Publications by authors named "Xing Zhang"

1,300 Publications

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Calycosin stimulates the proliferation of endothelial cells, but not breast cancer cells, via a feedback loop involving RP11-65M17.3, BRIP1 and ERα.

Aging (Albany NY) 2021 Mar 1;13. Epub 2021 Mar 1.

Key Laboratory of Tumor Immunology and Microenvironmental Regulation of Guangxi, Guilin Medical University, Guilin 541004, Guangxi, China.

It is widely accepted that estrogen can be replaced by phytoestrogens to treat postmenopausal cardiovascular disease and possibly decrease the risk of breast cancer. However, few studies have investigated the effects of phytoestrogens on vascular endothelial cells (ECs). In the present study, we show that the phytoestrogen calycosin (20 μM) stimulated the proliferation of ECs (HUVECs and HMEC-1) but inhibited the growth of breast cancer cells (BCCs) expressing ERα (MCF-7 and T47D). Here we provide evidence for the presence of a positive feedback loop between ERα and long noncoding RNA RP11-65M17.3 in both normal and cancer cells, and calycosin stimulated this feedback loop in ECs but decreased RP11-65M17.3 expression in BCCs. Subsequently, the calycosin-induced activation of this loop decreased the expression of the target of BRIP1 (BRCA1 interacting protein C-terminal helicase 1), increased the phosphorylation of Akt and ERK1/2, and finally inhibited the cleavage of PARP-1 in ECs. In nude mice bearing MCF-7 xenografts, calycosin did not stimulate tumor growth as strongly as 17β-estradiol. Together, these results suggest that calycosin promotes the proliferation of ECs, and notable inhibits the growth of BCCs. A possible reason for these results is the involvement of a feedback loop between ERα and RP11-65M17.3.
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http://dx.doi.org/10.18632/aging.202641DOI Listing
March 2021

The influence of interpersonal relationships on school adaptation among Chinese university students during COVID-19 control period: Multiple mediating roles of social support and resilience.

J Affect Disord 2021 Feb 17;285:97-104. Epub 2021 Feb 17.

Fuzhou Medical College of Nanchang University, Fuzhou, China.

Background: Owing to the government's effective epidemic control measures, universities in some areas of China gradually resumed offline teaching six months after the COVID-19 outbreak. Although attention should now be paid to the experiences of students after they returned to campus, few studies have explored the factors and mechanisms that have influenced these students' school adaptation. The present study investigated the multiple roles of social support and resilience in mediating associations the relationship between Chinese university students' interpersonal relationships and their school adaptation during COVID-19 control period.

Methods: A cross-sectional survey was conducted with 4534 Chinese university students (Mage = 19.70, SD = 1.14) at two universities in Jiangxi provinces. The independent variable was interpersonal relationships; mediating variables were social support and resilience; and the dependent variable was school adaptation. Multiple mediation analysis was performed using the MPlus software.

Results: Controlling for demographic variables, the quality of students' interpersonal relationships was significantly and positively related to their school adaptation, with students' ratings of social support and resilience mediating these associations. More interestingly, social support and resilience played multiple mediating roles in the relationship between interpersonal relationships and school adaptation.

Limitations: The age stage of the sample and the methods in which the data were collected may affect the generalizability of the results.

Conclusions: During COVID-19 control period, interpersonal relationships can influence school adaptation either directly or indirectly by enhancing social support or resilience (parallel mediation) or by activating resilience via the experience of social support (serial mediation). This study's results emphasize the role of interpersonal relationships, as well as the contributions of positive external and internal factors on students' school adaptation during the epidemic control period. Accordingly, these findings may have implications for the mental health education of college students in the post-epidemic era.
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http://dx.doi.org/10.1016/j.jad.2021.02.040DOI Listing
February 2021

Frequent amplification of HDAC genes and efficacy of HDAC inhibitor chidamide and PD-1 blockade combination in soft tissue sarcoma.

J Immunother Cancer 2021 Feb;9(2)

Department of Medical Melanoma and Sarcoma, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

Background: The advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.

Methods: Whole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.

Results: The HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8 T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.

Conclusions: The combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.
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http://dx.doi.org/10.1136/jitc-2020-001696DOI Listing
February 2021

Neural basis underlying the trait of attachment anxiety and avoidance revealed by the amplitude of low-frequency fluctuations and resting-state functional connectivity.

BMC Neurosci 2021 Feb 23;22(1):11. Epub 2021 Feb 23.

Research Center of Brain and Cognitive Neuroscience, Liaoning Normal University, Dalian, 116029, Liaoning Province, China.

Background: Attachment theory demonstrates that early attachment experience shapes internal working models with mental representations of self and close relationships, which affects personality traits and interpersonal relationships in adulthood. Although research has focused on brain structural and functional underpinnings to disentangle attachment styles in healthy individuals, little is known about the spontaneous brain activity associated with self-reported attachment anxiety and avoidance during the resting state.

Methods: One hundred and nineteen individuals participated in the study, completing the Experience in Close Relationship scale immediately after an 8-min fMRI scanning. We used the resting-state functional magnetic resonance imaging (rs-fMRI) signal of the amplitude of low-frequency fluctuation and resting-state functional connectivity to identify attachment-related regions and networks.

Results: Consequently, attachment anxiety is closely associated with the amplitude of low-frequency fluctuations in the right posterior cingulate cortex, over-estimating emotional intensity and exaggerating outcomes. Moreover, the functional connectivity between the posterior cingulate cortex and fusiform gyrus increases detection ability for potential threat or separation information, facilitating behavior motivation. The attachment avoidance is positively correlated with the amplitude of low-frequency fluctuation in the bilateral lingual gyrus and right postcentral and negatively correlated with the bilateral orbital frontal cortex and inferior temporal gyrus. Functional connection with attachment avoidance contains critical nodes in the medial temporal lobe memory system, frontal-parietal network, social cognition, and default mode network necessary to deactivate the attachment system and inhibit attachment-related behavior.

Conclusion And Implications: These findings clarify the amplitude of low-frequency fluctuation and resting-state functional connectivity neural signature of attachment style, associated with attachment strategies in attachment anxiety and attachment avoidance individuals. These findings may improve our understanding of the pathophysiology of the attachment-related disorder.
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http://dx.doi.org/10.1186/s12868-021-00617-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901076PMC
February 2021

Discoloration investigations of freeze-dried carrot cylinders from physical structure and color-related chemical compositions.

J Sci Food Agric 2021 Feb 20. Epub 2021 Feb 20.

Institute of Food Science and Technology, Chinese Academy of Agricultural Sciences (CAAS)/ Key Laboratory of Agro-Products Processing, Ministry of Agriculture and Rural Affairs.

Background: High carotenoids contents always led to a yellower/redder color of carrots, while a puzzling phenomenon still existed that freeze-dried carrots (FDC) had higher carotenoids contents but a lighter color compared with thermal-dried carrots. It seemed that carotenoid was not the only main factor that affected sample color. Hence, the discoloration characteristics of freeze-dried carrots were comprehensively analyzed from physical structure and color-related chemical compositions profiles.

Results: Outcomes of low field nuclear magnetic resonance and scanning electron microscope showed that sublimation of immobilized water preserved the intact porous structure of FDC, which kept the volume shrinkage less than 30% and led to less accumulations of color-related compositions. Besides, results of correlation and PCA-X model analysis proved that lutein and caffeic acid mainly affected a* value (r = 0.917) and b* value (r = 0.836) of FDC, respectively. Moreover, lipoxygenase indirectly affected sample color by degrading carotenoids, the lutein contents loss for fresh and blanching FDCs were 41.56% and 47.14%, respectively.

Conclusons: The discoloration of FDC was significantly affected by both of physical structure and color-related chemical compositions. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jsfa.11163DOI Listing
February 2021

Short-term but not long-term high fat diet feeding protects against pressure overload-induced heart failure through activation of mitophagy.

Life Sci 2021 Feb 16;272:119242. Epub 2021 Feb 16.

School of Aerospace Medicine, Fourth Military Medical University, Xi'an 710032, China.

Aims: Recent studies have shown that enhancement of fatty acid utilization through feeding animals a high fat diet (HFD) attenuated cardiac dysfunction in heart failure (HF). Here, we aimed to examine the temporal effects of HFD feeding on cardiac function in mice with heart failure and its underlying mechanism.

Main Methods: Pressure overload-induced HF was established via transverse aortic constriction (TAC) surgery. After surgery, the mice were fed on either normal diet or HFD for 8 or 16 weeks.

Key Findings: HFD feeding exerted opposite effects on cardiac function at different time points post-surgery. Short-term HFD feeding (8 wk) protected the heart against pressure overload, inhibiting cardiac hypertrophy and improving cardiac function, while long-term HFD feeding (16 wk) aggravated cardiac dysfunction in TAC mice. Short-term HFD feeding elevated cardiac fatty acid utilization, while long-term HFD feeding showed no significant effects on cardiac fatty acid utilization in TAC mice. Specifically, an increase in cardiac fatty acid utilization was accompanied with activated mitophagy and improved mitochondrial function. Palmitic acid treatment (400 μM, 2 h) stimulated fatty acid oxidation and mitophagy in neonatal myocytes. Mechanistically, fatty acid utilization stimulated mitophagy through upregulation of Parkin. Cardiac-specific knockdown of Parkin abolished the protective effects of short-term HFD feeding on cardiac function in TAC mice.

Significances: These results suggested that short-term but not long-term HFD feeding protects against pressure overload-induced heart failure through activation of mitophagy, and dietary fat intake should be used with caution in treatment of heart failure.
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http://dx.doi.org/10.1016/j.lfs.2021.119242DOI Listing
February 2021

Structural mechanism of cooperative activation of the human calcium-sensing receptor by Ca ions and L-tryptophan.

Cell Res 2021 Feb 18. Epub 2021 Feb 18.

Hefei National Laboratory of Physical Sciences at Microscale, Anhui Laboratory of Advanced Photonic Science and Technology, and School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, 230026, China.

The human calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor (GPCR) responsible for maintaining Ca homeostasis in the blood. The general consensus is that extracellular Ca is the principal agonist of CaSR. Aliphatic and aromatic L-amino acids, such as L-Phe and L-Trp, increase the sensitivity of CaSR towards Ca and are considered allosteric activators. Crystal structures of the extracellular domain (ECD) of CaSR dimer have demonstrated Ca and L-Trp binding sites and conformational changes of the ECD upon Ca/L-Trp binding. However, it remains to be understood at the structural level how Ca/L-Trp binding to the ECD leads to conformational changes in transmembrane domains (TMDs) and consequent CaSR activation. Here, we determined the structures of full-length human CaSR in the inactive state, Ca- or L-Trp-bound states, and Ca/L-Trp-bound active state using single-particle cryo-electron microscopy. Structural studies demonstrate that L-Trp binding induces the closure of the Venus flytrap (VFT) domain of CaSR, bringing the receptor into an intermediate active state. Ca binding relays the conformational changes from the VFT domains to the TMDs, consequently inducing close contact between the two TMDs of dimeric CaSR, activating the receptor. Importantly, our structural and functional studies reveal that Ca ions and L-Trp activate CaSR cooperatively. Amino acids are not able to activate CaSR alone, but can promote the receptor activation in the presence of Ca. Our data provide complementary insights into the activation of class C GPCRs and may aid in the development of novel drugs targeting CaSR.
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http://dx.doi.org/10.1038/s41422-021-00474-0DOI Listing
February 2021

IAA3-mediated repression of PIF proteins coordinates light and auxin signaling in Arabidopsis.

PLoS Genet 2021 Feb 18;17(2):e1009384. Epub 2021 Feb 18.

Key Laboratory of Molecular Design for Plant Cell Factory of Guangdong Higher Education Institutes, Department of Biology, Southern University of Science and Technology (SUSTech), Shenzhen, China.

The exogenous light signal and endogenous auxin are two critical factors that antagonistically regulate hypocotyl growth. However, the regulatory mechanisms integrating light and auxin signaling pathways need further investigation. In this study, we identified a direct link between the light and auxin signaling pathways mediated by the auxin transcriptional repressor IAA3 and light-controlled PIF transcription factors in Arabidopsis. The gain-of-function mutation in IAA3 caused hyposensitivity to light, whereas disruption of IAA3 led to an elongated hypocotyl under different light intensity conditions, indicating that IAA3 is required in light regulated hypocotyl growth. Genetic studies showed that the function of IAA3 in hypocotyl elongation is dependent on PIFs. Our data further demonstrated that IAA3 interacts with PIFs in vitro and in vivo, and it attenuates the DNA binding activities of PIFs to the target genes. Moreover, IAA3 negatively regulates the expression of PIFs-dependent genes. Collectively, our study reveals an interplay mechanism of light and auxin on the regulation of hypocotyl growth, coordinated by the IAA3 and PIFs transcriptional regulatory module.
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http://dx.doi.org/10.1371/journal.pgen.1009384DOI Listing
February 2021

Structure of photosystem I-LHCI-LHCII from the green alga Chlamydomonas reinhardtii in State 2.

Nat Commun 2021 02 17;12(1):1100. Epub 2021 Feb 17.

Photosynthesis Research Center, Key Laboratory of Photobiology, Institute of Botany, Chinese Academy of Sciences, Beijing, China.

Photosystem I (PSI) and II (PSII) balance their light energy distribution absorbed by their light-harvesting complexes (LHCs) through state transition to maintain the maximum photosynthetic performance and to avoid photodamage. In state 2, a part of LHCII moves to PSI, forming a PSI-LHCI-LHCII supercomplex. The green alga Chlamydomonas reinhardtii exhibits state transition to a far larger extent than higher plants. Here we report the cryo-electron microscopy structure of a PSI-LHCI-LHCII supercomplex in state 2 from C. reinhardtii at 3.42 Å resolution. The result reveals that the PSI-LHCI-LHCII of C. reinhardtii binds two LHCII trimers in addition to ten LHCI subunits. The PSI core subunits PsaO and PsaH, which were missed or not well-resolved in previous Cr-PSI-LHCI structures, are observed. The present results reveal the organization and assembly of PSI core subunits, LHCI and LHCII, pigment arrangement, and possible pathways of energy transfer from peripheral antennae to the PSI core.
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http://dx.doi.org/10.1038/s41467-021-21362-6DOI Listing
February 2021

Recent advances on the one-pot synthesis to assemble size-controlled glycans and glycoconjugates and polysaccharides.

Carbohydr Polym 2021 Apr 22;258:117672. Epub 2021 Jan 22.

School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Wenyuan Road 1, Nanjing 210023, China. Electronic address:

Glycans and glycoconjugates in nature include macromolecules with important biological activities and widely distributed in all living organisms. These oligosaccharides and polysaccharides play important roles in a variety of normal physiological and pathological processes, such as cell metastasis, signal transduction, intercellular adhesion, inflammation, and immune response. However, the heterogeneity of naturally occurring glycans and glycoconjugates complicates detailed structure-activity relationship studies resulting in an incomplete understanding of their mechanisms of action and hindering further applications. Therefore, the synthesis of homogeneous, or nearly homogeneous, structurally defined glycans is of great significance for the development of carbohydrate-based drugs. One-pot synthesis represents the fastest strategy to assemble oligosaccharides and polysaccharides, although unfortunately, typically relies on random assembly. In this review, we examine the progress that has been made in the controlled one-pot synthesis of homogeneous or nearly homogeneous oligosaccharides and polysaccharides providing a broad spectrum of options to access size-controlled glycan products.
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http://dx.doi.org/10.1016/j.carbpol.2021.117672DOI Listing
April 2021

Depressive, anxiety, and insomnia symptoms between population in quarantine and general population during the COVID-19 pandemic: a case-controlled study.

BMC Psychiatry 2021 02 16;21(1):99. Epub 2021 Feb 16.

Department of Psychiatry, Shenzhen Longgang Center for Chronic Disease Control, Longgang, Shenzhen, China.

Background: The COVID-19 pandemic have caused mental and psychological problems on the general population, patients, and related workers. Our study is to determine the impact of mental and psychological symptoms among population in quarantine for 2 weeks during COVID-19 pandemic.

Methods: A case-controlled study design have conducted at department of psychiatry of Shenzhen Longgang Center for Chronic Disease Control in Shenzhen, China mainland from 7th April to 15th June 2020.1674 participants (aged 18 to 65 years) in quarantine for 2 weeks and 1743 age-sex matched controls living in Shenzhen were recruited between 7th April 2020 and 15th June 2020. The assessment of depressive, anxiety, and insomnia symptoms were determined by self-reported questionnaires PHQ-9, GAD-7, and ISI, respectively.

Results: A total of 1674 participants in quarantine for 2 weeks and 1743 age-sex matched controls (32.6 ± 9.3 years vs. 32.7 ± 10.7 years, 49.8% vs. 47.8% females) were recruited. Population in quarantine had higher score on PHQ-9 (6.1 ± 5.5 vs. 3.0 ± 3.7, p < 0.001), GAD-7 (4.2 ± 4.7 vs. 1.9 ± 3.7, p < 0·001), and ISI (5.5 ± 5.8 vs. 3.1 ± 5.0%, p < 0.001) compared to general population. Population in quarantine showed significantly higher risks of depression (OR: 4.55, 95% CI: 3.82-5.41), anxiety (OR: 2.92, 95% CI: 2.43-3.51), and insomnia (OR: 2.40, 95% CI: 2.02-2.89), when compared to the general population. Younger, more education, non-married and lower household income showed higher risks of mental health problems.

Conclusions: Population in quarantine had a higher level of depressive, anxiety, and insomnia symptoms than controls. Specifically, they were at a higher risk prevalence of depression, anxiety, and insomnia, especially the severity of depression, when compared to controls. Younger, more education, non-married, and lower income population in quarantine were at higher risks of mental health problems. Mental health professionals should pay attention to the mental and psychological symptoms for population in quarantine.
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http://dx.doi.org/10.1186/s12888-021-03108-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884871PMC
February 2021

Salicylic Acid Suppresses Apical Hook Formation via NPR1-Mediated Repression of EIN3 and EIL1 in Arabidopsis.

Plant Cell 2020 Mar;32(3):612-629

Institute of Plant and Food Science, Department of Biology, Southern University of Science and Technology (SUSTech), Shenzhen, Guangdong 518055, China.

Salicylic acid (SA) and ethylene (ET) are important phytohormones that regulate numerous plant growth, development, and stress response processes. Previous studies have suggested functional interplay of SA and ET in defense responses, but precisely how these two hormones coregulate plant growth and development processes remains unclear. Our present work reveals antagonism between SA and ET in apical hook formation, which ensures successful soil emergence of etiolated dicotyledonous seedlings. Exogenous SA inhibited ET-induced expression of HOOKLESS1 (HLS1) in Arabidopsis (Arabidopsis thaliana) in a manner dependent on ETHYLENE INSENSITIVE3 (EIN3) and EIN3-LIKE1 (EIL1), the core transcription factors in the ET signaling pathway. SA-activated NONEXPRESSER OF PR GENES1 (NPR1) physically interacted with EIN3 and interfered with the binding of EIN3 to target gene promoters, including the HLS1 promoter. Transcriptomic analysis revealed that NPR1 and EIN3/EIL1 coordinately regulated subsets of genes that mediate plant growth and stress responses, suggesting that the interaction between NPR1 and EIN3/EIL1 is an important mechanism for integrating the SA and ET signaling pathways in multiple physiological processes. Taken together, our findings illuminate the molecular mechanism underlying SA regulation of apical hook formation as well as the antagonism between SA and ET in early seedling establishment and possibly other physiological processes.
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http://dx.doi.org/10.1105/tpc.19.00658DOI Listing
March 2020

Strong Reduction of the Chain Rigidity of Hyaluronan by Selective Binding of Ca Ions.

Macromolecules 2021 Feb 19;54(3):1137-1146. Epub 2021 Jan 19.

AMOLF, Science Park 104, 1098 XG Amsterdam, The Netherlands.

The biological functions of natural polyelectrolytes are strongly influenced by the presence of ions, which bind to the polymer chains and thereby modify their properties. Although the biological impact of such modifications is well recognized, a detailed molecular picture of the binding process and of the mechanisms that drive the subsequent structural changes in the polymer is lacking. Here, we study the molecular mechanism of the condensation of calcium, a divalent cation, on hyaluronan, a ubiquitous polymer in human tissues. By combining two-dimensional infrared spectroscopy experiments with molecular dynamics simulations, we find that calcium specifically binds to hyaluronan at millimolar concentrations. Because of its large size and charge, the calcium cation can bind simultaneously to the negatively charged carboxylate group and the amide group of adjacent saccharide units. Molecular dynamics simulations and single-chain force spectroscopy measurements provide evidence that the binding of the calcium ions weakens the intramolecular hydrogen-bond network of hyaluronan, increasing the flexibility of the polymer chain. We also observe that the binding of calcium to hyaluronan saturates at a maximum binding fraction of ∼10-15 mol %. This saturation indicates that the binding of Ca strongly reduces the probability of subsequent binding of Ca at neighboring binding sites, possibly as a result of enhanced conformational fluctuations and/or electrostatic repulsion effects. Our findings provide a detailed molecular picture of ion condensation and reveal the severe effect of a few, selective and localized electrostatic interactions on the rigidity of a polyelectrolyte chain.
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http://dx.doi.org/10.1021/acs.macromol.0c02242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879427PMC
February 2021

Early therapeutic interventions of traditional Chinese medicine in COVID-19 patients: A retrospective cohort study.

J Integr Med 2021 Jan 13. Epub 2021 Jan 13.

Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.

Objective: To observe the early interventions of traditional Chinese Medicine (TCM) on the conversion time of nucleic acid in patients with coronavirus disease 2019 (COVID-19), and find possible underlying mechanisms of action.

Methods: A retrospective cohort study was conducted on 300 confirmed COVID-19 patients who were treated with TCM, at a designated hospital in China. The patients were categorized into three groups: TCM1, TCM2 and TCM3, who respectively received TCM interventions within 7, 8-14, and greater than 15 days of hospitalization. Different indicators such as the conversion time of pharyngeal swab nucleic acid, the conversion time of fecal nucleic acid, length of hospital stay, and inflammatory markers (leukocyte count, and lymphocyte count and percentage) were analyzed to observe the impact of early TCM interventions on these groups.

Results: The median conversion times of pharyngeal swab nucleic acid in the three groups were 5.5, 7 and 16 d (P < 0.001), with TCM1 and TCM2 being statistically different from TCM3 (P < 0.01). TCM1 (P < 0.05) and TCM3 (P < 0.01) were statistically different from TCM2. The median conversion times of fecal nucleic acid in the three groups were 7, 9 and 17 d (P < 0.001). Conversion times of fecal nucleic acid in TCM1 were statistically different from TCM3 and TCM2 (P < 0.01). The median lengths of hospital stay in the three groups were 13, 16 and 21 d (P < 0.001). TCM1 and TCM2 were statistically different from TCM3 (P < 0.01); TCM1 and TCM3 were statistically different from TCM2 (P < 0.01). Both leucocyte and lymphocyte counts increased gradually with an increase in the length of hospital stay in TCM1 group patients, with a statistically significant difference observed at each time point in the group (P < 0.001). Statistically significant differences in lymphocyte count and percentage in TCM2 (P < 0.001), and in leucocyte count (P = 0.043) and lymphocyte count (P = 0.038) in TCM3 were observed. The comparison among the three groups showed a statistically significant difference in lymphocyte percentage on the third day of admission (P = 0.044).

Conclusion: In this study, it was observed that in COVID-19 patients treated with a combination of Chinese and Western medicines, TCM intervention earlier in the hospital stay correlated with faster conversion time of pharyngeal swab and fecal nucleic acid, as well as shorter length of hospital stay, thus helping promote faster recovery of the patient. The underlying mechanism of action may be related to improving inflammation in patients with COVID-19.
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http://dx.doi.org/10.1016/j.joim.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7832636PMC
January 2021

Acute glucose influx-induced mitochondrial hyperpolarization inactivates myosin phosphatase as a novel mechanism of vascular smooth muscle contraction.

Cell Death Dis 2021 Feb 12;12(2):176. Epub 2021 Feb 12.

School of Aerospace Medicine, Fourth Military Medical University, Xi'an, 710032, China.

It is well-established that long-term exposure of the vasculature to metabolic disturbances leads to abnormal vascular tone, while the physiological regulation of vascular tone upon acute metabolic challenge remains unknown. Here, we found that acute glucose challenge induced transient increases in blood pressure and vascular constriction in humans and mice. Ex vivo study in isolated thoracic aortas from mice showed that glucose-induced vascular constriction is dependent on glucose oxidation in vascular smooth muscle cells. Specifically, mitochondrial membrane potential (ΔΨm), an essential component in glucose oxidation, was increased along with glucose influx and positively regulated vascular smooth muscle tone. Mechanistically, mitochondrial hyperpolarization inhibited the activity of myosin light chain phosphatase (MLCP) in a Ca-independent manner through activation of Rho-associated kinase, leading to cell contraction. However, ΔΨm regulated smooth muscle tone independently of the small G protein RhoA, a major regulator of Rho-associated kinase signaling. Furthermore, myosin phosphatase target subunit 1 (MYPT1) was found to be a key molecule in mediating MLCP activity regulated by ΔΨm. ΔΨm positively phosphorylated MYPT1, and either knockdown or knockout of MYPT1 abolished the effects of glucose in stimulating smooth muscle contraction. In addition, smooth muscle-specific Mypt1 knockout mice displayed blunted response to glucose challenge in blood pressure and vascular constriction and impaired clearance rate of circulating metabolites. These results suggested that glucose influx stimulates vascular smooth muscle contraction via mitochondrial hyperpolarization-inactivated myosin phosphatase, which represents a novel mechanism underlying vascular constriction and circulating metabolite clearance.
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http://dx.doi.org/10.1038/s41419-021-03462-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881016PMC
February 2021

Zebularine elevates STING expression and enhances cGAMP cancer immunotherapy in mice.

Mol Ther 2021 Feb 9. Epub 2021 Feb 9.

Fujian Key Laboratory of Innate Immune Biology, Biomedical Research Center of South China, College of Life Science, Fujian Normal University Qishan Campus, Fuzhou, Fujian Province 350117, China; Key Laboratory of OptoElectronic Science and Technology for Medicine of Ministry of Education, Fujian Normal University, Fuzhou, Fujian 350117, China. Electronic address:

DNA methylation abnormality is closely related to tumor occurrence and development. Chemical inhibitors targeting DNA methyltransferase (DNMTis) have been used in treating cancer. However, the impact of DNMTis on antitumor immunity has not been well elucidated. In this study, we show that zebularine (a demethylating agent) treatment of cancer cells led to increased levels of interferon response in a cyclic guanosine monophosphate-AMP (cGAMP) synthase (cGAS)- and stimulator of interferon genes (STING)-dependent manner. This treatment also specifically sensitized the cGAS-STING pathway in response to DNA stimulation. Incorporation of zebularine into genomic DNA caused demethylation and elevated expression of a group of genes, including STING. Without causing DNA damage, zebularine led to accumulation of DNA species in the cytoplasm of treated cells. In syngeneic tumor models, administration of zebularine alone reduced tumor burden and extended mice survival. This effect synergized with cGAMP and immune checkpoint blockade therapy. The efficacy of zebularine was abolished in nude mice and in cGAS or STING mice, indicating its dependency on host immunity. Analysis of tumor cells indicates upregulation of interferon-stimulated genes (ISGs) following zebularine administration. Zebularine promoted infiltration of CD8 T cells and natural killer (NK) cells into tumor and therefore suppressed tumor growth. This study unveils the role of zebularine in sensitizing the cGAS-STING pathway to promote anti-tumor immunity and provides the foundation for further therapeutic development.
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http://dx.doi.org/10.1016/j.ymthe.2021.02.005DOI Listing
February 2021

Detection of Carboxylesterase 1 and Chlorpyrifos with ZIF-8 Metal-Organic Frameworks Using a Red Emission BODIPY-Based Probe.

ACS Appl Mater Interfaces 2021 Feb 11;13(7):8718-8726. Epub 2021 Feb 11.

School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, Jiangsu 210023, China.

In this work, a red emission fluorescent probe CBZ-BOD@zeolitic imidazolate framework-8 (ZIF-8) was fabricated based on metal-organic frameworks (MOFs) for detecting carboxylesterase 1 (CES1). The small molecule probe CBZ-BOD was first synthesized and then used to prepare the functionalized MOF material. ZIF-8 was chosen as an encapsulation shell to improve the detection properties of CBZ-BOD. Using this unique porous materials, ultrasensitive quantification of CES1 and chlorpyrifos was successfully realized. The low detection limit and high fluorescence quantum yield were calculated as 1.15 ng/mL and 0.65 for CBZ-BOD@ZIF-8, respectively. CBZ-BOD@ZIF-8 has good biocompatibility and was successfully applied to monitor the activity of CES1 in living cells. A molecular docking study was used to explore the binding of CES1 and CBZ-BOD, finding that CES1 can bind with the probe before and after hydrolysis. This type of materialized probe can inspire the development of fluorescent tools for further exploration of many pathological processes.
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http://dx.doi.org/10.1021/acsami.0c19811DOI Listing
February 2021

Multi-Layered, Corona Charged Melt Blown Nonwovens as High Performance PM Air Filters.

Polymers (Basel) 2021 Feb 4;13(4). Epub 2021 Feb 4.

Engineering Research Center of Technical Textiles, Ministry of Education, College of Textiles, Donghua University, Shanghai 201620, China.

Particulate matter (PM) and airborne viruses bring adverse influence on human health. As the most feasible way to prevent inhalation of these pollutants, face masks with excellent filtration efficiency and low press drop are in urgent demand. In this study, we report a novel methodology for producing high performance air filter by combining melt blown technique with corona charging treatment. Changing the crystal structure of polypropylene by adding magnesium stearate can avoid charge escape and ensure the stability of filtration performances. Particularly, the influence of fiber diameter, pore size, porosity, and charge storage on the filtration performances of the filter are thoroughly investigated. The filtration performances of the materials, including the loading test performance are also studied. The melt blown materials formed by four layers presented a significant filtration efficiency of 97.96%, a low pressure drop of 84.28 Pa, and a high quality factor (QF) of 0.046 Pa for paraffin oil aerosol particles. Meanwhile, a robust filtration efficiency of 99.03%, a low pressure drop of 82.32 Pa, and an excellent QF of 0.056 Pa for NaCl aerosol particles could be easily achieved. The multi-layered melt blown filtration material developed here would be potentially applied in the field of protective masks.
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http://dx.doi.org/10.3390/polym13040485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913826PMC
February 2021

Biomimetic inorganic-organic hybrid nanoparticles from magnesium-substituted amorphous calcium phosphate clusters and polyacrylic acid molecules.

Bioact Mater 2021 Aug 23;6(8):2303-2314. Epub 2021 Jan 23.

Institute of Metal Research, Chinese Academy of Sciences, Shenyang, Liaoning, 110016, China.

Amorphous calcium phosphate (ACP) has been widely found during bone and tooth biomineralization, but the meta-stability and labile nature limit further biomedical applications. The present study found that the chelation of polyacrylic acid (PAA) molecules with Ca ions in Mg-ACP clusters (~2.1 ± 0.5 nm) using a biomineralization strategy produced inorganic-organic Mg-ACP/PAA hybrid nanoparticles with better thermal stability. Mg-ACP/PAA hybrid nanoparticles (~24.0 ± 4.8 nm) were pH-responsive and could be efficiently digested under weak acidic conditions (pH 5.0-5.5). The internalization of assembled Mg-ACP/PAA nanoparticles by MC3T3-E1 cells occurred through endocytosis, indicated by laser scanning confocal microscopy and cryo-soft X-ray tomography. Our results showed that cellular lipid membranes remained intact without pore formation after Mg-ACP/PAA particle penetration. The assembled Mg-ACP/PAA particles could be digested in cell lysosomes within 24 h under weak acidic conditions, thereby indicating the potential to efficiently deliver encapsulated functional molecules. Both the and results preliminarily demonstrated good biosafety of the inorganic-organic Mg-ACP/PAA hybrid nanoparticles, which may have potential for biomedical applications.
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http://dx.doi.org/10.1016/j.bioactmat.2021.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841502PMC
August 2021

Therapeutic Effects and Mechanisms of Hydroxyasiaticoside Combined With Praziquantel in the Treatment of Schistosomiasis Induced Hepatic Fibrosis.

Front Bioeng Biotechnol 2020 22;8:613784. Epub 2021 Jan 22.

Department of Trauma and Reconstructive Surgery, Rheinisch-Westfälische Technische Hochschule Aachen University Hospital, Aachen, Germany.

Schistosomiasis has been a fatal obstinate disease that threatens global human health, resulting in the granulomatous inflammation and liver fibrosis. The aim of this study was to evaluate the therapeutic effects and mechanisms of hydroxyasiaticoside combined with praziquantel in the treatment of schistosomiasis-induced liver fibrosis. Mice were randomly distributed into four experimental groups: normal control group, model group, praziquantel group, praziquantel + hydroxyasiaticoside group. Except for the normal control group, they were infected with through the abdominal skin to induce liver fibrosis. In the intervention group, mice were administered with the respective drugs by gavage after 8 weeks of infection. At the end of the treatment, mice were sacrificed to collect blood for the determination of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) serum levels. Moreover, the liver was excised, weighed, and liver indices were calculated. Histopathological examination was performed to assess liver morphology. Besides, the expression of collagen type I and III in liver was determined; the mRNA expression levels of IL-6 and TNF-α in liver tissues were measured using Real-time PCR while ELISA and western blotting were performed on liver tissue homogenate to determine the protein expression of IL-6 and TNF-α. The combination of praziquantel and hydroxyasiaticoside lowered the pathological scores of schistosomiasis-induced hepatic fibrosis, the liver indice, serum AST and ALT levels, improved liver morphology, downregulated the expression levels of hepatic type I and III collagen, inhibited the mRNA expression levels of pro-inflammatory factors (IL-6 and TNF-α) in the liver of mice relative to the praziquantel alone. The combination of hydroxyasiaticoside and praziquantel is a potential therapeutic option for schistosomiasis-induced hepatic fibrosis. Notably, this combination noticeably suppresses the protein and mRNA expression levels of pro-inflammatory factors (TNF-α and IL-6) in the liver.
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http://dx.doi.org/10.3389/fbioe.2020.613784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862569PMC
January 2021

The Impact of Unplanned Excision on the Outcomes of Patients With Soft Tissue Sarcoma of the Trunk and Extremity: A Propensity Score Matching Analysis.

Front Oncol 2020 22;10:617590. Epub 2021 Jan 22.

State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.

Background: Unplanned excision (UPE) of soft tissue sarcoma (STS) is often chosen in the early phase by general physicians without any radiological evaluation.

Purpose: The present study aimed to evaluate the impact of UPE on the clinical outcomes of patients with STS of the trunk and extremity.

Materials And Methods: Patients with STS of the trunk and extremity who underwent R0 resection between 1998 and 2016 were included and divided into the UPE and planned excision (PE) groups. Propensity score matching (PSM) was used to control the selection bias. The endpoints were disease-specific survival (DSS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS).

Results: In total, 458 patients (277 males, 181 females; median age: 43 years) were included: 329 (71.8%) in the PE group and 129 (28.2%) in the UPE group. The follow-up time ranged from 7.1 to 313.78 months, with a median of 112.18 months. UPE patients were more likely to have a smaller or superficial lesion and were more frequently administered adjuvant therapy. After PSM, compared with the PE group, the UPE group had a longer LRFS (P=0.015), but there was no difference between the two groups regarding DSS and MFS. Residual disease was observed in 77.5% of the re-resected specimens in the UPE group and was a risk factor for DSS (P = 0.046) and MFS (P = 0.029) but was not associated with local recurrence (LR) (P=0.475) or LRFS (P=0.334). Moreover, we found no difference in DSS, LRFS or MFS according to the interval from UPE to definitive resection.

Conclusion: STS treated with UPE had distinct characteristics. Patients who undergo UPE followed by an additional wide R0 resection have similar oncological survival compared to patients who undergo an initial PE, although the high incidence of residual tumor in the UPE group leads to an unfavorable clinical course.
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http://dx.doi.org/10.3389/fonc.2020.617590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862753PMC
January 2021

DNA-templated silver nanoclusters as an efficient catalyst for reduction of nitrobenzene derivatives: a systematic study.

Nanotechnology 2021 May;32(19):195705

School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Wenyuan Road 1, Nanjing 210023, People's Republic of China.

Nitrobenzene compounds are highly toxic pollutants with good stability, and they have a major negative impact on both human health and the ecological environment. Herein, it was found for the first time that fluorescent DNA-silver nanoclusters (DNA-AgNCs) can catalyze the reduction of toxic and harmful nitro compounds into less toxic amino compounds with excellent tolerance to high temperature and organic solvents. In this study, the reduction of p-nitrophenol (4-NP) as a model was systematically investigated, followed by expending the substrate to disclose the versatility of this reaction. This report not only expanded the conditions for utilizing catalytic reduction conditions of DNA-AgNCs as an efficient catalyst in the control of hazardous chemicals but also widened the substrate range of DNA-AgNCs reduction, providing a new angle for the application of noble metal nanoclusters.
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http://dx.doi.org/10.1088/1361-6528/abe3b4DOI Listing
May 2021

Excess sarcoplasmic reticulum-mitochondria calcium transport induced by Sphingosine-1-phosphate contributes to cardiomyocyte hypertrophy.

Biochim Biophys Acta Mol Cell Res 2021 Jan 30;1868(5):118970. Epub 2021 Jan 30.

The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Institute of Health and Rehabilitation Science, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China. Electronic address:

Sphingosine-1-phosphate (S1P) has been shown to possess pro-hypertrophic properties in the heart, but the detailed molecular mechanism that underlies the pathological process is rarely explored. In the present study, we aim to explore the role of S1P-mediated intracellular Ca signaling, with a focus on sarcoplasmic reticulum (SR)-mitochondria communication, in cardiomyocyte hypertrophy. Cultured neonatal rat ventricular myocytes (NRVMs) displayed significantly hypertrophic growth after treatment with 1 μmol/L S1P for 48 h, as indicated by the cell surface area or mRNA expressions of hypertrophic marker genes (ANP, BNP and β-MHC). Importantly, mitochondrial Ca and reactive oxygen species (ROS) levels were dramatically elevated upon S1P stimulation, and pharmacological blockage of which abolished NRVM hypertrophy. 0.5 Hz electrical pacing induced similar cytosolic Ca kinetics to S1P stimulation, but unaffected the peak of mitochondrial [Ca]. With interference of the expression of type 2 inositol 1,4,5-trisphosphate receptors (IPR2), which are unemployed in electrical paced Ca activity but may be activated by S1P, alteration in mitochondrial Ca as well as the hypertrophic effect in NRVMs under S1P stimulation were attenuated. The hypertrophic effect of S1P can also be abolished by pharmacological block of S1PR1 or Gi signaling. Collectively, our study highlights the mechanistic role of IPR2-mediated excess SR-mitochondria Ca transport in S1P-induced cardiomyocyte hypertrophy.
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http://dx.doi.org/10.1016/j.bbamcr.2021.118970DOI Listing
January 2021

Signal-Amplified Detection of the Tumor Biomarker FEN1 Based on Cleavage-Induced Ligation of a Dumbbell DNA Probe and Rolling Circle Amplification.

Anal Chem 2021 Feb 2;93(6):3287-3294. Epub 2021 Feb 2.

School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing 210023, China.

Flap endonuclease 1 (FEN1), an endogenous nuclease with the ability to cleave the 5' overhang of branched dsDNA, is of significance in DNA replication and repair. The overexpression of FEN1 is common in cancer because of the ubiquitous upregulation of DNA replication; thus, FEN1 has been recognized as a potential biomarker in oncological investigations. However, few analytical methods targeting FEN1 with high sensitivity and simplicity have been developed. This work developed a signal-amplified detection of FEN1 based on the cleavage-induced ligation of a dumbbell DNA probe and rolling circle amplification (RCA). A flapped dumbbell DNA probe (FDP) was rationally designed with a FEN1 cleavable flap at the 5' end. The cleavage generated a nick site with juxtaposed 5' phosphate and 3' hydroxyl ends, which were linkable by T4 DNA ligase to form a closed dumbbell DNA probe (CDP) with a circular conformation. The CDP functioned as a template for RCA, which produced abundant DNA that could be probed using SYBR Green I. The highly sensitive detection of FEN1 with a limit of detection of 15 fM was achieved, and this method showed high specificity, which enabled the quantification of FEN1 in real samples. The inhibitory effects of chemicals on FEN1 were also evaluated. This study represents the first attempt to develop an FEN1 assay that involves signal amplification, and the novel biosensor method enriches the tools for FEN1-based diagnostics.
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http://dx.doi.org/10.1021/acs.analchem.0c05275DOI Listing
February 2021

Investor attention and cryptocurrency: Evidence from the Bitcoin market.

PLoS One 2021 1;16(2):e0246331. Epub 2021 Feb 1.

College of Economics, Shenzhen University, Shenzhen, Guangdong, China.

This paper adds to the growing literature of cryptocurrency and behavioral finance. Specifically, we investigate the relationships between the novel investor attention and financial characteristics of Bitcoin, i.e., return and realized volatility, which are the two most important characteristics of one certain asset. Our empirical results show supports in the behavior finance area and argue that investor attention is the granger cause to changes in Bitcoin market both in return and realized volatility. Moreover, we make in-depth investigations by exploring the linear and non-linear connections of investor attention on Bitcoin. The results indeed demonstrate that investor attention shows sophisticated impacts on return and realized volatility of Bitcoin. Furthermore, we conduct one basic and several long horizons out-of-sample forecasts to explore the predictive ability of investor attention. The results show that compared with the traditional historical average benchmark model in forecasting technologies, investor attention improves prediction accuracy in Bitcoin return. Finally, we build economic portfolios based on investor attention and argue that investor attention can further generate significant economic values. To sum up, investor attention is a non-negligible pricing factor for Bitcoin asset.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0246331PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850507PMC
February 2021

Fluorometric detection of cancer marker FEN1 based on double-flapped dumbbell DNA nanoprobe functionalized with silver nanoclusters.

Anal Chim Acta 2021 Mar 4;1148:238194. Epub 2021 Jan 4.

School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, 210023, China. Electronic address:

Flap endonuclease 1 (FEN1), a ubiquitous enzyme involved in DNA repair and replication, is overexpressed in highly proliferative cancer cells. FEN1 has been recognized as a promising diagnostic marker of cancers; however, very few analytical techniques have been developed for the convenient detection of FEN1. To realize the simplified quantification of FEN1, we developed a FEN1-responsive fluorescent nanoprobe based on DNA-silver nanoclusters (DNA-AgNCs). The nanoprobe was rationally designed with a double-flapped dumbbell conformation, where its 5' flap was produced with DNA-AgNCs, and the 3' flap was elongated by a guanine-rich enhancer sequence (GRS). Rigidified by the DNA scaffold, DNA-AgNCs and the GRS are in close proximity, resulting in high fluorescence because of the GRS-induced activation of DNA-AgNCs. Upon the addition of FEN1, the 5' flap of the nanoprobe is cleaved due to the structure-specific endonuclease activity of FEN1. This cleavage released the DNA-AgNCs from the nanoprobe, broke the proximity between DNA-AgNCs and the GRS, and caused decreased fluorescence. This nanoprobe can be applied in the sensitive detection of FEN1 with a detection limit of 40 fM, and it showed high specificity for the monitoring of FEN1 in clinical samples. As the first attempt to develop biosensors targeting FEN1 based on DNA-AgNCs, this work provided a potent platform for monitoring FEN1 and screening FEN1 inhibitors.
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http://dx.doi.org/10.1016/j.aca.2020.12.069DOI Listing
March 2021

Single-cell transcriptomics reveal the intratumoral landscape of infiltrated T cell subpopulations in oral squamous cell carcinoma.

Mol Oncol 2021 Jan 29. Epub 2021 Jan 29.

Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.

Systematic analysis of tumor-infiltrating lymphocytes is essential for the development of new cancer treatments and the prediction of clinical responses to immunotherapy. Immunomodulatory drugs are used for the treatment of oral squamous cell carcinoma (OSCC), depending on immune infiltration profiles of the tumor microenvironment. In this study, we isolated 11,866 single T cells from tumors and paired adjacent normal tissues of three patients with OSCC. Using single-cell RNA sequencing, we identified 14 distinct T-cell subpopulations within the tumors and 5 T-cell subpopulations in the adjacent normal tissues, and delineated their developmental trajectories. Exhausted CD8 T cells and regulatory CD4 T cells (CD4 Tregs) were enriched in OSCC tumors, potentially linked to tumor immunosuppression. Programmed death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) were identified as marker genes in exhausted CD8 T cells, whereas forkhead box P3 (FOXP3) and CTLA4 were identified as markers of CD4 Tregs. Furthermore, our data revealed that thymocyte selection associated high mobility group box (TOX) may be a key regulator of T cell dysfunction in the OSCC microenvironment. Overexpression of TOX upregulated expression of genes related to T-cell dysfunction. In vitro experiments demonstrated that cytotoxic activity and proliferation efficiency of CD8 T cells overexpressing PD-1 or TOX were reduced. Notable, the transcription factor PRDM1 was found to transactivate TOX expression via a binding motif in the TOX promoter. Our findings provide valuable insight into the functional states and heterogeneity of T cell populations in OSCC that could advance the development of novel therapeutic strategies.
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http://dx.doi.org/10.1002/1878-0261.12910DOI Listing
January 2021

Improved Safety and Anti-Glioblastoma Efficacy of CAT3-Encapsulated SMEDDS through Metabolism Modification.

Molecules 2021 Jan 18;26(2). Epub 2021 Jan 18.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.

13-()-3-pivaloyloxyl-6,7-dimethoxyphenanthro(9,10-)-indolizidine (CAT3) is a novel oral anti-glioma pro-drug with a potent anti-tumor effect against temozolomide-resistant glioma. 13()-3-hydroxyl-6,7-dimethoxyphenanthro(9,10-)-indolizidine (PF403) is the active in vivo lipase degradation metabolite of CAT3. Both CAT3 and PF403 can penetrate the blood-brain barrier to cause an anti-glioma effect. However, PF403, which is produced in the gastrointestinal tract and plasma, causes significant gastrointestinal side effects, limiting the clinical application of CAT3. The objective of this paper was to propose a metabolism modification for CAT3 using a self-microemulsifying drug delivery system (SMEDDS), in order to reduce the generation of PF403 in the gastrointestinal tract and plasma, as well as increase the bioavailability of CAT3 in vivo and the amount of anti-tumor substances in the brain. Thus, a CAT3-loaded self-microemulsifying drug delivery system (CAT3-SMEDDS) was prepared, and its physicochemical characterization was systematically carried out. Next, the pharmacokinetic parameters of CAT3 and its metabolite in the rats' plasma and brain were measured. Furthermore, the in vivo anti-glioma effects and safety of CAT3-SMEDDS were evaluated. Finally, Caco-2 cell uptake, MDCK monolayer cellular transfer, and the intestinal lymphatic transport mechanisms of SMEDDS were investigated in vitro and in vivo. Results show that CAT3-SMEDDS was able to form nanoemulsion droplets in artificial gastrointestinal fluid within 1 min, displaying an ideal particle size (15-30 nm), positive charge (5-9 mV), and controlled release behavior. CAT3-SMEDDS increased the membrane permeability of CAT3 by 3.9-fold and promoted intestinal lymphatic transport. Hence, the bioavailability of CAT3 was increased 79% and the level of its metabolite, PF403, was decreased to 49%. Moreover, the concentrations of CAT3 and PF403 were increased 2-6-fold and 1.3-7.2-fold, respectively, in the brain. Therefore, the anti-glioma effect in the orthotopic models was improved with CAT3-SMEDDS compared with CAT3 in 21 days. Additionally, CAT3-SMEDDS reduced the gastrointestinal side effects of CAT3, such as severe diarrhea, necrosis, and edema, and observed less inflammatory cell infiltration in the gastrointestinal tract, compared with the bare CAT3. Our work reveals that, through the metabolism modification effect, SMEDDS can improve the bioavailability of CAT3 and reduce the generation of PF403 in the gastrointestinal tract and plasma. Therefore, it has the potential to increase the anti-glioma effect and reduce the gastrointestinal side effects of CAT3 simultaneously.
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http://dx.doi.org/10.3390/molecules26020484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7831126PMC
January 2021

circRNA_0005529 facilitates growth and metastasis of gastric cancer via regulating miR-527/Sp1 axis.

BMC Mol Cell Biol 2021 Jan 20;22(1). Epub 2021 Jan 20.

Department of Emergency, Huai'an Hospital Affiliated of Xuzhou Medical University and Huai'an Second People's Hospital, No. 62 Huaihai South Road, Huai 'an City, Jiangsu Province, China.

Background: Circular RNAs (circRNAs) are endogenous non-coding RNAs, which are associated with various biological processes, including microRNA (miRNA) interaction, protein binding and regulatory splicing. circRNA_0005529 (circ_0005529) is derived from vacuolar protein sorting 33 homologue B (VPS33B), and its biological role in gastric cancer (GC) has not been examined. In this study, the expression and location of circ_0005529 and microRNA-527 (miR-527) were determined by qRT-PCR and fluorescence in situ hybridization (FISH). Cell proliferation and cell migration were determined by MTT, EdU incorporation, colony formation, wound scratch and transwell assays. In addition, immunohistochemistry and western blotting were performed to determine the expressions of specificity protein 1 (Sp1), PCNA, c-myc, E-cadherin and N-cadherin. Western blotting and luciferase reporter assay were performed to study the interaction between circ_0005529 and miR-527 or miR-527 and Sp1. The functional effects of circ_0005529 on GC through regulating Sp1 were further evaluated using xenograft and metastatic mouse models in vivo.

Results: Our results showed that circ_0005529 was upregulated in GC tissues and cells, and had promoting effects on cell proliferation and cell migration. Mechanism analysis suggested that circ_0005529 could bind to microRNA-527 (miR-527) and reduce its expression. The interaction between miR-527 and Sp1 in GC was systematically studied. In addition, the results indicated that Sp1 upregulation could rescue the effects on cell proliferation and migration caused by circ_0005529. Moreover, the inhibitory effects of circ_0005529 downregulation on GC growth and metastasis were evaluated in mouse models. These findings suggested that the axis of circ_0005529/miR-527/Sp1 may serve as a promising treatment target for GC diagnosis and treatment.

Conclusions: These findings suggested that the signal axis of circ_0005529/miR-527/Sp1 may has the potential to be explored as a novel therapeutic target for GC diagnosis and treatment. Mechanism diagram: During GC development, overexpressed circ_0005529 sponged miR-527 and then upregulated the expression of Sp1. Subsequently, epithelial-mesenchymal transition (EMT), cell proliferation and cell migration were promoted, which ultimately facilitated the tumor metastasis.
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http://dx.doi.org/10.1186/s12860-020-00340-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816457PMC
January 2021