Publications by authors named "Yu Fu"

796 Publications

Palladium-Catalyzed γ,γ'-Diarylation of Free Alkenyl Amines.

J Am Chem Soc 2021 Jun 23. Epub 2021 Jun 23.

Department of Chemistry & Biochemistry, School of Green Chemistry & Engineering, The University of Toledo, 2801 W. Bancroft St., Mailstop 602, Toledo, Ohio 43606, United States of America.

The direct difunctionalization of alkenes is an effective way to construct multiple C-C bonds in one-pot using a single functional group. The regioselective dicarbofunctionalization of alkenes is therefore an important area of research to rapidly obtain complex organic molecules. Herein, we report a palladium-catalyzed γ,γ'-diarylation of free alkenyl amines through interrupted chain walking for the synthesis of -selective alkenyl amines. Notably, while 1,3-dicarbofunctionalization of allyl groups is well precedented, the present disclosure allows 1,3-dicarbofunctionalization of highly substituted allylamines to give highly -selective trisubsubstituted olefin products. This cascade reaction operates via an unprotected amine-directed Mizoroki-Heck (MH) pathway featuring a β-hydride elimination to selectively chain walk to furnish a new terminal olefin which then generates the -selective alkenyl amines around the sterically crowded allyl moiety. This operationally simple protocol is applicable to a variety of cyclic, branched, and linear secondary and tertiary alkenylamines, and has a broad substrate scope with regard to the arene coupling partner as well. Mechanistic studies have been performed to help elucidate the mechanism, including the presence of a likely unproductive side C-H activation pathway.
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http://dx.doi.org/10.1021/jacs.1c04261DOI Listing
June 2021

RCoNet: Deformable Mutual Information Maximization and High-Order Uncertainty-Aware Learning for Robust COVID-19 Detection.

IEEE Trans Neural Netw Learn Syst 2021 Jun 18;PP. Epub 2021 Jun 18.

The novel 2019 Coronavirus (COVID-19) infection has spread worldwide and is currently a major healthcare challenge around the world. Chest computed tomography (CT) and X-ray images have been well recognized to be two effective techniques for clinical COVID-19 disease diagnoses. Due to faster imaging time and considerably lower cost than CT, detecting COVID-19 in chest X-ray (CXR) images is preferred for efficient diagnosis, assessment, and treatment. However, considering the similarity between COVID-19 and pneumonia, CXR samples with deep features distributed near category boundaries are easily misclassified by the hyperplanes learned from limited training data. Moreover, most existing approaches for COVID-19 detection focus on the accuracy of prediction and overlook uncertainty estimation, which is particularly important when dealing with noisy datasets. To alleviate these concerns, we propose a novel deep network named RCoNetks for robust COVID-19 detection which employs Deformable Mutual Information Maximization (DeIM), Mixed High-order Moment Feature (MHMF), and Multiexpert Uncertainty-aware Learning (MUL). With DeIM, the mutual information (MI) between input data and the corresponding latent representations can be well estimated and maximized to capture compact and disentangled representational characteristics. Meanwhile, MHMF can fully explore the benefits of using high-order statistics and extract discriminative features of complex distributions in medical imaging. Finally, MUL creates multiple parallel dropout networks for each CXR image to evaluate uncertainty and thus prevent performance degradation caused by the noise in the data. The experimental results show that RCoNetks achieves the state-of-the-art performance on an open-source COVIDx dataset of 15,134 original CXR images across several metrics. Crucially, our method is shown to be more effective than existing methods with the presence of noise in the data.
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http://dx.doi.org/10.1109/TNNLS.2021.3086570DOI Listing
June 2021

Gut microbiota-CRAMP axis shapes intestinal barrier function and immune responses in dietary gluten-induced enteropathy.

EMBO Mol Med 2021 Jun 14:e14059. Epub 2021 Jun 14.

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

In the gut, cathelicidin-related antimicrobial peptide (CRAMP) has been largely described for its anti-infective activities. With an increasing recognition of its immune regulatory effects in extra-intestinal diseases, the role of CRAMP in gluten-induced small intestinal enteropathy celiac disease remains unknown. This study aimed to investigate the unexplored role of CRAMP in celiac disease. By applying a mouse model of gluten-induced enteropathy (GIE) recapitulating small intestinal enteropathy of celiac disease, we observed defective CRAMP production in duodenal epithelium during GIE. CRAMP-deficient mice were susceptible to the development of GIE. Exogenous CRAMP corrected gliadin-triggered epithelial dysfunction and promoted regulatory immune responses at the intestinal mucosa. Additionally, GIE-associated gut dysbiosis with enriched Pseudomonas aeruginosa and production of the protease LasB contributed to defective intestinal CRAMP production. These results highlight microbiota-CRAMP axis in the modulation of barrier function and immune responses in GIE. Hence, modulating CRAMP may represent a therapeutic strategy for celiac disease.
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http://dx.doi.org/10.15252/emmm.202114059DOI Listing
June 2021

Analysis of sagittal curvature and its influencing factors in adolescent idiopathic scoliosis.

Medicine (Baltimore) 2021 Jun;100(23):e26274

Department of Anatomy, Inner Mongolia Medical University.

Abstract: This study aimed to explore the characteristics of changes in the sagittal arrangement of the spine between adolescent patients with idiopathic scoliosis (AIS) and normal adolescents, the risk factors for AIS and the factors affecting the progress of AIS.X-ray images of the full length of the spine in standing position were taken in AIS patients and normal adolescents. Radiographic measurements made at intermediate follow-up included the following:C1 and C2 cervical lordosis and C2 - C7 curvature of cervical lordosis, C2-C7sagittal horizontal distance (C2-C7SagittalVerticalAxis, C2-C7SVA), TS-CL, after thoracic lobe (Thoracic Kyphosis, TK), thoracic lumbar segment Angle (thoracolumbar kyphosis, [TLK]), lumbar lordosis Angle (Lumbar Lordosis, LL), sacral slope Angle (Sacrum Slope, SS), pelvic tilt Angle (Pelvic Tilt, PT), pelvic incidence (PI), L5 Incidence (Lumbar5 Slope (L5S), L5 incidence (Lumbar5 Incidence (L5I), sagittal horizontal distance (CSVA), lower depression Angle of the 2nd cervical spine. The difference of sagittal plane parameters between AIS group and normal adolescent group was compared. To evaluate the progress of AIS, correlation analysis was conducted between diagonal 2 and other parameters. The main risk factors of AIS were determined by binary Logistic analysis.The CSVA of AIS patients was higher than that of healthy adolescents (AIS: 27.64 ± 19.56) mm. Healthy adolescents: (17.74 ± 12.8) mm), L5S (AIS: 19.93°= 7.07° and healthy adolescents: 15.38°= 7.78°, P = .024 < .05), C2 downward sag Angle (AIS: 15.12°= 2.7°;Healthy adolescents: 12.97°= 4.56°); AIS patients had lower TS-CL (AIS: 22.48 ± 6.09 and healthy adolescents: 28.26°= 10.32°), PT (AIS: 10.42°= 4.53° and healthy adolescents: 15.80°=7.68°), (AIS: 41.87°=9.72° and healthy adolescents: 48.75°= 8.22°). The main risk factor for idiopathic scoliosis in adolescents was L5 (OR = 1.239, 95%CI = 1.049-1.463, P = .012 < .05).L5S is a major risk factor for idiopathic scoliosis in adolescents. The larger PI is, the higher the risk of scoliosis progression is. In AIS patients, lumbar lordosis is increased, cervical lordosis is reduced, and even cervical kyphosis occurs.
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http://dx.doi.org/10.1097/MD.0000000000026274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202640PMC
June 2021

Nanostructure-Mediated Phase Evolution in Lithiation/Delithiation of CoO.

ACS Appl Mater Interfaces 2021 Jun 10;13(24):28171-28180. Epub 2021 Jun 10.

School of System Design and Intelligent Manufacturing, Southern University of Science and Technology, Xueyuan Road 1088, Shen Zhen, Guang Dong 518055, China.

Nanostructured transition-metal oxides have been under intensive investigation for their tantalizing potential as anodes of next-generation lithium-ion batteries (LIBs). However, the exact mechanism for nanostructures to influence the LIB performance remains largely elusive. In this work, we discover the nanostructure-mediated lithiation mechanism in CoO anodes using transmission electron microscopy (TEM) and X-ray diffractometry: while CoO nanosheets exhibit a typical two-step conversion reaction (from CoO to CoO and then to Co), CoO nanoarrays can go through a direct conversion from CoO to Co at a high discharge rate. Such nanostructure-dependent lithiation can be rationalized by the slow lithiation kinetics intrinsic to CoO nanoarrays, which at a high discharge rate may cause local accumulation of lithium to initiate a one-step CoO-to-Co conversion. Combined with the larger volume change observed in CoO nanoarrays, the slow lithiation kinetics can lead to inhomogeneous expansion with large stress developed at the reaction front, which can eventually cause structure failure and irreversible capacity loss, as explicitly observed by TEM as well as galvanostatic discharge-charge measurement. Our observation resolves the nanostructure-dependent lithiation mechanism of CoO and provides important insights into the interplay among lithiation kinetics, phase evolution, and lithium-storage performance, which can be translated into electrode design strategies for next-generation LIBs.
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http://dx.doi.org/10.1021/acsami.1c05591DOI Listing
June 2021

Central nervous system (CNS) transcriptomic correlates of human immunodeficiency virus (HIV) brain RNA load in HIV-infected individuals.

Sci Rep 2021 Jun 9;11(1):12176. Epub 2021 Jun 9.

Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA.

To generate new mechanistic hypotheses on the pathogenesis and disease progression of neuroHIV and identify novel therapeutic targets to improve neuropsychological function in people with HIV, we investigated host genes and pathway dysregulations associated with brain HIV RNA load in gene expression profiles of the frontal cortex, basal ganglia, and white matter of HIV+ patients. Pathway analyses showed that host genes correlated with HIV expression in all three brain regions were predominantly related to inflammation, neurodegeneration, and bioenergetics. HIV RNA load directly correlated particularly with inflammation genesets representative of cytokine signaling, and this was more prominent in white matter and the basal ganglia. Increases in interferon signaling were correlated with high brain HIV RNA load in the basal ganglia and the white matter although not in the frontal cortex. Brain HIV RNA load was inversely correlated with genesets that are indicative of neuronal and synaptic genes, particularly in the cortex, indicative of synaptic injury and neurodegeneration. Brain HIV RNA load was inversely correlated with genesets that are representative of oxidative phosphorylation, electron transfer, and the tricarboxylic acid cycle in all three brain regions. Mitochondrial dysfunction has been implicated in the toxicity of some antiretrovirals, and these results indicate that mitochondrial dysfunction is also associated with productive HIV infection. Genes and pathways correlated with brain HIV RNA load suggest potential therapeutic targets to ameliorate neuropsychological functioning in people living with HIV.
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http://dx.doi.org/10.1038/s41598-021-88052-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190104PMC
June 2021

Clinical and molecular characteristics of COVID-19 patients with persistent SARS-CoV-2 infection.

Nat Commun 2021 06 9;12(1):3501. Epub 2021 Jun 9.

Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

The characteristics of COVID-19 patients with persistent SARS-CoV-2 infection are not yet well described. Here, we compare the clinical and molecular features of patients with long duration of viral shedding (LDs) with those from patients with short duration patients (SDs), and healthy donors (HDs). We find that several cytokines and chemokines, such as interleukin (IL)-2, tumor necrosis factor (TNF) and lymphotoxin α (LT-α) are present at lower levels in LDs than SDs. Single-cell RNA sequencing shows that natural killer (NK) cells and CD14 monocytes are reduced, while regulatory T cells are increased in LDs; moreover, T and NK cells in LDs are less activated than in SDs. Importantly, most cells in LDs show reduced expression of ribosomal protein (RP) genes and related pathways, with this inversed correlation between RP levels and infection duration further validated in 103 independent patients. Our results thus indicate that immunosuppression and low RP expression may be related to the persistence of the viral infection in COVID-19 patients.
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http://dx.doi.org/10.1038/s41467-021-23621-yDOI Listing
June 2021

Emerging understanding of apoptosis in mediating mesenchymal stem cell therapy.

Cell Death Dis 2021 Jun 9;12(6):596. Epub 2021 Jun 9.

Fujian Key Laboratory of Developmental and Neural Biology & Southern Center for Biomedical Research, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, 350117, China.

Mesenchymal stem cell transplantation (MSCT) has been recognized as a potent and promising approach to achieve immunomodulation and tissue regeneration, but the mechanisms of how MSCs exert therapeutic effects remain to be elucidated. Increasing evidence suggests that transplanted MSCs only briefly remain viable in recipients, after which they undergo apoptosis in the host circulation or in engrafted tissues. Intriguingly, apoptosis of infused MSCs has been revealed to be indispensable for their therapeutic efficacy, while recipient cells can also develop apoptosis as a beneficial response in restoring systemic and local tissue homeostasis. It is notable that apoptotic cells produce apoptotic extracellular vesicles (apoEVs), traditionally known as apoptotic bodies (apoBDs), which possess characterized miRnomes and proteomes that contribute to their specialized function and to intercellular communication. Importantly, it has been demonstrated that the impact of apoEVs is long-lasting in health and disease contexts, and they critically mediate the efficacy of MSCT. In this review, we summarize the emerging understanding of apoptosis in mediating MSCT, highlighting the potential of apoEVs as cell-free therapeutics.
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http://dx.doi.org/10.1038/s41419-021-03883-6DOI Listing
June 2021

Association of KCTD15 gene with fat deposition in pigs.

J Anim Physiol Anim Nutr (Berl) 2021 Jun 9. Epub 2021 Jun 9.

National Engineering Laboratory for Animal Breeding, China Agricultural University, Beijing, China.

KCTD15 is associated with body mass index and fat deposition in humans, mice and chickens. However, the function of KCTD15 in pig fat deposition remains unclear. In this study, we cloned and analysed the cDNA sequence of porcine KCTD15. The full length of the mRNA sequence of KCTD15 is 4,091 bp, encoding 283 amino acids. The protein is hydrophilic, it has a relative molecular mass of about 31.9 kDa and an isoelectric point of 7.09 with no signal peptide sequence or transmembrane structure. Expression analysis showed that KCTD15 expression level was significantly higher in the tissues of Large White pigs (LW) than in those of Tibetan pigs (TP) and Diannan Small-ear pigs (DN) at 6 months of age, whereas its expression level in embryonic tissues of LW at 60 days was lower than that in tissues of TP and Wujin pigs (WJ). In pig primary adipocytes, the expression level of KCTD15 is high in the early stage of differentiation and gradually decreases in later stages. Additionally, the single-nucleotide polymorphism (SNP) site T-2030C (T/C mutation, located 2,030 bp upstream of the start codon) showed a dominant allele T with high promoter activity in the LW population and a dominant allele C in the TP and WJ populations. Our results indicate that KCTD15 is involved in pig fat deposition and that T-2030C is an important regulatory site for transcriptional activity, affecting fat deposition.
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http://dx.doi.org/10.1111/jpn.13587DOI Listing
June 2021

The partial replacement of sodium chloride with sodium bicarbonate or sodium sulfate in laying hen diets improved laying performance, and eggshell quality and ultrastructure.

Poult Sci 2021 Mar 12;100(7):101102. Epub 2021 Mar 12.

Key Laboratory of Feed Biotechnology of Ministry of Agriculture & Rural Affairs, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing 100081, China. Electronic address:

This study investigated the effects of dietary chloride (Cl) reduction on laying performance and eggshell quality by substitution of sodium bicarbonate (NaHCO) or sodium sulfate (NaSO) for part of dietary sodium chloride (NaCl), and further explored its mechanism for improving eggshell quality. A total of 360 29-wk-old Hy-line Brown laying hens were randomly allocated to 5 dietary treatments, including a basal diet contained 0.33% NaCl (control group, 0.27% dietary Cl), and 4 experimental diets that contained 0.21% and 0.15% dietary Cl by substituting NaSO or NaHCO for part of NaCl in the basal diet. No significant differences were observed in blood Na, Cl, K and Ca levels and pH value as well as serum creatinine and uric acid contents among 5 treatments (P > 0.05). Dietary Cl reduction increased egg production and ADFI during wk 33 to 36, 37 to 40 and 29 to 40 of age and decreased feed conversion ratio during wk 37 to 40 of age (P < 0.05). The hens fed with diets containing 0.15% Cl increased eggshell breaking strength, thickness and weight ratio in wk 40 of age (P < 0.05). Birds fed with dietary 0.21% and 0.15% Cl exhibited higher effective layer thickness and lower mammillary layer thickness of eggshell than those fed with dietary 0.27% Cl (P < 0.05). Apparent Ca metabolizability of hens was increased with dietary Cl reduction (P < 0.05). Total Ca of eggshell of dietary 0.15% Cl group was higher than that of dietary 0.27% Cl group (P < 0.05). No significant differences in laying performance, eggshell quality and Ca metabolism of layers were observed between NaSO and NaHCO replacement groups (P > 0.05). Overall, dietary Cl reductions could improve laying performance and eggshell quality by substitution of NaHCO or NaSO for part of NaCl, and there were no differences in the improvements between these two substitutes. The improved eggshell quality may be attributed to improved eggshell ultrastructure and increased supply of eggshell CaCO.
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http://dx.doi.org/10.1016/j.psj.2021.101102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8181175PMC
March 2021

Development of a myelodysplastic/myeloproliferative neoplasm-unclassifiable in a patient with acute myeloid leukemia: a case report and literature review.

J Int Med Res 2021 May;49(5):3000605211018426

The First Hospital of Jilin University, Changchun, China.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) are a heterogeneous group of hematologic malignancies characterized by dysplastic and myeloproliferative overlapping features in the bone marrow and blood. The occurrence of the disease is related to age, prior history of MPN or MDS, and recent cytotoxic or growth factor therapy, but it rarely develops after acute myeloid leukemia (AML). We report a rare case of a patient diagnosed with AML with t(8; 21)(q22; q22) who received systematic chemotherapy. After 4 years of follow-up, MDS/MPN-unclassifiable occurred without signs of primary AML recurrence.
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http://dx.doi.org/10.1177/03000605211018426DOI Listing
May 2021

Downregulation of GLUT3 impairs STYK1/NOK-mediated metabolic reprogramming and proliferation in NIH-3T3 cells.

Oncol Lett 2021 Jul 14;22(1):527. Epub 2021 May 14.

Cell Engineering Laboratory, College of Biological Science and Engineering, Hebei University of Science and Technology, Shijiazhuang, Hebei 050018, P.R. China.

Serine threonine tyrosine kinase 1 (STYK1)/novel oncogene with kinase domain (NOK) has been demonstrated to promote cell carcinogenesis and tumorigenesis, as well as to strengthen cellular aerobic glycolysis, which is considered to be a defining hallmark of cancer. As the carriers of glucose into cells, glucose transporters (GLUTs) are important participants in cellular glucose metabolism and even tumorigenesis. However, to the best of our knowledge, the role of GLUTs in biological events caused by STYK1/NOK has not yet been reported. The present study assessed GLUT3 as a key transporter, and glucose consumption and lactate production assays revealed that downregulation of GLUT3 impaired STYK1/NOK-induced augmented glucose uptake and lactate production, and RT-qPCR and western blotting confirmed that GLUT3 knockdown attenuated the STYK1/NOK-induced increase in the expression levels of key enzymes implicated in glycolysis. Furthermore, MTT and Transwell assays demonstrated that STYK1/NOK-triggered cell proliferation and migration were also markedly decreased following knockdown of GLUT3. To the best of our knowledge, the present study is the first to demonstrate that GLUT3 serves a prominent role in STYK1/NOK-driven aerobic glycolysis and cell proliferation characteristics. These findings may provide a clue for the investigation of the oncogenic activity of STYK1/NOK and for the identification of potential tumor therapy targets associated with GLUT3.
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http://dx.doi.org/10.3892/ol.2021.12788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138895PMC
July 2021

[Network Meta-analysis of oral Chinese patent medicine for adjuvant treatment of primary liver cancer].

Zhongguo Zhong Yao Za Zhi 2021 May;46(9):2333-2343

Henan University of Chinese Medicine Zhengzhou 450046, China.

Network Meta-analysis was used to evaluate the efficacy and safety of different oral Chinese patent medicines combined with transcatheter arterial chemoembolization(TACE) in the treatment of primary liver cancer. Randomized controlled trials of oral Chinese patent medicines for primary liver cancer were retrieved from CNKI, Wanfang, VIP, SinoMed, PubMed, Cochrane Library and EMbase databases from inception to May 2020. According to the Cochrane recommendation standard, the quality of the included articles was evaluated, and the data were analyzed by RevMan, R software and GeMTC software. A total of 10 kinds of oral Chinese patent medicines and 68 RCTs were included. Network Meta-analysis results showed that: as compared with TACE alone, 10 kinds of oral Chinese patent medicines combined with TACE showed advantages in effective rate, 1-year survival rate, 2-year survival rate, KPS score improvement rate and reduced adverse reaction incidence. In the pairwise comparison of oral Chinese patent medicines, the results showed that Cidan Capsules were superior to Jinlong Capsules and Xihuang Pills in 1-year survival rate. According to the probabi-lity ranking results: Shenyi Capsules and Ganfule were more obvious in improving the effective rate; Cidan Capsules and Shenyi Capsules were more effective in improving the 1-year survival rate; Pingxiao Capsules and Shenyi Capsules had better efficacy in improving 2-year survival rate; Huaier Granules and Shenyi Capsules had better efficacy in improving the quality of life; Huisheng Oral Liquid and Ganfule were more effective in reducing the incidence of adverse reactions(such as nausea, vomiting and leukocytosis). The current evidence showed that oral Chinese patent medicine combined with TACE was superior to TACE alone in efficacy and safety. In terms of the effective rate, 1-year survival rate, 2-year survival rate, KPS score improvement rate and reduced adverse reaction incidence, the optimal treatment measures were Shenyi Capsules, Cidan Capsules, Pingxiao Capsules, Huaier Granules and Huisheng Oral Liquid in turn. However, due to the limitations of the research, the current level of evidence is not high, and clear conclusions and evi-dence strength still need to be further verified and improved by high-quality researches.
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http://dx.doi.org/10.19540/j.cnki.cjcmm.20200721.501DOI Listing
May 2021

Fabrication of a robust MOF/aerogel composite a covalent post-assembly method.

Chem Commun (Camb) 2021 Jun;57(48):5961-5964

Department of Chemistry, College of Sciences, Northeastern University, Shenyang 110819, China.

A covalent post-assembly strategy is developed to prepare a composite of dispersive MOF particles in an aerogel matrix. Briefly, the anhydride group-decorated MOF (UiO-66-NH2) particles covalently coupled with polyimide (PI) monomers through a one-pot amidation polymerization reaction, succeeding a process of gel-sol, freeze-drying and thermal-imidization to obtain the UiO-66-PI aerogel. The designed composite shows outstanding catalytic activity in CO2 cycloaddition and excellent adsorption capacity for dyes.
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http://dx.doi.org/10.1039/d1cc01613jDOI Listing
June 2021

Ginseng polysaccharides alter the gut microbiota and kynurenine/tryptophan ratio, potentiating the antitumour effect of antiprogrammed cell death 1/programmed cell death ligand 1 (anti-PD-1/PD-L1) immunotherapy.

Gut 2021 May 18. Epub 2021 May 18.

Dr Neher's Biophysics Laboratory for Innovative Drug Discovery/State Key laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau, China.

Objective: Programmed death 1 and its ligand 1 (PD-1/PD-L1) immunotherapy is promising for late-stage lung cancer treatment, however, the response rate needs to be improved. Gut microbiota plays a crucial role in immunotherapy sensitisation and has been shown to possess immunomodulatory potential. In this study, we aimed to investigate whether the combination treatment of ginseng polysaccharides (GPs) and αPD-1 monoclonal antibody (mAb) could sensitise the response by modulating gut microbiota.

Design: Syngeneic mouse models were administered GPs and αPD-1 mAb, the sensitising antitumour effects of the combination therapy on gut microbiota were assessed by faecal microbiota transplantation (FMT) and 16S PacBio single-molecule real-time (SMRT) sequencing. To assess the immune-related metabolites, metabolomics analysis of the plasma samples was performed.

Results: We found GPs increased the antitumour response to αPD-1 mAb by increasing the microbial metabolites valeric acid and decreasing L-kynurenine, as well as the ratio of Kyn/Trp, which contributed to the suppression of regulatory T cells and induction of T cells after combination treatment. Besides, the microbial analysis indicated that the abundance of and was higher in responders to anti-PD-1 blockade than non-responders in the clinic. Furthermore, the combination therapy sensitised the response to PD-1 inhibitor in the mice receiving microbes by FMT from six non-responders by reshaping the gut microbiota from non-responders towards that of responders.

Conclusion: Our results demonstrate that GPs combined with αPD-1 mAb may be a new strategy to sensitise non-small cell lung cancer patients to anti-PD-1 immunotherapy. The gut microbiota can be used as a novel biomarker to predict the response to anti-PD-1 immunotherapy.
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http://dx.doi.org/10.1136/gutjnl-2020-321031DOI Listing
May 2021

Hepatotoxic evaluation of toosendanin via biomarker quantification and pathway mapping of large-scale chemical proteomics.

Food Chem Toxicol 2021 Jul 15;153:112257. Epub 2021 May 15.

State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau SAR, 999078, PR China. Electronic address:

Drug-induced liver injury (DILI) is a major side effect, sometimes can't be exactly evaluated by current approaches partly as the covalent modification of drug or its reactive metabolites (RMs) with proteins is a possible reason. In this study, we developed a rapid, sensitive, and specific analytical method to assess the hepatotoxicity induced by drug covalently modified proteins based on the quantification of the modified amino acids using toosendanin (TSN), a hepatotoxic chemical, as an example. TSN RM-protein adducts both in rat liver and blood showed good correlation with the severity of hepatotoxicity. Thus, TSN RM-protein adducts in serum can potentially serve as minimally invasive biomarkers of hepatotoxicity. Meanwhile, large-scale chemical proteomics analysis showed that at least 84 proteins were modified by TSN RMs in rat liver, and the bioinformatics analysis revealed that TSN might induce hepatotoxicity through multi-target protein-protein interaction especially involved in energy metabolism. These findings suggest that our approach may serve as a valuable tool to evaluate DILI and investigate the possible mechanism, especially for complex compounds.
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http://dx.doi.org/10.1016/j.fct.2021.112257DOI Listing
July 2021

Dietary supplemental xylooligosaccharide modulates nutrient digestibility, intestinal morphology, and gut microbiota in laying hens.

Anim Nutr 2021 Mar 12;7(1):152-162. Epub 2021 Feb 12.

Laboratory of Quality & Safety Risk Assessment for Animal Products on Feed Hazards (Beijing) of the Ministry of Agriculture & Rural Affairs, and National Engineering Research Center of Biological Feed, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, 100081, China.

This study was conducted to evaluate the prebiotic effects of dietary xylooligosaccharide (XOS) supplementation on performance, nutrient digestibility, intestinal morphology, and gut microbiota in laying hens. In a 12-wk experiment, a total of 288 Hy-Line Brown layers at 50 wk of age were randomly assigned into 3 dietary treatments supplemented with XOS at 0, 200 or 400 mg/kg. Each treatment had 8 replicates with 12 birds each. Hens fed XOS diets showed a lower feed-to-egg ratio during wk 7 to 12 and a higher egg yolk color value in wk 12 compared with those fed the control diet ( < 0.05). Dietary XOS supplementation improved the apparent total tract digestibility of gross energy and nitrogen at the end of the 12th wk ( < 0.05). In addition, a higher villus height-to-crypt depth ratio of the ileum was observed in XOS-added groups ( < 0.05). The high throughput sequencing analysis of bacterial 16S rRNA revealed that dietary XOS supplementation at 200 mg/kg altered cecal microbiota. Alpha diversity analysis illustrated a higher cecal bacterial richness in birds fed with XOS at 200 mg/kg. The composition of cecal microbiota modulated by the XOS addition was characterized by an increased abundance of Firmicutes along with a reduced abundance of Bacteroidetes. At the genus level, dietary XOS supplementation triggered decreases in and concurrent with increases in and several short chain fatty acid producers including , , , and 5 genera of family Lachnospiraceae. Collectively, dietary XOS addition improved the feed conversion ratio by modulating nutrient digestibility and ileal morphology in laying hens, which could be attributed to the enhancement of bacterial diversity and alteration of microbial composition.
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http://dx.doi.org/10.1016/j.aninu.2020.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110867PMC
March 2021

Tunable reflective dual-band line-to-circular polarization convertor with opposite handedness based on graphene metasurfaces.

Opt Express 2021 Apr;29(9):13373-13387

In this letter, we propose a dual-band tunable reflective linear-to-circular (LTC) polarization converter, which is composed of a graphene sheet etched with an I-shaped carved-hollow array. In the mid-infrared region, two LTC bands with opposite handedness are simultaneously realized due to the excitation of the three graphene surface plasmon (GSP) modes. The band of line-to-right-circular-polarization (LTRCP) ranges from 9.87 to 11.03THz with ellipticity χ <-0.95, and from 9.69 to 11.36 THz with an axial ratio of less than 3 dB; the band of line-to-left-circular-polarization (LTLCP) ranges from 13.16 to 14.43THz with χ >0.95, and from 12.79 to 14.61 THz with an axial ratio of less than 3 dB. The tunable responses of the reflective polarizer with Fermi energy (Ef) and electron scattering time (τ) are discussed, and especially the perfect LTLCP can be changed to LTRCP with increasing Ef. Also, the influences of geometric parameters, incident angle, and polarization angle on the performances of the dual-band LTC are also investigated, and it is found that our polarizer converter shows angle insensitivity. All simulation results are conducted by the finite element method. Our design enriches the research of tunable LTC polarizers and has potential applications in integrated terahertz systems.
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http://dx.doi.org/10.1364/OE.423017DOI Listing
April 2021

The Protective Effect of 1,25(OH)D on Myocardial Function is Mediated Sirtuin 3-Regulated Fatty Acid Metabolism.

Front Cell Dev Biol 2021 26;9:627135. Epub 2021 Apr 26.

Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang, China.

Energy substrate imbalance is a major cause of cardiac dysfunction. Vitamin D/vitamin D receptor (VD/VDR) deficiency is involved in the pathogenesis of various cardiac diseases; however, the exact underlying mechanism remains unclear. The aim of this study was to investigate whether vitamin D modulates mitochondrial fatty acid oxidase sirtuin 3 signaling to protect the myocardium. 1-Alpha-hydroxylase-defficient mice exhibited a high metabolic rate and lower myocardial contractility than wild-type mice. Sirtuin 3 upregulation was detected in high-fat diet-fed mice receiving vitamin D3 compared with that in high-fat diet-fed mice. Both sirtuin 3 blockade and knockout inhibited the VD/VDR-induced downregulation of fatty acid oxidase in myocardial mitochondria. VD/VDR suppressed fatty acid metabolism by upregulating sirtuin 3 and lowering mitochondrial fat uptake, thereby improving myocardial function and balancing energy substrates, rather than by altering fat endocytosis and exocytosis.
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http://dx.doi.org/10.3389/fcell.2021.627135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107292PMC
April 2021

Association of Rotavirus Vaccines With Reduction in Rotavirus Gastroenteritis in Children Younger Than 5 Years: A Systematic Review and Meta-analysis of Randomized Clinical Trials and Observational Studies.

JAMA Pediatr 2021 May 10:e210347. Epub 2021 May 10.

Department of Laboratory Medicine, the First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, China.

Importance: Rotavirus vaccines have been introduced worldwide, and the clinical association of different rotavirus vaccines with reduction in rotavirus gastroenteritis (RVGE) after introduction are noteworthy.

Objective: To evaluate the comparative benefit, risk, and immunogenicity of different rotavirus vaccines by synthesizing randomized clinical trials (RCTs) and observational studies.

Data Sources: Relevant studies published in 4 databases: Embase, PubMed, the Cochrane Library, and Web of Science were searched until July 1, 2020, using search terms including "rotavirus" and "vaccin*."

Study Selection: Randomized clinical trials and cohort and case-control studies involving more than 100 children younger than 5 years that reported the effectiveness, safety, or immunogenicity of rotavirus vaccines were included.

Data Extraction And Synthesis: A random-effects model was used to calculate relative risks (RRs), odds ratios (ORs), risk differences, and 95% CIs. Adjusted indirect treatment comparison was performed to assess the differences in the protection of Rotarix and RotaTeq.

Main Outcomes And Measures: The primary outcomes were RVGE, severe RVGE, and RVGE hospitalization. Safety-associated outcomes involved serious adverse events, intussusception, and mortality.

Results: A meta-analysis of 20 RCTs and 38 case-control studies revealed that Rotarix (RV1) significantly reduced RVGE (RR, 0.316 [95% CI, 0.224-0.345]) and RVGE hospitalization risk (OR, 0.347 [95% CI, 0.279-0.432]) among children fully vaccinated; RotaTeq (RV5) had similar outcomes (RVGE: RR, 0.350 [95% CI, 0.275-0.445]; RVGE hospitalization risk: OR, 0.272 [95% CI, 0.197-0.376]). Rotavirus vaccines also demonstrated higher protection against severe RVGE. Additionally, no significant differences in the protection of RV1 and RV5 against rotavirus disease were noted in adjusted indirect comparisons. Moderate associations were found between reduced RVGE risk and Rotavac (RR, 0.664 [95% CI, 0.548-0.804]), Rotasiil (RR, 0.705 [95% CI, 0.605-0.821]), and Lanzhou lamb rotavirus vaccine (RR, 0.407 [95% CI, 0.332-0.499]). All rotavirus vaccines demonstrated no risk of serious adverse events. A positive correlation was also found between immunogenicity and vaccine protection (eg, association of RVGE with RV1: coefficient, -1.599; adjusted R2, 99.7%).

Conclusions And Relevance: The high protection and low risk of serious adverse events for rotavirus vaccines in children who were fully vaccinated emphasized the importance of worldwide introduction of rotavirus vaccination. Similar protection provided by Rotarix and RotaTeq relieves the pressure of vaccines selection for health care authorities.
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http://dx.doi.org/10.1001/jamapediatrics.2021.0347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111566PMC
May 2021

A Programmed Cell-Mimicking Nanoparticle Driven by Potato Alkaloid for Targeted Cancer Chemoimmunotherapy.

Adv Healthc Mater 2021 May 8:e2100311. Epub 2021 May 8.

Medical Research Institute, College of Pharmaceutical Sciences, Southwest University, Chongqing, 400715, China.

Membrane camouflaged-nanoparticles (CM-NPs) have been exploited to inherit desired functionalities from source cells. Despite those advantages, membrane cloak may play a "double-edged sword" role in tumor-targeting therapy, as the intact membrane coating may hinder function-exertion of loaded drugs after reaching predetermined site. Therefore, further optimization of CM-NPs is still needed to enhance their delivery efficiency. Herein, natural product, Solamargine (SM), a cholesterol-affiliative amphiphilic potato alkaloid is first applied as core component of "inner core," to design a cell-mimicking "core-shell" nanoparticle (RBC-SLip) with acid-responsive off-coating properties for tumor-targeted therapy. Owing to red blood cell membrane (RBCm)-derived outer coating, it circulates stably in physiological conditions. While it would undergo an off-coating morphological change in response to acid stimuli in tumor microenvironment (TME), afterwards, the resulting off-coating liposome (SLip) shows active tumor-targeting and endosomal escape abilities, thus contributing to superior antitumor efficacy. In addition, SM also possesses natural TME-modulating ability; therefore, RBC-SLip can synergize with the PD1/PD-L1 blockade immunotherapy when encapsulated with PTX to achieve enhanced chemoimmunotherapy. The off-coating strategy developed by natural products SM, provide a brand-new perspective to optimize CM-NPs, and it also embodies application value of "unification of medicines and excipients" of natural products.
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http://dx.doi.org/10.1002/adhm.202100311DOI Listing
May 2021

A distinct parabrachial-to-lateral hypothalamus circuit for motivational suppression of feeding by nociception.

Sci Adv 2021 May 7;7(19). Epub 2021 May 7.

Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), 138667, Singapore.

The motivation to eat is not only shaped by nutrition but also competed by external stimuli including pain. How the mouse hypothalamus, the feeding regulation center, integrates nociceptive inputs to modulate feeding is unclear. Within the key nociception relay center parabrachial nucleus (PBN), we demonstrated that neurons projecting to the lateral hypothalamus (PBN) are nociceptive yet distinct from danger-encoding central amygdala-projecting (PBN) neurons. Activation of PBN strongly suppressed feeding by limiting eating frequency and also reduced motivation to work for food reward. Refined approach-avoidance paradigm revealed that suppression of PBN, but not PBN, sustained motivation to obtain food. The effect of PBN neurons on feeding was reversed by suppressing downstream LH neurons. Thus, distinct from a circuit for fear and escape responses, PBN neurons channel nociceptive signals to LH neurons to suppress motivational drive for feeding. Our study provides a new perspective in understanding feeding regulation by external competing stimuli.
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http://dx.doi.org/10.1126/sciadv.abe4323DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104871PMC
May 2021

Deciphering superior quality of Pu-erh tea from thousands of years' old trees based on the chemical profile.

Food Chem 2021 Oct 26;358:129602. Epub 2021 Mar 26.

State Key Laboratory of Quality Research in Chinese Medicine, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Avenida Wai Long, Taipa 999078, Macau Special Administrative Region. Electronic address:

Pu-erh teas from thousands of years' old trees (TPT) equip with both superior flavors and powerful antioxidative capacities. With UHPLC-Q-TOF-MS approach, TPTs' chemical profiles were characterized by comparing with Pu-erh teas from ecological trees (EPT). TPTs are discovered to possess higher contents of amino acids, fatty acids, phenolic acids, nucleosides and nucleobases but lower contents of flavonoids and caffeine congeners based on 117 discriminative constituents from 305 identified ones. Particularly, a series of caffeic acid congeners including ten new hydroxycinnamic acid depsides with higher contents in TPTs are discovered, and caffeic acid with a fold change of 638 is the foremost discriminative component. Furthermore, distinguishing constituent proportion including caffeic acid congeners in TPTs are found to take great responsibilities for their more powerful antioxidative abilities and superior flavors especially more aroma and pleasant bitterness. This research provides information for deciphering formation of TPTs' superior qualities based on chemical profile.
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http://dx.doi.org/10.1016/j.foodchem.2021.129602DOI Listing
October 2021

NSL2CD: identifying potential circRNA-disease associations based on network embedding and subspace learning.

Brief Bioinform 2021 May 5. Epub 2021 May 5.

Hunan University, China.

Many studies have evidenced that circular RNAs (circRNAs) are important regulators in various pathological processes and play vital roles in many human diseases, which could serve as promising biomarkers for disease diagnosis, treatment and prognosis. However, the functions of most of circRNAs remain to be unraveled, and it is time-consuming and costly to uncover those relationships between circRNAs and diseases by conventional experimental methods. Thus, identifying candidate circRNAs for human diseases offers new opportunities to understand the functional properties of circRNAs and the pathogenesis of diseases. In this study, we propose a novel network embedding-based adaptive subspace learning method (NSL2CD) for predicting potential circRNA-disease associations and discovering those disease-related circRNA candidates. The proposed method first calculates disease similarities and circRNA similarities by fully utilizing different data sources and learns low-dimensional node representations with network embedding methods. Then, we adopt an adaptive subspace learning model to discover potential associations between circRNAs and diseases. Meanwhile, an integrated weighted graph regularization term is imposed to preserve local geometric structures of data spaces, and L1,2-norm constraint is also incorporated into the model to realize the smoothness and sparsity of projection matrices. The experiment results show that NSL2CD achieves comparable performance under different evaluation metrics, and case studies further confirm its ability to discover potential candidate circRNAs for human diseases.
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http://dx.doi.org/10.1093/bib/bbab177DOI Listing
May 2021

Preoperative prediction of perineural invasion with multi-modality radiomics in rectal cancer.

Sci Rep 2021 May 3;11(1):9429. Epub 2021 May 3.

Department of Radiology, The First Hospital of Jilin University, Jilin Provincial Key Laboratory of Medical Imaging and Big Data, Changchun, China.

Perineural invasion (PNI) as a grossly underreported independent risk predictor in rectal cancer is hard to identify preoperatively. We aim to predict PNI status in rectal cancer using multi-modality radiomics. In total, 396 radiomics features were extracted from T2-weighted images (T2WIs), diffusion-weighted images (DWIs), and portal venous phase of contrast-enhanced CT (CE-CT) respectively of 94 consecutive patients with histologically confirmed rectal cancer. T2WI score, DWI score, and CT score were calculated via the radiomics features selection and optimization. Discrimination, calibration, and clinical benefit ability were used to evaluate the performance of the radiomics scores in both training and testing datasets. CT score and T2WI score were independent risk predictors [CT score, OR (95% CI) = 4.218 (1.070-16.620); T2WI score, OR (95% CI) = 105.721 (3.091-3615.790)]. The concise score which combined CT score and T2WI score, showed the best performance [training dataset, AUC (95% CI) = 0.906 (0.833-0.979); testing dataset, AUC (95% CI) = 0.884 (0.761-1.000)] and good calibration (P > 0.05 in the Hosmer-Lemeshow test for the training and testing datasets). Decision curve analysis showed that the multi-modality radiomics nomogram had a higher clinical net benefit. The multi-modality radiomics score could be used to preoperatively assess PNI status in rectal cancer.
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http://dx.doi.org/10.1038/s41598-021-88831-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093213PMC
May 2021

Combined topical and systemic administration with human adipose-derived mesenchymal stem cells (hADSC) and hADSC-derived exosomes markedly promoted cutaneous wound healing and regeneration.

Stem Cell Res Ther 2021 May 1;12(1):257. Epub 2021 May 1.

Research Center for Translational Medicine, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.

Background: Cutaneous wound healing and regeneration have become a recognized health challenge in the world, which causes severe damage to the mental and physical health of patients. Human adipose-derived mesenchymal stem cells (hADSC) play an essential role in wound healing via their paracrine function. Exosomes secreted by hADSC may contribute to this progress. In this study, we investigated the potential clinical application roles of hADSC and hADSC-derived exosomes (hADSC-Exo) in cutaneous wound healing.

Methods: hADSC-Exo was isolated from human hADSC by ultracentrifugation. Mice were subjected to a full-thickness skin biopsy experiment and treated with either control vehicle or hADSC or hADSC-Exo by smearing administration (sm) or subcutaneous administration (sc) or intravenous administration (iv). The efficacy of hADSC and hADSC-Exo on wound healing was evaluated by measuring wound closure rates, histological analysis.

Results: Combined application of local hADSC-Exo smearing and hADSC/hADSC-Exo intravenous administration offered the additional benefit of promoting wound healing, accelerating re-epithelialization, reducing scar widths, and enhancing angiogenesis and collagen synthesis. Either topical application of hADSC-Exo or systemic administration with hADSC/hADSC-Exo appeared more effective in stimulating cell proliferation, inhibiting cell apoptosis and inflammation, and promoting skin elasticity and barrier integrity, with increased genes expression of PCNA, VEGF, collagen III, Filaggrin, Loricrin, and AQP3, with decreased genes expression of TNF-alpha.

Conclusion: Our findings suggest that the combined administration of hADSC/hADSC-Exo can facilitate cutaneous wound healing and reduce scar formation. These data provide the first evidence for the feasibility of smearing of hADSC-Exo as a cell-free therapy in treating cutaneous wounds, and the potential clinical value of combined administration of hADSC/hADSC-Exo.
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http://dx.doi.org/10.1186/s13287-021-02287-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088044PMC
May 2021

An opioid receptor-independent mechanism underlies motility dysfunction and visceral hyperalgesia in opioid-induced bowel dysfunction.

Am J Physiol Gastrointest Liver Physiol 2021 Jun 28;320(6):G1093-G1104. Epub 2021 Apr 28.

Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas.

Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As patients with OBD often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms. A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed with normal pellet food, or with clear liquid diet. Morphine treatment (Mor) reduced fecal outputs starting on , and caused fecal retention afterward. Compared with controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability, and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was upregulated in the smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked upregulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats. Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in rats with OBD. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechanotranscription of COX-2 and NGF. Our preclinical study shows that fecal retention is a pathogenic factor in opioid-induced bowel dysfunction, as prevention of fecal retention with liquid diet improved motility and attenuated visceral hyperalgesia in morphine-treated animals by blocking expression of cyclooxygenase-2 and nerve growth factor in the colon.
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http://dx.doi.org/10.1152/ajpgi.00400.2020DOI Listing
June 2021

Study of melanocyte density and epidermal thickness in vulvar lichen sclerosus lesions.

Int J Dermatol 2021 Apr 18. Epub 2021 Apr 18.

Department of Dermatology, Beijing Hospital, National Center of Gerontology, Beijing, China.

Objective: This study aimed to analyze changes in melanocyte density and epidermal thickness in vulvar lichen sclerosus (VLS).

Methods: Vulvar skin tissues were collected from 15 VLS female patients in Beijing Hospital, classified into early (n = 7) and late VLS (n = 8) groups according to pathological manifestations. Melanocyte density and full epidermal and cell-layer (from the bottom of the stratum corneum to that of the basal layer) thickness were calculated using an image analysis software. The control group was normal vulvar skin tissues from 15 females after plastic surgery.

Results: The early VLS (0.170 ± 0.071 µm) and late VLS (0.110 ± 0.035 µm) groups had significantly lower densities of epidermal melanocytes than the control group (0.275 ± 0.036) (F = 36.426, P < 0.001). The cell-layer thickness did not differ between the early VLS (154.603 ± 121.984 µm) and control (176.974 ± 80.296 µm) groups (P = 0.899) but significantly decreased in the late VLS group (83.455 ± 37.129 µm) compared to the control group (P = 0.003).

Conclusions: Melanocyte density decreased in early and late VLS. The full epidermal and cell-layer thickness did not significantly change in early VLS, but the cell-layer thickness decreased in late VLS.
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http://dx.doi.org/10.1111/ijd.15555DOI Listing
April 2021

Identification of the canonical and noncanonical role of miR-143/145 in estrogen-deficient bone loss.

Theranostics 2021 13;11(11):5491-5510. Epub 2021 Mar 13.

Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China.

Postmenopausal-induced bone loss is mainly caused by declining core transcription factors (TFs) of bone mesenchymal stem cells (BMSCs), but little is known about how miRNAs regulate chromatin structure remodeling of TFs gene to maintain BMSCs function in bone homeostasis. We examined the serum, salivary and bone samples from Pre- and Post-menopause women by paired analysis and confirmed canonical ceRNA role of MIR143HG and miR-143/145 complexes in cytoplasm and noncanonical role for SOX2 transcription in nucleus (FISH, qRT-PCR, immunostaining, Luciferase assays and ChIP). Moreover, we took advantage of transgenic mice under OVX-induced osteoporosis, studying the and effect of miR-143/145 deletion on BMSCs function and bone homeostasis. Last, using miRNA antagonism, antagomiR-143/145 were delivered into bone marrow to treat estrogen-deficient bone loss. Here, we identified miR-143/145 as potential diagnostic candidates for postmenopausal osteoporosis, and miR-143/145 overexpression impaired BMSCs self-renewing and differentiation function. Mechanistically, we confirmed that cytoplasmic miR-143/145 and LncRNA MIR143HG, that controlled by ERβ, cooperatively regulated pluripotency genes translation via canonical ceRNA pathway, and MIR143HG cooperates with miR‑143 to nuclear translocation for co-activation of SOX2 transcription via opening promoter chromatin. Meanwhile, miR‑143/145 were shuttled into osteoclasts in extracellular vesicles and triggered osteoclastic activity by targeting Cd226 and Srgap2. Furthermore, mice or using chemically‑modified antagomiR-143/145 significantly alleviated estrogen-deficient osteoporosis. Our findings reveal a canonical and noncanonical role of miR-143/145 in controlling BMSCs pluripotency and unfold their dual effect on bone formation and bone resorption, suggesting miR-143/145 as promising therapeutic targets for treating estrogen-deficient bone loss.
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http://dx.doi.org/10.7150/thno.55041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039936PMC
March 2021

Inhibition of lung cancer by vitamin D depends on downregulation of histidine-rich calcium-binding protein.

J Adv Res 2021 03 27;29:13-22. Epub 2020 Aug 27.

Department of Clinical Nutrition, Shengjing Hospital of China Medical University, Shenyang 110004, China.

Introduction: Intrinsic vitamin D affects the proliferation, apoptosis, invasion, metastasis, and tumorigenesis of lung cancer by regulating tumor signaling pathways. Histidine-rich calcium-binding protein (HRC) maintains Ca homeostasis, which plays crucial roles in the occurrence and development of cancer.

Objectives: Our study aims to investigate the ability of vitamin D in the regulation of HRC and the role of HRC playing in lung cancer.

Methods: We investigated the effects of vitamin D on lung cancer and the underlying mechanisms, by measuring HRC and vitamin D receptor (VDR) expression in lung cancer, paracancer, and normal tissues from patients using immunohistochemistry, western blotting, and real time RT-PCR. We transfected H460 lung cancer cells (supplemented or not with vitamin D) with PX458-HRC and pcDNA3.1-HRC plasmids and injected mice with lung cancer cells harboring pcDNA3.1-vector or pcDNA3.1-HRC plasmids.

Results: Vitamin D inhibited HRC expression and H460 cell migration and proliferation, and promoted apoptosis compared with controls. The expression of HRC and VDR was significantly upregulated and downregulated, respectively, in lung cancer versus paracancer or normal tissues. Cell proliferation and migration were reduced, apoptotic cells were more and tumors were smaller in mice treated with vitamin D/cholecalciferol cholesterol emulsion (CCE) than in vitamin D/CCE+HRC mice.

Conclusion: Vitamin D inhibited lung cancer tumor growth, migration, and proliferation by downregulating HRC.
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http://dx.doi.org/10.1016/j.jare.2020.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020154PMC
March 2021