Publications by authors named "Yuying Li"

172 Publications

Therapeutic effect of osimertinib plus cranial radiotherapy compared to osimertinib alone in NSCLC patients with EGFR-activating mutations and brain metastases: a retrospective study.

Radiat Oncol 2021 Dec 5;16(1):233. Epub 2021 Dec 5.

Shantou University Medical College, Shantou, 515041, Guangdong Province, China.

Background: The study aimed to compare the efficacy of osimertinib plus cranial radiotherapy (RT) with osimertinib alone in advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations and brain metastases (BMs).

Methods: The clinical data of advanced NSCLC patients with BMs who received osimertinib were retrospectively collected. The patients were assigned to one of the two groups according to the therapeutic modality used: the osimertinib monotherapy group or the osimertinib plus RT group.

Results: This was a retrospective study and 61 patients were included from December 2015 to August 2020. Forty patients received osimertinib monotherapy, and twenty-one patients received osimertinib plus RT. Radiotherapy included whole-brain radiation therapy (WBRT, n = 14), WBRT with simultaneous integrated boost (WBRT-SIB, n = 5) and stereotactic radiosurgery (SRS, n = 2). The median number of prior systemic therapies in the two groups was one. Intracranial and systemic ORR and DCR were not significantly different between the two groups. No difference in iPFS was observed between the two groups (median iPFS: 16.67 vs. 13.50 months, P = 0.836). The median OS was 29.20 months in the osimertinib plus RT group compared with 26.13 months in the osimertinib group (HR = 0.895, P = 0.826). In the L858R mutational subgroup of 31 patients, the osimertinib plus RT group had a longer OS (P = 0.046). In the exon 19 deletion mutational subgroup of 30 patients, OS in the osimertinib alone group was longer than that in the osimertinib plus RT group (P = 0.011). The incidence of any-grade adverse events was not significantly different between the osimertinib plus RT group and the osimertinib alone group (47.6% vs. 32.5%, P = 0.762). However, six patients (28.5%) experienced leukoencephalopathy in the osimertinib plus RT group, and 50% (3/6) of the leukoencephalopathy was greater than or equal to grade 3.

Conclusion: The therapeutic effect of osimertinib with RT was similar to that of osimertinib alone in EGFR-positive NSCLC patients with BM. However, for patients with the L858R mutation, osimertinib plus RT could provide more benefit than osimertinib alone.
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http://dx.doi.org/10.1186/s13014-021-01955-7DOI Listing
December 2021

Characteristics of the Phytoplankton Community Structure and Water Quality Evaluation in Autumn in the Huaihe River (China).

Int J Environ Res Public Health 2021 11 18;18(22). Epub 2021 Nov 18.

International Joint Laboratory of Watershed Ecological Security and Collaborative Innovation Center of Water Security for Water Source Region of Middle Route Project of South-North Water Diversion in Henan Province, College of Water Resource and Environment Engineering, Nanyang Normal University, Nanyang 473061, China.

As an important indicator of phytoplankton in water quality evaluation, the phytoplankton community structure is very sensitive to changes in water quality, and analyzing their community composition and function is of great significance for the ecological management and maintenance of watershed environments. To understand the environment and ecological status as well as reconstruct or restore a healthy aquatic ecosystem in the Huaihe River Basin in China, a comprehensive phytoplankton survey was conducted in the main stream and main tributaries of the Huaihe River in 2019. A total of 266 species or genera of phytoplankton were identified, mainly belonging to Bacillariophyta and Chlorophyta. The number of phytoplankton species upstream and downstream was higher than that in the middle. The results of phytoplankton biomass showed significant spatial differences in different river reaches ( < 0.05). The identified phytoplankton functional groups (FGs) were divided into 27 groups, including 16 representative functional groups (RFGs), followed by A, B, F, G, H1, J, K, L, L, M, MP, P, T, T, W and X2. The mean values of the Shannon-Wiener index and Margalef index were 2.47 and 2.50, respectively, showing that most of the water in the Huaihe River Basin was in a state of moderate nutritional status. The results of this study provided a reference for studying the composition and distribution of phytoplankton communities, nutrient status, and pollution levels in the Huaihe River Basin, as well as in other similar watersheds.
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http://dx.doi.org/10.3390/ijerph182212092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8619162PMC
November 2021

Fibroblast growth factor 21 associating with serotonin and dopamine in the cerebrospinal fluid predicts impulsivity in healthy subjects.

BMC Neurosci 2021 Nov 20;22(1):68. Epub 2021 Nov 20.

The Affiliated Kangning Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.

Background: Impulsivity is more commonly reported in subjects with mental disorders compared to healthy subjects, suggesting a potential application of impulsivity in predicting impulsivity-related mental disorders. However, no biomarker of impulsivity available so far. This study explored the association between cerebrospinal fluid (CSF) fibroblast growth factor 21 (FGF21), a key hormonal mediator of the stress response, and impulsivity in healthy subjects.

Methods: A total of 126 healthy persons subjected to surgery of anterior cruciate ligament were recruited in the present study. The impulsiveness of the subjects was evaluated by the Chinese version of the Barratt Impulsiveness Scale (BIS)-11 before surgery. CSF and blood samples of the subjects were collected before spinal anesthesia for surgery. The levels of FGF21, serotonin and dopamine in CSF and the level of FGF21 in blood of the subjects were measured by ELISA using commercial kits.

Results: Negative correlations were found between BIS-11 total score and either FGF21, serotonin or dopamine in CSF. However, BIS-11 total score was not correlated with FGF21 in blood. In addition, FGF21 was positively correlated with serotonin and dopamine in CSF, respectively. Multivariable linear regression models indicated that the decrease of FGF21 level associating with the decrease of serotonin and dopamine level in CSF contributed to the higher impulsivity. Furthermore, receiver operating characteristic curve (ROC) analysis indicated an important role of CSF FGF21 predicting high impulsivity.

Conclusions: FGF21, serotonin and dopamine in CSF associate with impulsivity in opposite directions. The decrease of CSF FGF21 is related to higher impulsivity, and indicate that CSF FGF21 may predict impulsivity in healthy subjects.
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http://dx.doi.org/10.1186/s12868-021-00676-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8605581PMC
November 2021

Facile Construction of Bio-Based Supramolecular Hydrogels from Dehydroabietic Acid with a Tricyclic Hydrophenanthrene Skeleton and Stabilized Gel Emulsions.

Molecules 2021 Oct 28;26(21). Epub 2021 Oct 28.

College of Chemical Engineering, Huaqiao University, Xiamen 361021, China.

Supramolecular hydrogels have attracted great attention due to their special properties. In this research, bio-based supramolecular hydrogels were conveniently constructed by heating and ultrasounding two components of dehydroabietic acid with a rigid tricyclic hydrophenanthrene skeleton and morpholine. The microstructures and properties of hydrogels were investigated by DSC, rheology, SAXS, CD spectroscopy, and cryo-TEM, respectively. The critical gel concentration (CGC) of the hydrogel was 0.3 mol·L and the gel temperature was 115 °C. In addition, the hydrogel showed good stability and mechanical properties according to rheology results. Cryo-TEM images reveal that the microstructure of hydrogel is fibrous meshes; its corresponding mechanism has been studied using FT-IR spectra. Additionally, oil-in-water gel emulsions were prepared by the hydrogel at a concentration above its CGC, and the oil mass fraction of the oil-in-water gel emulsions could be freely adjusted between 5% and 70%. This work provides a convenient way to prepare bio-based supramolecular hydrogels and provides a new method for the application of rosin.
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http://dx.doi.org/10.3390/molecules26216526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586928PMC
October 2021

Inducible Enrichment of Osa-miR1432 Confers Rice Bacterial Blight Resistance through Suppressing .

Int J Mol Sci 2021 Oct 21;22(21). Epub 2021 Oct 21.

Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.

MicroRNAs (miRNAs) handle immune response to pathogens by adjusting the function of target genes in plants. However, the experimentally documented miRNA/target modules implicated in the interplay between rice and pv. () are still in the early stages. Herein, the expression of osa-miR1432 was induced in resistant genotype IRBB5, but not susceptible genotype IR24, under strain PXO86 attack. Overexpressed osa-miR1432 heightened rice disease resistance to , indicated by enhancive enrichment of defense marker genes, raised reactive oxygen species (ROS) levels, repressed bacterial growth and shortened leaf lesion length, whilst the disruptive accumulation of osa-miR1432 accelerated rice susceptibility to infection. Noticeably, () was experimentally confirmed as a target gene of osa-miR1432, and the overexpressing transgenic plants exhibited compromised resistance to infestation. Our results indicate that osa-miR1432 and were differently responsive to invasion at the transcriptional level and fine-tune rice resistance to infection, which may be referable in resistance gene discovery and valuable in the pursuit of improving resistance in rice breeding.
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http://dx.doi.org/10.3390/ijms222111367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583624PMC
October 2021

Exudative pleural effusion caused by lung fluke infection: case report.

Int J Infect Dis 2021 Nov 7;114:175-177. Epub 2021 Nov 7.

Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China. Electronic address:

The global incidence of lung fluke disease is low, and the infection is a rare cause of pleural effusion in adults. This article reports a case of exudative pleural effusion accompanied by eosinophilia in a 19-year-old male which was finally proven to be caused by lung fluke infection through antibody testing. This case highlights that lung fluke infection is an easily overlooked cause of pleural effusion. Eosinophilia is a potential marker of infection, and serological tests could further confirm the diagnosis.
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http://dx.doi.org/10.1016/j.ijid.2021.11.005DOI Listing
November 2021

NK cell tumor therapy modulated by UV-inactivated oncolytic herpes simplex virus type 2 and checkpoint inhibitors.

Transl Res 2021 Oct 29. Epub 2021 Oct 29.

National "111" Centre for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Provincial Cooperative Innovation Centre of Industrial Fermentation, Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan 430068, China. Electronic address:

Oncolytic virotherapy is a new and safe therapeutic strategy for cancer treatment. In our previous study, a new type of oncolytic herpes simplex virus type 2 (oHSV2) was constructed. Following the completion of a preclinical study, oHSV2 has now entered into clinical trials for the treatment of melanoma and other solid tumors (NCT03866525). Oncolytic viruses (OVs) are generally able to directly destroy tumor cells and stimulate the immune system to fight tumors. Natural killer (NK) cells are important components of the innate immune system and critical players against tumor cells. But the detailed interactions between oncolytic viruses and NK cells and these interaction effects on the antitumor immune response remain to be elucidated. In particular, the functions of activating surface receptors and checkpoint inhibitors on oHSV2-treated NK cells and tumor cells are still unknown. In this study, we found that UV-oHSV2 potently activates human peripheral blood mononuclear cells, leading to increased antitumor activity in vitro and in vivo. Further investigation indicated that UV-oHSV2-stimulated NK cells release IFN-γ via Toll-like receptor 2 (TLR2)/NF-κB signaling pathway and exert antitumor activity via TLR2. We found for the first time that the expression of a pair of checkpoint molecules, NKG2A (on NK cells) and HLA-E (on tumor cells), is upregulated by UV-oHSV2 stimulation. Anti-NKG2A and anti-HLA-E treatment could further enhance the antitumor effects of UV-oHSV2-stimulated NK92 cells in vitro and in vivo. As our oHSV2 clinical trial is ongoing, we expect that the combination therapy of oncolytic virus oHSV2 and anti-NKG2A/anti-HLA-E antibodies may have synergistic antitumor effects in our future clinical trials.
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http://dx.doi.org/10.1016/j.trsl.2021.10.006DOI Listing
October 2021

Evaluation of N, O-Benzamide difluoroboron derivatives as near-infrared fluorescent probes to detect β-amyloid and tau tangles.

Eur J Med Chem 2022 Jan 31;227:113968. Epub 2021 Oct 31.

Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing, 100875, China; Center for Advanced Materials Research, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai 519087, China. Electronic address:

β-Amyloid (Aβ) plaques and Tau tangles are cognitive impairment markers vital for diagnosing and preventing Alzheimer's disease (AD). To systematically explore the relationship between the number or position of nitrogen atoms and their optical properties and biological properties, five series of new N, O-coordinated organo-difluoroboron probes were introduced as binding scaffolds for Aβ plaques and Tau tangles. These probes exhibited suitable optical properties for near-infrared (NIR) imaging. Probe 4PmNO-2 (4-((1E,3E)-4-(1,1-difluoro-1H-1λ,9λ-pyrimido[1,6-c][1,3,5,2]oxadiazaborinin-3-yl)buta-1,3-dien-1-yl)-N,N-dimethylaniline) displayed the excellent emission maximum (716 nm in PBS), a high quantum yield (61.4% in CHCl), and a high affinity for synthetic Aβ (K = 23.64 ± 1.08 nM) and Tau (K18) aggregates (K = 26.38 ± 1.29 nM), as well as for native Aβ plaques and NFTs in the brain tissue from AD patients. 4PmNO-2, with significantly enhanced fluorescence (Aβ, 136 fold; Tau (K18), 96 fold) and the highest initial brain uptake (11.57% ID/g at 2 min) in normal ICR mice, was evaluated further. In vivo NIR fluorescent imaging studies in living Aβ and Tau transgenic mice revealed that it could differentiate healthy and diseased animals. Further ex vivo fluorescent staining studies showed that 4PmNO-2 specifically bound to Aβ plaques and Tau tangles in transgenic mice. In summary, the probe 4PmNO-2 may be a useful near-infrared fluorescence (NIRF) probe for AD biomarkers.
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http://dx.doi.org/10.1016/j.ejmech.2021.113968DOI Listing
January 2022

Transcription Factor TaWRKY51 Is a Positive Regulator in Root Architecture and Grain Yield Contributing Traits.

Front Plant Sci 2021 21;12:734614. Epub 2021 Oct 21.

College of Agronomy, Henan Agricultural University, Zhengzhou, China.

Wheat is one of the staple food crops. The utilization of elite genetic resources to develop resource-efficient wheat varieties is an effective approach to deal with the challenges of climate change and population growth. WRKY transcription factors (TFs) are multifaceted regulators of plant growth and development and response to environmental stress. The previous studies have shown that TaWRKY51 positively regulates the development of lateral roots, while its roles in agronomic trait development are not clear, and there is no functional marker for molecular breeding. To bridge the gap, we cloned the three members of and found they were highly expressed in the roots and flag leaves at the flowering stage and were induced by the multiple abiotic stresses and phytohormones. The highest expression level was observed in , followed by and . The two haplotypes/alleles for each member were identified in the natural populations, and functional markers were developed accordingly. The association assays revealed that -2A-I was an elite haplotype for the large spike, -2B-II and allele-G were favorable haplotypes/alleles for long root. However, only -2A-I was selected for wheat breeding in China. The results of transgenic experiments showed that the rice lines overexpressing had large panicle, high thousand-grain-weight, and more crown and lateral roots, which further confirmed the results of association analysis. In short, is a positive regulator of the root architecture and grain yield (GY) contributing traits. The elite gene resources and functional markers may be utilized in the marker-assisted selection for high-yield breeding in wheat.
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http://dx.doi.org/10.3389/fpls.2021.734614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8567066PMC
October 2021

Identification and functional study of FOXC1 variants in Chinese families with glaucoma.

Am J Med Genet A 2021 Nov 6. Epub 2021 Nov 6.

Birth Defect Group, Clinical Research Center for Mental Disorders, Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University, Shanghai, China.

This study aimed to identify the disease-causing gene of three Chinese families with glaucoma. Whole exome sequencing was performed on the probands and detected three different variants (c.405C>A (p.Cys135Ter), c.851G>T (p.Ser284Ile), and c.392C>T (p.Ser131Leu)) in FOXC1 as a causative gene of glaucoma, and Sanger sequencing was performed for verification and cosegregation analysis. Three in silico tools all predicted these two missense variants to be probably disease-causing. Western blot analysis, immunofluorescence, and dual-luciferase assay were further used to evaluate the effect of FOXC1 missense variants, and demonstrated that the two variants resulted in decreased transactivation activity of FOXC1 although the variants had no effect on the protein amount and the nucleus subcellar localization of FOXC1 compared with the wild type, which implies that both of two variants may be probably pathogenic. In this study, we reported two novel FOXC1 variants as well as a reported variant and the phenotypes associated to these variants, which expands the spectrum and relevant phenotypes of FOXC1 variants. Additionally, the functional analysis of FOXC1 variants provides further insight into the possible pathogenesis of anterior segment anomaly related to FOXC1.
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http://dx.doi.org/10.1002/ajmg.a.62551DOI Listing
November 2021

Hepatic P38 Activation Modulates Systemic Metabolism Through Fgf21-Mediated Interorgan Communication.

Diabetes 2021 Oct 21. Epub 2021 Oct 21.

CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of 1CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Sciences; Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China;

The mechanisms underlying the pathogenesis of steatosis and insulin resistance in nonalcoholic fatty liver disease remain elusive. Increased phosphorylation of hepatic p38 has long been noticed in fatty liver; however, whether the activation of hepatic p38 is a cause or consequence of liver steatosis is unclear. Here, we demonstrate that hepatic p38 activation by MKK6 overexpression in the liver of mice induces severe liver steatosis, reduces fat mass, and elevates circulating fatty acid levels in a hepatic p38α- and FGF21-dependent manner. Mechanistically, through increasing the FGF21 production from liver, hepatic p38 activation increases the influx of fatty acids from adipose tissue to liver, leading to hepatic ectopic lipid accumulation and insulin resistance. Although hepatic p38 activation exhibits favorable effects in peripheral tissues, it impairs the hepatic FGF21 action by facilitating the ubiquitination and degradation of FGF21 receptor cofactor β-Klotho. Consistently, we show that p38 phosphorylation and FGF21 expffression are increased, β-Klotho protein levels are decreased in the fatty liver of either mice or patients. In conclusion, our study reveals previously undescribed effects of hepatic p38 activation on systemic metabolism and provides new insights into the roles of hepatic p38α, FGF21, and β-Klotho in the pathogenesis of nonalcoholic fatty liver disease.
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http://dx.doi.org/10.2337/db21-0240DOI Listing
October 2021

Circ_0075804 promotes the malignant behaviors of retinoblastoma cells by binding to miR-138-5p to induce PEG10 expression.

Int Ophthalmol 2021 Oct 11. Epub 2021 Oct 11.

Department of Ophthalmology, Shenzhen Longhua District Maternity & Child Healthcare Hospital, Shenzhen, Guangdong Province, China.

Background: It has been gradually recognized that circular RNAs (circRNAs) are important modulators in multiple malignancies. Here, we analyzed the function of circ_0075804 and explored its associated mechanism in regulating retinoblastoma (RB) progression.

Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay were utilized to measure RNA and protein expression, respectively. Cell proliferation was analyzed by Cell counting kit-8 (CCK8) assay and 5-Ethynyl-2'-deoxyuridine (EdU) assay. Cell apoptosis was assessed by flow cytometry. Cell migration and invasion abilities were analyzed by wound healing assay and transwell invasion assay. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were applied to verify intermolecular target relations. Xenograft tumor model was used to analyze the role of circ_0075804 in tumor growth in vivo.

Results: Circ_0075804 expression was markedly up-regulated in RB tissues and cell lines. Circ_0075804 knockdown restrained the proliferation, migration and invasion whereas promoted the apoptosis of RB cells. Circ_0075804 acted as a molecular sponge for microRNA-138-5p (miR-138-5p), and circ_0075804 silencing-induced effects were partly reversed by miR-138-5p knockdown in RB cells. MiR-138-5p interacted with the 3' untranslated region (3'UTR) of paternally expressed 10 (PEG10). Circ_0075804 positively regulated PEG10 level by sponging miR-138-5p in RB cells. PEG10 overexpression largely overturned miR-138-5p overexpression-mediated effects in RB cells. Circ_0075804 knockdown blocked xenograft tumor growth in vivo.

Conclusion: Circ_0075804 promoted RB progression via miR-138-5p-dependent regulation of PEG10, which provided new insight in RB therapy.
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http://dx.doi.org/10.1007/s10792-021-02067-7DOI Listing
October 2021

Saringosterol from Modulates Cholesterol Metabolism and Alleviates Atherosclerosis in ApoE-Deficient Mice.

Mar Drugs 2021 Aug 26;19(9). Epub 2021 Aug 26.

Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.

Dysregulation of cholesterol homeostasis is a major risk factor of atherosclerosis, which can lead to serious health problems, including heart attack and stroke. Liver X receptor (LXR) α and β are transcription factors belonging to the nuclear receptor superfamily, which play important roles in cholesterol homeostasis. Selectively activating LXRβ provides a promising strategy for the treatment of atherosclerosis. Here, we employed atherosclerotic apoE-knockout mice to evaluate the effects of saringosterol, a phytosterol with potent and selective action for LXRβ, which we identified previously in edible marine seaweed . We found that saringosterol treatment reduced the atherosclerotic plaque burden without having undesirable adverse hepatic effects in apoE-deficient mice fed an atherogenic diet. Meanwhile, reduced serum levels of cholesterol, accompanied by altered expression of LXR-regulated genes involved in cholesterol absorption, transport, efflux, excretion, and elimination, were observed in apoE-knockout mice after saringosterol treatment. Together, our study not only establishes saringosterol as an effective cholesterol-lowering and anti-atherogenic phytosterol but also provides insights into the underlying mechanism.
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http://dx.doi.org/10.3390/md19090485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8466875PMC
August 2021

Geniposide exerts protective effects on spinal cord injury in rats by inhibiting the IKKs/NF-κB signaling pathway.

Int Immunopharmacol 2021 Nov 20;100:108158. Epub 2021 Sep 20.

Department of Medicine, Quzhou College of Technology, Quzhou, 324000, Zhejiang, China.

Background: Spinal cord injury (SCI) is a traumatic condition of the central nervous system , which can cause nerve injury and affect nerve regeneration, thus leading to severe dysfunction of motor and sensory pathways, and unfortunately these effects are irreversible. Inflammatory response constitutes one of the important mechanisms of spinal cord secondary injury. Geniposide (Gen) is reported to possess anti-inflammation and neuronal repair capacities.

Objectives: To investigate the effect and mechanism of Gen on motor function and inflammatory response in SCI rats.

Methods: Sprague-Dawley (SD) rats were randomly grouped, and the SCI model was established by Allen's method. The motor function of rats was evaluated by the Basso, Beattie, and Bresnahan (BBB) scale. The protective effect of Gen on the injured spinal cord tissues was evaluated by measuring the water content, myeloperoxidase (MPO) activity, and levels of tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and IL-6. Moreover, the protein level of the inflammation-related pathway was detected by spectrometry and Western blot assays.

Results: Gen significantly promoted the recovery of SCI rats, decreased the edema of spinal cord tissues, reduced the area of cavity, increased the number of NF-200-positive neurons, as well as increased the number of horseradish peroxidase (HRP) retrograde tracing-positive neurons and regenerated axons with myelin sheath. Additionally, compared with the control group, the neutrophil infiltration, contents of TNF-α, IL-1β, and IL-6, the activity of inhibitor of nuclear factor κB kinase subunit β (IKKβ) kinase, and protein levels of (nuclear factor κB) NF-κB p65 and phosphorylated inhibitor of NF-κB (p-I-κB) in the Gen experimental group were significantly decreased.

Conclusion: Gen effectively alleviated inflammatory response after SCI by inhibiting the IKKs/NF-κB signaling pathway and promoted the recovery of motor function and axon regeneration in rats.

Significance: This study can provide novel insights for the early and effective intervention of SCI and confer basic data for the treatment of spinal cord secondary injury.
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http://dx.doi.org/10.1016/j.intimp.2021.108158DOI Listing
November 2021

CRISPR/Cas9/AAV9-mediated in vivo editing identifies MYC regulation of 3D genome in skeletal muscle stem cell.

Stem Cell Reports 2021 Oct 16;16(10):2442-2458. Epub 2021 Sep 16.

Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China. Electronic address:

Skeletal muscle satellite cells (SCs) are stem cells responsible for muscle development and regeneration. Although CRISPR/Cas9 has been widely used, its application in endogenous SCs remains elusive. Here, we generate mice expressing Cas9 in SCs and achieve robust editing in juvenile SCs at the postnatal stage through AAV9-mediated short guide RNA (sgRNA) delivery. Additionally, we reveal that quiescent SCs are resistant to CRISPR/Cas9-mediated editing. As a proof of concept, we demonstrate efficient editing of master transcription factor (TF) Myod1 locus using the CRISPR/Cas9/AAV9-sgRNA system in juvenile SCs. Application on two key TFs, MYC and BCL6, unveils distinct functions in SC activation and muscle regeneration. Particularly, we reveal that MYC orchestrates SC activation through regulating 3D genome architecture. Its depletion results in strengthening of the topologically associating domain boundaries thus may affect gene expression. Altogether, our study establishes a platform for editing endogenous SCs that can be harnessed to elucidate the functionality of key regulators governing SC activities.
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http://dx.doi.org/10.1016/j.stemcr.2021.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8514971PMC
October 2021

Structural insights into the activation of human calcium-sensing receptor.

Elife 2021 09 1;10. Epub 2021 Sep 1.

The CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.

Human calcium-sensing receptor (CaSR) is a G-protein-coupled receptor that maintains Ca homeostasis in serum. Here, we present the cryo-electron microscopy structures of the CaSR in the inactive and agonist+PAM bound states. Complemented with previously reported structures of CaSR, we show that in addition to the full inactive and active states, there are multiple intermediate states during the activation of CaSR. We used a negative allosteric nanobody to stabilize the CaSR in the fully inactive state and found a new binding site for Ca ion that acts as a composite agonist with L-amino acid to stabilize the closure of active Venus flytraps. Our data show that agonist binding leads to compaction of the dimer, proximity of the cysteine-rich domains, large-scale transitions of seven-transmembrane domains, and inter- and intrasubunit conformational changes of seven-transmembrane domains to accommodate downstream transducers. Our results reveal the structural basis for activation mechanisms of CaSR and clarify the mode of action of Ca ions and L-amino acid leading to the activation of the receptor.
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http://dx.doi.org/10.7554/eLife.68578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476121PMC
September 2021

Translational control by DHX36 binding to 5'UTR G-quadruplex is essential for muscle stem-cell regenerative functions.

Nat Commun 2021 08 19;12(1):5043. Epub 2021 Aug 19.

Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China.

Skeletal muscle has a remarkable ability to regenerate owing to its resident stem cells (also called satellite cells, SCs). SCs are normally quiescent; when stimulated by damage, they activate and expand to form new fibers. The mechanisms underlying SC proliferative progression remain poorly understood. Here we show that DHX36, a helicase that unwinds RNA G-quadruplex (rG4) structures, is essential for muscle regeneration by regulating SC expansion. DHX36 (initially named RHAU) is barely expressed at quiescence but is highly induced during SC activation and proliferation. Inducible deletion of Dhx36 in adult SCs causes defective proliferation and muscle regeneration after damage. System-wide mapping in proliferating SCs reveals DHX36 binding predominantly to rG4 structures at various regions of mRNAs, while integrated polysome profiling shows that DHX36 promotes mRNA translation via 5'-untranslated region (UTR) rG4 binding. Furthermore, we demonstrate that DHX36 specifically regulates the translation of Gnai2 mRNA by unwinding its 5' UTR rG4 structures and identify GNAI2 as a downstream effector of DHX36 for SC expansion. Altogether, our findings uncover DHX36 as an indispensable post-transcriptional regulator of SC function and muscle regeneration acting through binding and unwinding rG4 structures at 5' UTR of target mRNAs.
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http://dx.doi.org/10.1038/s41467-021-25170-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377060PMC
August 2021

Cardioprotective effect of icariin against myocardial fibrosis and its molecular mechanism in diabetic cardiomyopathy based on network pharmacology: Role of ICA in DCM.

Phytomedicine 2021 Oct 24;91:153607. Epub 2021 May 24.

Department of Echocardiography, The First Hospital of Jilin University, Changchun 130021, PR China. Electronic address:

Background: Diabetic cardiomyopathy (DCM) is one of the most severe symptoms of diabetes. It continues to be a major clinical problem, but our knowledge of its molecular mechanisms and effective treatments are limited. Traditional Chinese medicine has been shown to be a pool of novel drugs for diabetes.

Purpose: Herein, we aim to define the molecular mechanism of icariin (ICA), an extract from a traditional Chinese medicine herb, in protecting cardiac structures and restoring cardiac functions of in a rat model of type 2 diabetes mellitus (T2DM).

Study Design And Methods: Candidate genes related to T2DM were identified through bioinformatics screening and their interactions were constructed by molecule docking technique, followed by pathway enrichment analyses of their cellular functions. A T2DM rat model was then established to evaluate the effects of ICA on cardiac structures, myocardial fibrosis, and cellular Ca inflow, as reflected by HE and Masson staining, qRT-PCR and Western blot determination of related genes, and measurement of the L-type Ca current.

Results: Four potential target genes (Jun, p65, NOS3, and PDE5A) were identified. ICA ameliorated the structural damage and myocardial fibrosis in T2DM rats. Intracellular Ca2+ hyperactivities and dysfunction in myocardium of T2DM rats were also repressed by ICA treatment. Furthermore, ICA-induced inhibition of Jun and p65 ameliorated the irregular collagen metabolism and myocardial fibrosis. NOS3, PDE5A and the related sGC-cGMP-PKG signaling pathway mediated the ICA-induced improvement of intracellular Ca inflow.

Conclusion: In conclusion, these results demonstrate the regulatory roles of potential target genes in DCM and suggest ICA as an effective treatment of DCM by targeting these genes specifically.
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http://dx.doi.org/10.1016/j.phymed.2021.153607DOI Listing
October 2021

The Role of Cytokines in Predicting the Response and Adverse Events Related to Immune Checkpoint Inhibitors.

Front Immunol 2021 22;12:670391. Epub 2021 Jul 22.

Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.

Recently, the overall survival (OS) and progression-free survival (PFS) of patients with advanced cancer has been significantly improved due to the application of immune checkpoint inhibitors (ICIs). Low response rate and high occurrence of immune-related adverse events (irAEs) make urgently need for ideal predictive biomarkers to identity efficient population and guide treatment strategies. Cytokines are small soluble proteins with a wide range of biological activity that are secreted by activated immune cells or tumor cells and act as a bridge between innate immunity, infection, inflammation and cancer. Cytokines can be detected in peripheral blood and suitable for dynamic detection. During the era of ICIs, many studies investigated the role of cytokines in prediction of the efficiency and toxicity of ICIs. Herein, we review the relevant studies on TNF-α, IFN-γ, IL-6, IL-8, TGF-β and other cytokines as biomarkers for predicting ICI-related reactions and adverse events, and explore the immunomodulatory mechanisms. Finally, the most important purpose of this review is to help identify predictors of ICI to screen patients who are most likely to benefit from immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2021.670391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8339552PMC
October 2021

Autophagy Modulators From Chinese Herbal Medicines: Mechanisms and Therapeutic Potentials for Asthma.

Front Pharmacol 2021 23;12:710679. Epub 2021 Jul 23.

Inflammation and Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

Asthma has become a global health issue, suffering more than 300 million people in the world, which is a heterogeneous disease, usually characterized by chronic airway inflammation and airway hyperreactivity. Combination of inhaled corticosteroids (ICS) and long acting β-agonists (LABA) can relieve asthma symptoms and reduce the frequency of exacerbations, especially for patients with refractory asthma, but there are limited treatment options for people who do not gain control on combination ICS/LABA. The increase in ICS dose generally provides little additional benefit, and there is an increased risk of side effects. Therefore, therapeutic interventions integrating the use of different agents that focus on different targets are needed to overcome this set of diseases. Some findings suggest autophagy is closely correlated with the severity of asthma through eosinophilic inflammation, and its modulation may provide novel therapeutic approaches for severe allergic asthma. The chinese herbal medicine (CHM) have been demonstrated clinically as potent therapeutic interventions for asthma. Moreover some reports have found that the bioactive components isolated from CHM could modulate autophagy, and exhibit potent Anti-inflammatory activity. These findings have implied the potential for CHMs in asthma or allergic inflammation therapy via the modulation of autophagy. In this review, we discuss the basic pathomechanisms underpinning asthma, and the potential role of CHMs in treating asthma with modulating autophagy.
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http://dx.doi.org/10.3389/fphar.2021.710679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342996PMC
July 2021

miR-183 and miR-96 orchestrate both glucose and fat utilization in skeletal muscle.

EMBO Rep 2021 09 6;22(9):e52247. Epub 2021 Aug 6.

State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, China.

Our knowledge of the coordination of fuel usage in skeletal muscle is incomplete. Whether and how microRNAs are involved in the substrate selection for oxidation is largely unknown. Here we show that mice lacking miR-183 and miR-96 have enhanced muscle oxidative phenotype and altered glucose/lipid homeostasis. Moreover, loss of miR-183 and miR-96 results in a shift in substrate utilization toward fat relative to carbohydrates in mice. Mechanistically, loss of miR-183 and miR-96 suppresses glucose utilization in skeletal muscle by increasing PDHA1 phosphorylation via targeting FoxO1 and PDK4. On the other hand, loss of miR-183 and miR-96 promotes fat usage in skeletal muscle by enhancing intramuscular lipolysis via targeting FoxO1 and ATGL. Thus, our study establishes miR-183 and miR-96 as master coordinators of fuel selection and metabolic homeostasis owing to their capability of modulating both glucose utilization and fat catabolism. Lastly, we show that loss of miR-183 and miR-96 can alleviate obesity and improve glucose metabolism in high-fat diet-induced mice, suggesting that miR-183 and miR-96 may serve as therapeutic targets for metabolic diseases.
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http://dx.doi.org/10.15252/embr.202052247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8419684PMC
September 2021

A synthetic peptide AWRK6 ameliorates metabolic associated fatty liver disease: involvement of lipid and glucose homeostasis.

Peptides 2021 09 10;143:170597. Epub 2021 Jun 10.

Department of Stem Cells and Regenerative Medicine, Key Laboratory of Cell Biology, National Health Commission of China, And Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, Shenyang, 110122, China. Electronic address:

Metabolic associated fatty liver disease (MAFLD) is the leading common chronic liver disease affecting more than one-quarter of the population worldwide, but no pharmacological therapy was approved specifically. A synthetic peptide AWRK6 developed in our group based on the antimicrobial peptide Dybowskin-2CDYa was found to attenuated diabetes as a novel GLP-1 receptor agonist candidate. The effects of AWRK6 on MAFLD and its underlying mechanisms were investigated in this paper. In high energy diet (HED)-induced MAFLD mice, obesity and hepatic steatosis were alleviated by AWRK6 via intraperitoneal injection. The biochemistry measurements data indicated that the abnormal lipid metabolism was relieved and the glucose metabolism was improved significantly. Further, the phosphorylation of liver PI3K/AKT/AMPK/ACC was elevated significantly by AWRK6 treatment. Moreover, the effects of AWRK6 on lipid accumulation and insulin sensitivity in human cells were verified using oleic acid-induced HepG2 fatty liver cell model and insulin-induced HepG2 cells, respectively. These in vitro and in vivo results demonstrated that the peptide AWRK6 ameliorates MAFLD by improving lipid and glucose metabolism homeostasis, and it is mediated by the PI3K/AKT/AMPK/ACC signaling pathway. Thus, AWRK6 has a potential in preventing MAFLD.
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http://dx.doi.org/10.1016/j.peptides.2021.170597DOI Listing
September 2021

Combined Effects of Mother's, Father's and Teacher's Psychological Distress on Schoolchildren's Mental Health Symptoms.

Neuropsychiatr Dis Treat 2021 3;17:1735-1743. Epub 2021 Jun 3.

Institute of Preventive Medicine, China Medical University, Shenyang, People's Republic of China.

Purpose: Few studies have assessed the individual and joint effects of the mother's, father's and teacher's mental health symptoms on schoolchildren's behavior and emotional well-being simultaneously in the same study.

Patients And Methods: A cross-sectional survey was conducted among 8488 Chinese schoolchildren aged 6-17 years in northeast China. The Strengths and Difficulties Questionnaire (SDQ) and General Health Questionnaire (GHQ) were used to measure the mental health of the students, their parents and the teacher in charge of the class, respectively. A total of 6173 students (72.73%) with full mental health information from all three caretakers were included in the final analysis.

Results: We found a significantly elevated risk of mental health symptoms in children when their mothers (odds ratios (OR)=2.30, 95% CI=1.93-2.73), fathers (OR=2.08, 95% CI=1.73-2.50) and teachers (OR=1.18, 95% CI=1.01-1.39) reported poorer mental health, and the risk increased significantly with the number of the caretakers with mental symptoms. A father with poor mental health has both direct and indirect effects on a child's emotional health, by worsening the influence of a mother's poor mental health.

Conclusion: All three caretakers have a significant negative influence on schoolchildren's emotional well-being, in the order of mother > father > teacher. It is desirable to assess and manage students' mental health in the both the family and school contexts.
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http://dx.doi.org/10.2147/NDT.S302782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184235PMC
June 2021

Transmission Dynamics, Heterogeneity and Controllability of SARS-CoV-2: A Rural-Urban Comparison.

Int J Environ Res Public Health 2021 05 14;18(10). Epub 2021 May 14.

Department of Biostatistics, School of Public Health, Peking University, Beijing 100191, China.

Few studies have examined the transmission dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in rural areas and clarified rural-urban differences. Moreover, the effectiveness of non-pharmaceutical interventions (NPIs) relative to vaccination in rural areas is uncertain. We addressed this knowledge gap through using an improved statistical stochastic method based on the Galton-Watson branching process, considering both symptomatic and asymptomatic cases. Data included 1136 SARS-2-CoV infections of the rural outbreak in Hebei, China, and 135 infections of the urban outbreak in Tianjin, China. We reconstructed SARS-CoV-2 transmission chains and analyzed the effectiveness of vaccination and NPIs by simulation studies. The transmission of SARS-CoV-2 showed strong heterogeneity in urban and rural areas, with the dispersion parameters = 0.14 and 0.35, respectively ( < 1 indicating strong heterogeneity). Although age group and contact-type distributions significantly differed between urban and rural areas, the average reproductive number () and did not. Further, simulation results based on pre-control parameters ( = 0.81, = 0.27) showed that in the vaccination scenario (80% efficacy and 55% coverage), the cumulative secondary infections will be reduced by more than half; however, NPIs are more effective than vaccinating 65% of the population. These findings could inform government policies regarding vaccination and NPIs in rural and urban areas.
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http://dx.doi.org/10.3390/ijerph18105221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156721PMC
May 2021

Large scale RNA-binding proteins/LncRNAs interaction analysis to uncover lncRNA nuclear localization mechanisms.

Brief Bioinform 2021 Nov;22(6)

Department of Orthaepedics and Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Long non-coding RNAs (lncRNAs) are key regulators of major biological processes and their functional modes are dictated by their subcellular localization. Relative nuclear enrichment of lncRNAs compared to mRNAs is a prevalent phenomenon but the molecular mechanisms governing their nuclear retention in cells remain largely unknown. Here in this study, we harness the recently released eCLIP data for a large number of RNA-binding proteins (RBPs) in K562 and HepG2 cells and utilize multiple bioinformatics methods to comprehensively survey the roles of RBPs in lncRNA nuclear retention. We identify an array of splicing RBPs that bind to nuclear-enriched lincRNAs (large intergenic non-coding RNAs) thus may act as trans-factors regulating their nuclear retention. Further analyses reveal that these RBPs may bind with distinct core motifs, flanking sequence compositions, or secondary structures to drive lincRNA nuclear retention. Moreover, network analyses uncover potential co-regulatory RBP clusters and the physical interaction between HNRNPU and SAFB2 proteins in K562 cells is further experimentally verified. Altogether, our analyses reveal previously unknown factors and mechanisms that govern lincRNA nuclear localization in cells.
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http://dx.doi.org/10.1093/bib/bbab195DOI Listing
November 2021

Visualizing Tumors in Real Time: A Highly Sensitive PSMA Probe for NIR-II Imaging and Intraoperative Tumor Resection.

J Med Chem 2021 06 28;64(11):7735-7745. Epub 2021 May 28.

Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.

Owing to the complex anatomical structure, precise resection of a tumor while maintaining adjacent tissue is a challenge in radical prostatectomy for prostate cancer (PCa). Optical imaging in near-infrared window II (NIR-II) is a promising technology for intraoperative guidance, whereas there is no available probe for PCa yet. In this article, a novel probe () bearing two prostate-specific membrane antigen (PSMA) binding motifs was developed, displaying excellent optical properties (λ = 1092 nm) and ultrahigh affinity ( = 80 pM) toward PSMA. The tumor was visualized with high resolution (tissue-to-normal tissue ratio = 7.62 ± 1.05) and clear margin by NIR-II imaging using in a mouse model. During the tumor resection, residual tumors missed by visible inspection were detected by the real-time imaging. Overall, displayed excellent performance in delineating the tumor margin and detecting residual tumors, demonstrating promising potential for precise PCa tumor resection in clinical practice.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00444DOI Listing
June 2021

First detection and complete genome analysis of the Lyon IARC polyomavirus in China from samples of diarrheic cats.

Virus Genes 2021 Jun 10;57(3):284-288. Epub 2021 May 10.

Institute of Military Veterinary Medicine, The Academy of Military Medical Sciences, Changchun, 130122, China.

Lyon IARC polyomavirus (LIPyV), a newly discovered polyomavirus (PyV), was first identified in 2017 in human skin samples in the USA. Later, it was detected in several other countries in samples of human and feline origin. Our aim was to find out if the virus occurs in China. To this end, 100 fecal samples were collected from cats with diarrhea in Guangxi Province during 2016 and 2018 and tested with polymerase chain reaction (PCR). Only 2 samples that originated from two related individuals were found to be positive. Based on the sequence identity of the 240-bp PCR products, the two positive samples supposedly contained identical viruses. Therefore, only one of them, which was designated as LIPyV-GXNN01, was selected for full genome amplification, cloning, sequencing and analysis. LIPyV-GXNN01, which comprises 5,263 nucleotides, has an early region that consists of small T antigen (ST-Ag) and large T antigen (LT-Ag) and a late region coding for the VP1, VP2, and VP3 structural proteins. Moreover, the LIPyV-GXNN01 strain structural proteins share 95.9-99.4%, 97.6-99.2%, and 97.1-99.2% nucleic acid identity with the VP1, VP2, and VP3of other LIPyV reference strains, respectively. A phylogenetic analysis revealed that GXNN01 clustered together with previously reported LIPyV strain. This present study is the first report of LIPyV in China.
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http://dx.doi.org/10.1007/s11262-021-01840-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107205PMC
June 2021

Ultrafine MoP Nanoparticle Splotched Nitrogen-Doped Carbon Nanosheets Enabling High-Performance 3D-Printed Potassium-Ion Hybrid Capacitors.

Adv Sci (Weinh) 2021 Apr 2;8(7):2004142. Epub 2021 Feb 2.

State Key Laboratory for Modification of Chemical Fibers and Polymer Materials College of Materials Science and Engineering Innovation Center for Textile Science and Technology Donghua University Shanghai 201620 P. R. China.

Size engineering is deemed to be an adoptable method to boost the electrochemical properties of potassium-ion storage; however, it remains a critical challenge to significantly reduce the nanoparticle size without compromising the uniformity. In this work, a series of MoP nanoparticle splotched nitrogen-doped carbon nanosheets ([email protected]) is synthesized. Due to the coordinate and hydrogen bonds in the water-soluble polyacrylamide hydrogel, MoP is uniformly confined in a 3D porous NC to form ultrafine nanoparticles which facilitate the extreme exposure of abundant three-phase boundaries (MoP, NC, and electrolyte) for ionic binding and storage. Consequently, [email protected] delivers an excellent capacity performance (256.1 mAh g at 0.1 A g) and long-term cycling durability (89.9% capacitance retention after 800 cycles). It is further confirmed via density functional theory calculations that the smaller the MoP nanoparticle, the larger the three-phase boundary achieved for favoring competitive binding energy toward potassium ions. Finally, [email protected] is applied as highly electroactive additive for 3D printing ink to fabricate 3D-printed potassium-ion hybrid capacitors, which delivers high gravimetric energy/power density of 69.7 Wh kg/2041.6 W kg, as well as favorable areal energy/power density of 0.34 mWh cm/9.97 mW cm.
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http://dx.doi.org/10.1002/advs.202004142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025015PMC
April 2021

miR-130b inhibits proliferation and promotes differentiation in myocytes via targeting Sp1.

J Mol Cell Biol 2021 09;13(6):422-432

CAS Key laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai 200031, China.

Muscle regeneration after damage or during myopathies requires a fine cooperation between myoblast proliferation and myogenic differentiation. A growing body of evidence suggests that microRNAs play critical roles in myocyte proliferation and differentiation transcriptionally. However, the molecular mechanisms underlying the orchestration are not fully understood. Here, we showed that miR-130b is able to repress myoblast proliferation and promote myogenic differentiation via targeting Sp1 transcription factor. Importantly, overexpression of miR-130b is capable of improving the recovery of damaged muscle in a freeze injury model. Moreover, miR-130b expression is declined in the muscle of muscular dystrophy patients. Thus, these results indicated that miR-130b may play a role in skeletal muscle regeneration and myopathy progression. Together, our findings suggest that the miR-130b/Sp1 axis may serve as a potential therapeutic target for the treatment of patients with muscle damage or severe myopathies.
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http://dx.doi.org/10.1093/jmcb/mjab012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8436675PMC
September 2021

Anthraquinone derivative C10 inhibits proliferation and cell cycle progression in colon cancer cells via the Jak2/Stat3 signaling pathway.

Toxicol Appl Pharmacol 2021 05 13;418:115481. Epub 2021 Mar 13.

Key Laboratory of Chemical Biology and Molecular Engineering of the Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan 030006, China.

Since its discovery, anthraquinone has become very valuable as a lead compound in the development of anti-cancer drugs. Previously, we designed and synthesized a new type of amide anthraquinone derivative (1-nitro-2-acylanthraquinone glycine, C10) with good activity against colon cancer. However, its effect and the underlying mechanism are unclear. In this study, C10 significantly inhibited the proliferation of HCT116 and HT29 colon cancer cells by blocking the cell cycle at the G2/M phase. C10 also plays a role in cell cycle arrest by reducing the protein and gene expression levels of cyclin B1 and its downstream signaling molecule cyclin-dependent kinase (CDK1). In addition, molecular docking studies showed that C10 has high affinity for Jak2, the first target in the cell cycle-related Jak2/Stat3 signaling pathway. Furthermore, C10 downregulated the expression of Jak2/Stat3 signaling pathway-related signaling molecules proteins and genes, and up-regulated the expression of PIAS-3, the upstream signaling molecule of Stat3, thereby down-regulating Stat3 phosphorylation. C10 reversed the expression of Jak2/Stat3 signaling pathway-related molecules activated by IL-6. Overall, our results indicate for the first time that C10 induces cell cycle arrest and inhibits cell proliferation by inhibiting the Jak2/Stat3 signaling pathway. This study provides new insights into the potential role of Jak2/Stat3 in the regulating cell cycle-related signaling pathways that mediate the inhibitory effects of C10 on colon cancer cell proliferation.
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http://dx.doi.org/10.1016/j.taap.2021.115481DOI Listing
May 2021
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