantee. Machine learning technology's help in guiding the sports training process has become a hot spot. In this work, we investigate the use of deep learning in real-time analysis of basketball sports data, utilizing research approaches such as scientific reporting, audio/video analysis, experimental research, and mathematical statistics. The suggested basketball stance action recognition and analysis system are made up of two pieces that are sequentially connected. The bottom-up stance estimate approach is utilized to locate the joint locations in the first segment, which is then used to extract the target's posture sequence from the video. The analyses are needed for a Support Vector Machine (SVM) algorithm based on the deep learning method of the space-time graph. The basketball activity of the set classification is recognized and extracted from the segmented stance sequence. The study used an auxiliary method, which is contrasted to standard training, in order to get higher accuracy and also correct player errors in a timely manner. The approach can help players rectify technical errors, develop muscle memory, and increase their abilities. The results revealed that the algorithm generated 97.7% accuracy in evaluating data from basketball training.
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http://dx.doi.org/10.1155/2022/6711331DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8890852PMC
March 2022

CircSLC16A12 Absence Inhibits High Glucose-Induced Dysfunction in Retinal Microvascular Endothelial Cells through Mediating miR-140-3p/FGF2 Axis in Diabetic Retinopathy.

Curr Eye Res 2022 Mar 27:1-11. Epub 2022 Mar 27.

Department of Ophthalmic Clinic, Harbin Eye Hospital, Harbin, China.

Purpose: Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus which can cause irreversible visual impairment and blindness. We intended to investigate the function of circular RNA (circRNA) solute carrier family 16 member 12 (SLC16A12) in DR progression.

Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were applied to measure RNA and protein expression. Cell apoptosis was analyzed by flow cytometry (FCM) analysis. The angiogenesis ability was assessed by tube formation assay. Enzyme-linked immunosorbent assay (ELISA) was performed to analyze the release of inflammatory cytokines. Cell oxidative stress status was evaluated using commercial kits. Dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, and RNA-pull down assay were conducted to confirm the intermolecular interactions.

Results: CircSLC16A12 level was enhanced in the serum samples of DR patients and high glucose (HG)-treated HRECs. CircSLC16A12 absence protected HRECs from HG-induced apoptosis, blood-retinal barrier (BRB) injury, tube formation, inflammatory response, and oxidative stress. CircSLC16A12 acted as a sponge for microRNA-140-3p (miR-140-3p), and circSLC16A12 knockdown-mediated effects were largely reversed by the absence of miR-140-3p in HRECs under HG condition. miR-140-3p interacted with the 3' untranslated region (3'UTR) of fibroblast growth factor 2 (FGF2), and the overexpression of FGF2 largely overturned miR-140-3p overexpression-mediated effects in HRECs. CircSLC16A12 interference reduced the expression of FGF2 by up-regulating miR-140-3p in HRECs.

Conclusion: CircSLC16A12 silencing suppressed HG-induced dysfunction in HRECs partly by targeting miR-140-3p/FGF2 axis.
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http://dx.doi.org/10.1080/02713683.2022.2025845DOI Listing
March 2022

Long non-coding RNA OIP5-AS1 suppresses microRNA-92a to augment proliferation and metastasis of ovarian cancer cells through upregulating ITGA6.

J Ovarian Res 2022 Feb 16;15(1):25. Epub 2022 Feb 16.

Gynaecology and Obstetrics Department, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, No. 32, West Second Section First Ring Rd, Chengdu, 610072, Sichuan, China.

Objective: Recently, long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified as essential biomarkers during development of malignancies. This study was performed to study the roles of lncRNA opa-interacting protein 5 antisense transcript 1 (OIP5-AS1) and miR-92a in ovarian cancer (OC).

Methods: OIP5-AS1, miR-92a and integrin alpha 6 (ITGA6) expression in OC tissues and cells was assessed. The screened OC cells were respectively with OIP5-AS1-, miR-92a- and ITGA6-related vectors or oligonucleotides . The viability, migration, invasion and apoptosis of the cells were determined and the levels of epithelial-mesenchymal transition (EMT)-related proteins were also measured. The interactions between OIP5-AS1 and miR-92a, and between miR-92a and ITGA6 were confirmed.

Results: OIP5-AS1 and ITGA6 were upregulated while miR-92a was downregulated in OC. Inhibited OIP5-AS1 or downregulated ITGA6 or elevated miR-92a repressed EMT, viability, migration and invasion, and promoted apoptosis of OC cells. OIP5-AS1 as a competing endogenous RNA interacted with miR-92a to regulate ITGA6. These effects that induced by silenced OIP5-AS1 could be reversed by miR-92a inhibition while those that induced by up-regulated miR-92a were reduced by restored ITGA6.

Conclusion: OIP5-AS1 silencing promoted miR-92a to repress proliferation and metastasis of OC cells through inhibiting ITGA6.
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http://dx.doi.org/10.1186/s13048-021-00937-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848981PMC
February 2022

The System Profile of Renal Drug Transporters in Tubulointerstitial Fibrosis Model and Consequent Effect on Pharmacokinetics.

Molecules 2022 Jan 21;27(3). Epub 2022 Jan 21.

Biopharmaceutics, NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.

With the widespread clinical use of drug combinations, the incidence of drug-drug interactions (DDI) has significantly increased, accompanied by a variety of adverse reactions. Drug transporters play an important role in the development of DDI by affecting the elimination process of drugs in vivo, especially in the pathological state. Tubulointerstitial fibrosis (TIF) is an inevitable pathway in the progression of chronic kidney disease (CKD) to end-stage renal disease. Here, the dynamic expression changes of eleven drug transporters in TIF kidney have been systematically investigated. Among them, the mRNA expressions of Oat1, Oat2, Oct1, Oct2, Oatp4C1 and Mate1 were down-regulated, while Oat3, Mrp2, Mrp4, Mdr1-α, Bcrp were up-regulated. Pearson correlation analysis was used to analyze the correlation between transporters and Creatinine (Cr), OCT2 and MATE1 showed a strong negative correlation with Cr. In contrast, Mdr1-α exhibited a strong positive correlation with Cr. In addition, the pharmacokinetics of cimetidine, ganciclovir, and digoxin, which were the classical substrates for OCT2, MATE1 and P-glycoprotein (P-gp), respectively, have been studied. These results reveal that changes in serum creatinine can indicate changes in drug transporters in the kidney, and thus affect the pharmacokinetics of its substrates, providing useful information for clinical use.
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http://dx.doi.org/10.3390/molecules27030704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8838889PMC
January 2022

Mitochondrial inhibitors circumvent adaptive resistance to venetoclax and cytarabine combination therapy in acute myeloid leukemia.

Nat Cancer 2021 11 11;2(11):1204-1223. Epub 2021 Nov 11.

Centre de Recherches en Cancérologie de Toulouse, Université de Toulouse, Inserm, CNRS, Toulouse, France.

Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a 'MitoScore' signature, which identifies high mitochondrial oxidative phosphorylation in vivo and in patients with AML. Primary AML cells with cytarabine (AraC) resistance and a high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) + AraC (but not to VEN + azacytidine). Single-cell transcriptomics of VEN + AraC-residual cell populations revealed adaptive resistance associated with changes in oxidative phosphorylation, electron transport chain complex and the TP53 pathway. Accordingly, treatment of VEN + AraC-resistant AML cells with electron transport chain complex inhibitors, pyruvate dehydrogenase inhibitors or mitochondrial ClpP protease agonists substantially delayed relapse following VEN + AraC. These findings highlight the central role of mitochondrial adaptation during AML therapy and provide a scientific rationale for alternating VEN + azacytidine with VEN + AraC in patients with a high MitoScore and to target mitochondrial metabolism to enhance the sensitivity of AML cells to currently approved therapies.
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http://dx.doi.org/10.1038/s43018-021-00264-yDOI Listing
November 2021

Intensive masculinization caused by chronic heat stress in juvenile Cynoglossus semilaevis: Growth performance, gonadal histology and gene responses.

Ecotoxicol Environ Saf 2022 Mar 1;232:113250. Epub 2022 Feb 1.

Key Laboratory of Marine Genetics and Breeding, Ministry of Education, Ocean University of China, Qingdao, Shandong, China; Laboratory for Marine Fisheries Science and Food Production Processes, Qingdao National Laboratory for Marine Science and Technology, Qingdao, Shandong, China; Key Laboratory of Tropical Aquatic Germplasm of Hainan Province, Sanya Oceanographic Institution, Ocean University of China, Sanya 572000, China. Electronic address:

The sea temperature has been observed to chronically increase during the past decades, leaving unpredictable influences to the marine biological resources. Thus, it is of vital significance to study the biological responses of ocean inhabited organisms with the artificially stimulated heat stress environment. Cynoglossus semilaevis provides us with an ideal model to study the influence of chronic heat stress on the sexual differentiation in marine teleosts for its genetic sex determination (GSD) + environmental effected (EE) sex determination system. In this study, the comparative experiment was conducted employing heated seawater (HT group) and ambient seawater (CT group) to cultivate juvenile C. semilaevis respectively. Significant differences were exhibited in growth performance and a delayed germ cell development effect was found in pseudomales formed under chronic heat stress. Using transcriptome analysis, the transcription profile of 55 days post fertilization (dpf) and 100 dpf juveniles' gonads were studied. A total of 47 libraries were constructed with an average mapping rate of 94.63% after assembling. GO and KEGG enrichment were proceeded using DEGs screened out between (1) pseudomale gonads at 55 dpf and 100 dpf in HT and CT group (2) pseudomale and female gonads at 55 dpf and 100 dpf in HT and CT group. Terms and pathways involved in steroid stimulation, reproduction ability, germ cell proliferation et al. were shed light on. The expression pattern of 29 DEGs including amh, hsp90b1, pgr et al. were also provided to supplement the results of functional enrichment. Weighted gene co-expression networks analysis (WGCNA) was constructed and hspb8-like, histone H2A.V were exhibited to play vital roles in the heat-induced masculinization. Our findings facilitate the understanding for transcriptional variations in intensive masculinization cause by chronic heat stress of C. semilaevis and provide referable study of the influences on the teleosts in elevated sea temperature.
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http://dx.doi.org/10.1016/j.ecoenv.2022.113250DOI Listing
March 2022

Comparison of clinical outcomes between cystotome-assisted prechop phacoemulsification surgery and femtosecond laser-assisted cataract surgery for hard nucleus cataracts.

Eye (Lond) 2022 Jan 29. Epub 2022 Jan 29.

National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Hunan, China.

Background/objectives: To compare the safety and efficacy of cystotome-assisted prechop phacoemulsification surgery (CAPPS) and femtosecond laser-assisted cataract surgery (FLACS) in patients with hard nucleus cataract.

Subjects/methods: Ninety-six eyes of 64 patients with grade IV hard nucleus cataract were assigned to 1 of the 2 groups (49 CAPPS and 47 FLACS). Follow-up visits were performed at 1 day, 1 week, 1 month, 3 months, 6 months, and 1 year, and the outcome measures comprised ultrasound power, effective phacoemulsification time (EPT), corrected distance visual acuity (CDVA), endothelial cell density (ECD), corneal endothelium cell loss rate (ECL), central corneal thickness (CCT), and intraoperative and postoperative complications.

Results: The ultrasound power and EPT were lower in the CAPPS group (p = 0.03 and <0.0001, respectively). Patients in both groups gained better CDVA postoperatively. The ECD value decreased at each follow-up visit and did not return to the preoperative level; FLACS resulted in greater endothelial cell loss compared to CAPPS. CCT increased immediately after the surgery and decreased thereafter. The mean CCT value returned to the preoperative level 3 months postoperatively in the CAPPS group, while in the FLACS group, CCT value took 6 months to return to the preoperative level. Miosis was more likely to occur in the FLACS group.

Conclusions: Due to its efficacy and cost-effectiveness, CAPPS is worth promoting and applying to clinical work in the future.
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http://dx.doi.org/10.1038/s41433-021-01900-8DOI Listing
January 2022

Nfe2l2 Regulates Metabolic Rewiring and Epigenetic Reprogramming in Mediating Cancer Protective Effect by Fucoxanthin.

AAPS J 2022 01 18;24(1):30. Epub 2022 Jan 18.

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, 08854, USA.

Fucoxanthin (FX) is a carotenoid with many pharmaceutical properties due to its antioxidant/anti-inflammatory and epigenetic effects. NFE2L2 is involved in the defense against oxidative stress/inflammation-mediated diseases, like anticancer effects elicited by phytochemicals including FX. However, the role of FX and NFE2L2 in metabolic rewiring, epigenomic reprogramming, and transcriptomic network in blocking pro-tumorigenic signaling and eliciting cancer-protective effects remains unknown. Herein, we utilized multi-omics approaches to evaluate the role of NFE2L2 and the impact of FX on tumor promoter TPA-induced skin cell transformation. FX blocked TPA-induced ROS and oxidized GSSG/reduced GSH in Nfe2l2wild-type(WT) but not Nfe2l2-knockdown (KD) cells. Both Nfe2l2 KD and TPA altered cellular metabolisms and metabolites which are tightly coupled to epigenetic machinery. The suppressive effects of FX on TPA-enhancedSAM/SAH was abrogated by Nfe2l2 KD indicating Nfe2l2 plays a critical role in FX-mediated metabolic rewiring and its potential consequences on epigenetic reprogramming. Epigenomic CpG methyl-seq revealed that FX attenuated TPA-induced differentially methylated regions (DMRs) of Uhrf1 and Dnmt1 genes. Transcriptomic RNA-seq showed that FX abrogated TPA-induced differentially expressed genes (DEGs) of Nfe2l2-related genes Nqo1, Ho1, and Keap1. Associative analysis of DEGs and DMRs identified that the mRNA expressions of Uhrf1 and Dnmt1 were correlated with the promoter CpG methylation status. Chromatin immunoprecipitation assay showed that FX restored Uhrf1 expression by regulating H3K27Me3 enrichment in the promoter region. In this context, FX/Nfe2l2's redox signaling drives metabolic rewiring causing epigenetic and transcriptomic reprogramming potentially contributing to the protection of TPA-induced JB6 cellular transformation skin cancer model. Graphical abstract.
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http://dx.doi.org/10.1208/s12248-022-00679-0DOI Listing
January 2022

2-(4-Hydroxyphenyl)benzothiazole dicarboxylate ester TACN chelators for Cu PET imaging in Alzheimer's disease.

Dalton Trans 2022 Jan 17;51(3):1216-1224. Epub 2022 Jan 17.

Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, Illinois 61801, USA.

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid β aggregates, strong binding affinity towards Cu(II), and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate ester pendant arms show high binding affinity towards Cu(II). The BFCs form stable Cu-radiolabeled complexes and exhibit favorable partition coefficient (log ) values of 0.75-0.95. Among the five compounds tested, 64Cu-YW-1 and 64Cu-YW-13 complexes exhibit significant staining of amyloid plaques in autoradiography studies.
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http://dx.doi.org/10.1039/d1dt02767kDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8969080PMC
January 2022

Optimized 3D Culture of Hepatic Cells for Liver Organoid Metabolic Assays.

Cells 2021 11 24;10(12). Epub 2021 Nov 24.

Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, NJ 08901, USA.

The liver is among the principal organs for glucose homeostasis and metabolism. Studies of liver metabolism are limited by the inability to expand primary hepatocytes in vitro while maintaining their metabolic functions. Human hepatic three-dimensional (3D) organoids have been established using defined factors, yet hepatic organoids from adult donors showed impaired expansion. We examined conditions to facilitate the expansion of adult donor-derived hepatic organoids (HepAOs) and HepG2 cells in organoid cultures (HepGOs) using combinations of growth factors and small molecules. The expansion dynamics, gluconeogenic and HNF4α expression, and albumin secretion are assessed. The conditions tested allow the generation of HepAOs and HepGOs in 3D cultures. Nevertheless, gluconeogenic gene expression varies greatly between conditions. The organoid expansion rates are limited when including the TGFβ inhibitor A8301, while are relatively higher with Forskolin (FSK) and Oncostatin M (OSM). Notably, expanded HepGOs grown in the optimized condition maintain detectable gluconeogenic expression in a spatiotemporal distribution at 8 weeks. We present optimized conditions by limiting A8301 and incorporating FSK and OSM to allow the expansion of HepAOs from adult donors and HepGOs with gluconeogenic competence. These models increase the repertoire of human hepatic cellular tools available for use in liver metabolic assays.
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http://dx.doi.org/10.3390/cells10123280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699701PMC
November 2021

Seasonal and spatial variations in nutrients under the influence of natural and anthropogenic factors in coastal waters of the northern Yellow Sea, China.

Mar Pollut Bull 2022 Feb 26;175:113171. Epub 2021 Nov 26.

Muping Coastal Environmental Research Station, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong 264003, P.R. China; Center for Ocean Mega-Science, Chinese Academy of Sciences, Qingdao, Shandong 266071, PR China; Laboratory of Coastal Environmental Processes and Ecological Remediation, Yantai Institute of Coastal Zone Research, Chinese Academy of Sciences, Yantai, Shandong 264003, PR China. Electronic address:

Analysis of the common and most influential natural and anthropogenic activities on the spatiotemporal variation in nutrients at a multiannual scale is important. Eleven cruises from 2015 to 2017 were carried out to better elucidate the seasonal and spatial variations in nutrients, as well as the impact factors on dissolved inorganic nitrogen (DIN), phosphorus (DIP) and silicate (DSi). Both nutrient concentrations and forms showed similar and significant seasonal variations over the 3 years, and were closely related to the biomass and species of phytoplankton. Terrestrial inputs had significant effects on the spatial distribution of nutrients throughout the year, especially in the surface water, which showed DIN > DIP>DSi. In summer, shellfish aquaculture and hypoxia jointly affected the spatial distribution of nutrients. The bottom water nutrient concentrations in the aquaculture area were 1.1-2.3 times higher than those outside of the aquaculture area. Seasonal hypoxia can increase the release of DSi and NH from the sediment to the water. In summary, anthropogenic activities and physical conditions jointly influenced the nutrient distributions.
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http://dx.doi.org/10.1016/j.marpolbul.2021.113171DOI Listing
February 2022

Triterpenoid ursolic acid drives metabolic rewiring and epigenetic reprogramming in treatment/prevention of human prostate cancer.

Mol Carcinog 2022 01 2;61(1):111-121. Epub 2021 Nov 2.

Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.

Ursolic acid (UA) is a triterpenoid phytochemical with a strong anticancer effect. The metabolic rewiring, epigenetic reprogramming, and chemopreventive effect of UA in prostate cancer (PCa) remain unknown. Herein, we investigated the efficacy of UA in PCa xenograft, and its biological effects on cellular metabolism, DNA methylation, and transcriptomic using multi-omics approaches. The metabolomics was quantified by liquid-chromatography-mass spectrometry (LC-MS) while epigenomic CpG methylation in parallel with transcriptomic gene expression was studied by next-generation sequencing technologies. UA administration attenuated the growth of transplanted human VCaP-Luc cells in immunodeficient mice. UA regulated several cellular metabolites and metabolism-related signaling pathways including S-adenosylmethionine (SAM), methionine, glucose 6-phosphate, CDP-choline, phosphatidylcholine biosynthesis, glycolysis, and nucleotide sugars metabolism. RNA-seq analyses revealed UA regulated several signaling pathways, including CXCR4 signaling, cancer metastasis signaling, and NRF2-mediated oxidative stress response. Epigenetic reprogramming study with DNA Methyl-seq uncovered a list of differentially methylated regions (DMRs) associated with UA treatment. Transcriptome-DNA methylome correlative analysis uncovered a list of genes, of which changes in gene expression correlated with the promoter CpG methylation status. Altogether, our results suggest that UA regulates metabolic rewiring of metabolism including SAM potentially driving epigenetic CpG methylation reprogramming, and transcriptomic signaling resulting in the overall anticancer chemopreventive effect.
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http://dx.doi.org/10.1002/mc.23365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8665082PMC
January 2022

SomaMutDB: a database of somatic mutations in normal human tissues.

Nucleic Acids Res 2022 01;50(D1):D1100-D1108

Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, USA.

De novo mutations, a consequence of errors in DNA repair or replication, have been reported to accumulate with age in normal tissues of humans and model organisms. This accumulation during development and aging has been implicated as a causal factor in aging and age-related pathology, including but not limited to cancer. Due to their generally very low abundance mutations have been difficult to detect in normal tissues. Only with recent advances in DNA sequencing of single-cells, clonal lineages or ultra-high-depth sequencing of small tissue biopsies, somatic mutation frequencies and spectra have been unveiled in several tissue types. The rapid accumulation of such data prompted us to develop a platform called SomaMutDB (https://vijglab.einsteinmed.org/SomaMutDB) to catalog the 2.42 million single nucleotide variations (SNVs) and 0.12 million small insertions and deletions (INDELs) thus far identified using these advanced methods in nineteen human tissues or cell types as a function of age or environmental stress conditions. SomaMutDB employs a user-friendly interface to display and query somatic mutations with their functional annotations. Moreover, the database provides six powerful tools for analyzing mutational signatures associated with the data. We believe such an integrated resource will prove valuable for understanding somatic mutations and their possible role in human aging and age-related diseases.
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http://dx.doi.org/10.1093/nar/gkab914DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8728264PMC
January 2022

Identification of groundwater microbial communities and their connection to the hydrochemical environment in southern Laizhou Bay, China.

Environ Sci Pollut Res Int 2022 Feb 4;29(10):14263-14278. Epub 2021 Oct 4.

State Key Laboratory of Estuarine and Coastal Research, East China Normal University, Shanghai, 200062, China.

The microbial community plays an important role in the biogeochemical cycle in coastal groundwater ecosystems. However, the composition and controlling factors of the microbial community in coastal closed groundwater systems (CCGSs) with high salinity have rarely been studied. Here, we investigated and analyzed the hydrochemical characteristics and microbial community composition of seven brine samples with high total dissolved solid (TDS) values ranging from 74.5 to 132.3 g/L within and across three coastal saltworks (Yangkou, Hanting, and Changyi) in southern Laizhou Bay (SLB). The bacterial diversity was independent of salinity. Compared with those of low-salinity groundwater, the diversity of the microbial community in brine was lower, but the richness was slightly higher. There was a significant correlation between the microbial community diversity and groundwater sources, which indicated that the microbial communities were affected by groundwater sources. A comparison of the microbial community compositions of the three saltworks showed that the Hanting and Changyi saltworks had similar microbial communities due to their similar sampling depths. In addition, the main force shaping the differences in the microbial communities in both coastal open groundwater systems (COGSs) and CCGSs was identified as the hydraulic connection with the seawater controlled by hydrogeological conditions formed throughout geological history. This study can help to elucidate the biogeochemical processes in coastal aquifers.
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http://dx.doi.org/10.1007/s11356-021-16812-zDOI Listing
February 2022

Programmed genome editing by a miniature CRISPR-Cas12f nuclease.

Nat Chem Biol 2021 11 2;17(11):1132-1138. Epub 2021 Sep 2.

School of Physical Science and Technology, ShanghaiTech University, Shanghai, China.

The RNA-guided CRISPR-associated (Cas) nucleases are versatile tools for genome editing in various organisms. The large sizes of the commonly used Cas9 and Cas12a nucleases restrict their flexibility in therapeutic applications that use the cargo-size-limited adeno-associated virus delivery vehicle. More compact systems would thus offer more therapeutic options and functionality for this field. Here, we report a miniature class 2 type V-F CRISPR-Cas genome-editing system from Acidibacillus sulfuroxidans (AsCas12f1, 422 amino acids). AsCas12f1 is an RNA-guided endonuclease that recognizes 5' T-rich protospacer adjacent motifs and creates staggered double-stranded breaks to target DNA. We show that AsCas12f1 functions as an effective genome-editing tool in both bacteria and human cells using various delivery methods, including plasmid, ribonucleoprotein and adeno-associated virus. The small size of AsCas12f1 offers advantages for cellular delivery, and characterizations of AsCas12f1 may facilitate engineering more compact genome-manipulation technologies.
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http://dx.doi.org/10.1038/s41589-021-00868-6DOI Listing
November 2021

Coastal eutrophication in China: Trend, sources, and ecological effects.

Harmful Algae 2021 07 13;107:102058. Epub 2021 Jun 13.

Key Laboratory of Marine Eco-Environmental Science and Technology, First Institute of Oceanography, Ministry of Natural Resources, Qingdao, 266061, PR China. Electronic address:

Eutrophication in coastal waters caused by excess nutrient inputs has occurred widely on a global scale. Due to the rapid economic development over the last four decades, most of the Chinese coastal waters have experienced a eutrophic process. Major observed trends of coastal eutrophication include two periods, a slow development from the 1970s to 1990s and a fast development after 2000, with major contributions of increased nitrogen (N) and phosphorus (P) from river inputs, atmospheric deposition, and submarine groundwater discharge (SGD). Nutrient composition and stoichiometry have been significantly changed, including increased ammonium, bioavailable organic N and P, and asymmetric ratios between N, P and silicate (Si). Most of these changes were related to the rapid increases in population density, fertilizer application, sewage discharge, aquaculture and fossil fuel combustion, and have resulted in distinctly increased harmful algal blooms. Coastal eutrophication combined with the effects of climate change is projected to continually grow in coming decades. Targeted research is therefore needed on nitrogen reduction and control, potential adaptation strategies and the consequences for ecosystems and economic sustainability.
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http://dx.doi.org/10.1016/j.hal.2021.102058DOI Listing
July 2021

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy.

Cancer Cell 2021 10 19;39(10):1375-1387.e6. Epub 2021 Aug 19.

Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA. Electronic address:

Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by Braf, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by Kras. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γ, and CD8 cytotoxic and proliferative (versus CD4 regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.
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http://dx.doi.org/10.1016/j.ccell.2021.07.023DOI Listing
October 2021

Amyloid β-Binding Bifunctional Chelators with Favorable Lipophilicity for Cu Positron Emission Tomography Imaging in Alzheimer's Disease.

Inorg Chem 2021 Aug 5;60(16):12610-12620. Epub 2021 Aug 5.

Department of Chemistry, University of Illinois at Urbana-Champaign, 600 S. Mathews Avenue, Urbana, Illinois 61801, United States.

Herein, we report a new series of bifunctional chelators (BFCs) with a high affinity for amyloid aggregates, a strong binding affinity toward Cu(II), and favorable lipophilicity for potential blood-brain barrier penetration. The alkyl carboxylate ester pendant arms offer up to 3 orders of magnitude higher binding affinity toward Cu(II) and enable the BFCs to form stable Cu-radiolabeled complexes. Among the five compounds tested, the Cu-YW-7 and Cu-YW-10 complexes exhibit strong and specific staining of amyloid plaques in ex vivo autoradiography studies. Importantly, these BFCs have promising partition coefficient (log ) values of 0.91-1.26 and show some brain uptake in biodistribution studies using CD-1 mice. Overall, these BFCs could serve as lead compounds for the development of positron emission tomography imaging agents for AD diagnosis.
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http://dx.doi.org/10.1021/acs.inorgchem.1c02079DOI Listing
August 2021

Up-regulation of microRNA-135 or silencing of PCSK6 attenuates inflammatory response in preeclampsia by restricting NLRP3 inflammasome.

Mol Med 2021 07 23;27(1):82. Epub 2021 Jul 23.

Genaecology and Obstetrics Department, Sichuan Academy of Medical Sciences, Sichuan Provincial People's Hospital, No. 32, West Second Section First Ring Rd, Chengdu, 610072, China.

Objective: Numerous studies have confirmed the correlation of microRNAs (miRNAs) with human disease, yet few have explored the role of miR-135 in preeclampsia (PE). This study intends to discuss miR-135's function in inflammatory response in PE by modulating proprotein convertase subtilisin/kexin-6 (PCSK6) and NLR pyrin domain containing 3 (NLRP3).

Methods: The venous blood and placental tissues were collected from PE pregnant women and 25 normal ones. The levels of miR-135, PCSK6 and NLRP3 in placenta tissues of patients were detected. Hypoxia/reoxygenation HTR-8/SVneo and HPT-8 models were established to mimic PE in vitro, and cell proliferation, colony formation, apoptosis rate, invasion, migration and inflammation were detected through gain-of and loss-of-function assays.

Results: MiR-135 was down-regulated, and PCSK6 and NLRP3 were up-regulated in PE patients. Up-regulating miR-135 or silencing PCSK6 strengthened colony formation ability, viability, invasion and migration ability, and weakened apoptosis and inflammation of H/R-treated HTR-8/SVneo and HPT-8 cells. Inhibition of NLRP3 negated the effects of silenced PCSK6 in H/R-treated HTR-8/SVneo and HPT-8 cells.

Conclusions: Altogether, we demonstrate that up-regulated miR-135 or reduced PCSK6 attenuates inflammatory response in PE by restricting NLRP3 inflammasome, which provides novel therapy for PE treatment.
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http://dx.doi.org/10.1186/s10020-021-00335-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299578PMC
July 2021

AccuCor2: isotope natural abundance correction for dual-isotope tracer experiments.

Lab Invest 2021 10 30;101(10):1403-1410. Epub 2021 Jun 30.

Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, USA.

Stable isotope labeling techniques have been widely applied in the field of metabolomics and proteomics. Before the measured mass spectral data can be used for quantitative analysis, it must be accurately corrected for isotope natural abundance and tracer isotopic impurity. Despite the increasing popularity of dual-isotope tracing strategy such as C-N or C-H, there are no accurate tools for correcting isotope natural abundance for such experiments in a resolution-dependent manner. Here, we present AccuCor2 as an R-based tool to perform the correction for C-N or C-H labeling experiments. Our method uses a newly designed algorithm to construct the correction matrices that link labeling pattern and measured mass fractions, then use non-negative least-squares to solve the labeling patterns. Our results show that the dual-isotope experiments often require a mass resolution that is high enough to resolve C and N or C and H. Otherwise, the labeling pattern is not solvable. However, this mass resolution may not be sufficiently high to resolve other non-tracer elements such as oxygen or sulfur from the tracer elements. Therefore, we design AccuCor2 to perform the correction based on the actual mass resolution of the measurements. Using both simulated and experimental data, we show that AccuCor2 performs accurate and resolution-dependent correction for dual-isotope tracer data.
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http://dx.doi.org/10.1038/s41374-021-00631-4DOI Listing
October 2021

Transplantation of reprogrammed peripheral blood cells differentiates into retinal ganglion cells in the mouse eye with NMDA-induced injury.

J Cell Physiol 2021 12 8;236(12):8099-8109. Epub 2021 Jun 8.

Hunan Key Laboratory of Ophthalmology, Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, China.

The generation of patient-specific induced pluripotent stem cells (iPSCs) holds significant implications for replacement therapy in treating optic neuropathies such as glaucoma. Stem-cell-based therapy targeted at replacing and replenishing retinal ganglion cells is progressing at a fast pace. However, clinical application necessitates an efficient and robust approach for cell manufacturing. Here, we examine whether the embryo body derived from human peripheral blood-derived iPSC can localize into the host retina and differentiate into retinal ganglion cells after transplantation into a glaucoma injury model. Human peripheral blood T cells were isolated and reprogrammed into an induced pluripotent stem cell (TiPSC) line using Sendai virus transduction carrying transcription factors Sox2, Klf4, c-Myc, and Oct4. TiPSCs were differentiated into RGC using neural basal culture. For in vivo studies, embryo bodies derived from TiPSCs (TiPSC-EB) were injected into the vitreous cavity of N-Methyl-d-aspartic acid (NMDA)-treated mice 2 weeks before sacrifice and retinal dissection. Induced pluripotent stem cells generated from human peripheral blood T cells display stem cell morphology and pluripotency markers. Furthermore, RGC-like cells differentiated from TiPSC exhibit extending axons and RGC marker TUJ1. When transplanted intravitreally into NMDA-treated mice, embryo bodies derived from TiPSC survived, migrated, and incorporated into the retina's GCL layer. In addition, TiPSC-EB transplants were able to differentiate into TUJ1 positive RGC-like cells. Retinal ganglion cells can be differentiated using human peripheral blood cells derived iPSC. Transplantation of embryo body derived from TiPSCs into a glaucoma mouse model could incorporate into host GCL and differentiate into RGC-like cells.
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http://dx.doi.org/10.1002/jcp.30464DOI Listing
December 2021

Links between the optical properties and chemical compositions of brown carbon chromophores in different environments: Contributions and formation of functionalized aromatic compounds.

Sci Total Environ 2021 Sep 4;786:147418. Epub 2021 May 4.

State Key Joint Laboratory of Environmental Simulation and Pollution Control, College of Environmental Sciences and Engineering, Peking University, Beijing 100871, China.

Links between the optical properties and chemical compositions of brown carbon (BrC) are poorly understood because of the complexity of BrC chromophores. We conducted field studies simultaneously at both vehicle-influenced site and biomass burning-affected site in China in polluted winter. The chemical compositions and light absorption values of functionalized aromatic compounds, including phenyl aldehyde, phenyl acid, and nitroaromatic compounds, were measured. P-phthalic acid, nitrophenols and nitrocatechols were dominant BrC species, accounting for over 50% of the concentration of identified chromophores. Nitrophenols and nitrocatechols contributed more than 50% of the identified BrC absorbance between 300 and 400 nm. Oxidation of biomass burning-related products (e.g., pyrocatechol and methylcatechols) and anthropogenic volatile organic compounds (e.g., benzene and toluene) generated similar BrC chromophores, implying that these functionalized aromatic compounds play an important role in both environments. Compared with the biomass burning-affected site (22%), functionalized aromatic compounds at vehicle-influenced site accounted for a higher percentage of BrC absorption (25%). This research improves our understanding of the links between optical properties and composition of BrC, and the difference between BrC chromophores from BB-influenced area and vehicle-affected area under polluted atmospheric conditions.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147418DOI Listing
September 2021

Multifunctional CuS- and DOX-loaded [email protected] platform for combined melanoma therapy with inspired antitumor immunity.

Biomater Sci 2021 Jun;9(11):4086-4098

Department of Dermatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan 430022, China.

Combined antitumor therapies based on nanomedicines have shown efficacy in various tumor models in recent years, overcoming the disadvantages of inefficiency and undesired toxicity of traditional therapies. Herein, we present a copper sulfide- and doxorubicin-loaded gold [email protected] SiO2 multifunctional nanocomposite ([email protected]@DOX-CuxS-PEG) to integrate chemotherapy, the photothermal properties of AuNRs, and the photodynamic properties of CuxS into a single nanoplatform based on hydrophobic interaction and electrostatic attraction. Upon near-infrared light irradiation, the [email protected]@DOX-CuxS-PEG nanocomposites exhibit a synergistic therapeutic effect and inhibit the in situ tumor growth and lung metastasis in a melanoma model. This occurs because of the high photothermal conversion efficiency, boosted intracellular reactive oxygen species production, and excellent doxorubicin (DOX) release, as well as an induced tumor-specific immune response. The inspired antitumor immunity was confirmed by elevated infiltration of activated T cells in tumor tissues and improved maturation and activation of dendritic cells in tumor-draining lymph nodes. This study highlights the superior antitumor therapeutic effect elicited by a multifunctional nanoplatform for skin with in situ melanoma and lung metastasis inhibition, indicating its satisfactory clinical application prospects.
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http://dx.doi.org/10.1039/d1bm00373aDOI Listing
June 2021

Extracellular vesicle-derived microRNA-18b ameliorates preeclampsia by enhancing trophoblast proliferation and migration via Notch2/TIM3/mTORC1 axis.

J Cell Mol Med 2021 05 9;25(10):4583-4595. Epub 2021 Apr 9.

Department of Obstetrics and Gynecology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.

Preeclampsia (PE), a common disorder of pregnancy, is characterized by insufficient trophoblast migration and inadequate vascular remodelling, such that promotion of trophoblast proliferation might ameliorate PE. In the current study, we sought to study the underlying mechanism of extracellular vesicle (EV)-derived microRNA-18 (miR-18b) in PE. Human umbilical cord mesenchymal stem cells (HUCMSCs) isolated from placental tissues were verified through osteogenic, adipogenic and chondrogenic differentiation assays. Bioinformatics analyses and dual-luciferase reporter gene assay were adopted to confirm the targeting relationship between miR-18b and Notch2. The functional roles of EV-derived miR-18b and Notch2 in trophoblasts were determined using loss- and gain-of-function experiments, and trophoblast proliferation and migration were assayed using CCK-8 and Transwell tests. In vivo experiments were conducted to determine the effect of EV-derived miR-18b, Notch2 and TIM3/mTORC1 in a rat model of PE, with monitoring of blood pressure and urine proteinuria. TUNEL staining was conducted to observe the cell apoptosis of placental tissues of PE rats. We found down-regulated miR-18b expression, and elevated Notch2, TIM3 and mTORC1 levels in the placental tissues of PE patients compared with normal placenta. miR-18b was delivered to trophoblasts and targeted Notch2 and negatively its expression, whereas Notch2 positively mediated the expression of TIM3/mTORC1. EV-derived miR-18b or Notch2 down-regulation enhanced trophoblast proliferation and migration in vitro and decreased blood pressure and 24 hours urinary protein in PE rats by deactivating the TIM3/mTORC1 axis in vivo. In summary, EV-derived miR-18b promoted trophoblast proliferation and migration via down-regulation of Notch2-dependent TIM3/mTORC1.
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http://dx.doi.org/10.1111/jcmm.16234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107107PMC
May 2021
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