Publications by authors named "Xiaozhe Zhang"

86 Publications

IP-assisted CSN-COP1 competition regulates a CRL4-ETV5 proteolytic checkpoint to safeguard glucose-induced insulin secretion.

Nat Commun 2021 04 28;12(1):2461. Epub 2021 Apr 28.

School of Life Sciences, Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China.

COP1 and COP9 signalosome (CSN) are the substrate receptor and deneddylase of CRL4 E3 ligase, respectively. How they functionally interact remains unclear. Here, we uncover COP1-CSN antagonism during glucose-induced insulin secretion. Heterozygous Csn2 mice with partially disrupted binding of IP, a CSN cofactor, display congenital hyperinsulinism and insulin resistance. This is due to increased Cul4 neddylation, CRL4 E3 assembly, and ubiquitylation of ETV5, an obesity-associated transcriptional suppressor of insulin secretion. Hyperglycemia reciprocally regulates CRL4-CSN versus CRL4 assembly to promote ETV5 degradation. Excessive ETV5 degradation is a hallmark of Csn2, high-fat diet-treated, and ob/ob mice. The CRL neddylation inhibitor Pevonedistat/MLN4924 stabilizes ETV5 and remediates the hyperinsulinemia and obesity/diabetes phenotypes of these mice. These observations were extended to human islets and EndoC-βH1 cells. Thus, a CRL4-ETV5 proteolytic checkpoint licensing GSIS is safeguarded by IP-assisted CSN-COP1 competition. Deregulation of the IP-CSN-CRL4-ETV5 axis underlies hyperinsulinemia and can be intervened to reduce obesity and diabetic risk.
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http://dx.doi.org/10.1038/s41467-021-22941-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080631PMC
April 2021

Computational exploration of natural peptides targeting ACE2.

J Biomol Struct Dyn 2021 Apr 7:1-12. Epub 2021 Apr 7.

CAS Key Laboratory of Separation Sciences of Analytical Chemistry, Dalian Institute of Chemical Physics, Dalian, China.

Interaction between the SARS-COV-2 (2019 novel coronavirus) spike protein and ACE2 receptors expressed on cellular surfaces initialises viral attachment and consequent infection. Blocking this interaction shows promise for blocking or ameliorating the virus' pathological effects on the body. By contrast to work focusing on the coronavirus, which has significant potential diversity through possible accumulation of mutations during transmission, targeting the conserved ACE2 protein expressed on human cells offers an attractive alternative route to developing pharmacological prophylactics against viral invasion. In this study, we screened a virtual database of natural peptides , with ACE2 as the target, and performed structural analyses of the interface region in the SARS-COV-2 RBD/ACE2 complex. These analyses have identified 15 potentially effective compounds. Analyses of ACE2/polypeptide interactions suggest that these peptides can block viral invasion of cells by stably binding in the ACE2 active site pocket. Molecular simulation results for Complestatin and Valinomycin indicate that they may share this mechanism. The discovery of this probable binding mechanism provides a frame of reference for further optimization, and design of high affinity ACE2 inhibitors that could serve as leads for production of drugs with preventive and therapeutic effects against SARS-COV-2.Communicated by Ramaswamy H. Sarma.
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http://dx.doi.org/10.1080/07391102.2021.1905555DOI Listing
April 2021

Pentamode metamaterials with ultra-low-frequency single-mode band gap based on constituent materials.

J Phys Condens Matter 2021 Apr 23;33(18). Epub 2021 Apr 23.

School of Materials Science and Engineering, Xi'an Polytechnic University, Xi'an 710048, People's Republic of China.

An effective method for realizing ultra-low-frequency single-mode band gap in pentamode metamaterials is proposed based on constituent materials. Results show that the decreasing ratio/(stiffness/mass density) of constituent material can significantly lower the frequency range of single-mode band gap. By merely replacing the constituent material from Al to rubber, the center frequencyof single-mode band gap can be reduced nearly 600 times (from 3621 Hz to 6.5 Hz), while the normalized bandwidth Δ/and the ratio of bulk modulusto shear modulusof pentamode structure keep substantially stable. The nonlinear fitting demonstrates that the relation betweenand/satisfies the logarithmic function. The two-component pentamode structure is designed to further explore the ultra-low-frequency single-mode band gap. The effects of thick-end diameterof double-cone, diameterand material type of additional sphere, on single-mode band gap of two-component system are analyzed. This work is attractive for several ∼Hz acoustic/elastic wave regulations using pentamode metamaterials.
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http://dx.doi.org/10.1088/1361-648X/abeebdDOI Listing
April 2021

Small-molecule antagonist of VLA-4 (GW559090) attenuated neuro-inflammation by targeting Th17 cell trafficking across the blood-retinal barrier in experimental autoimmune uveitis.

J Neuroinflammation 2021 Feb 18;18(1):49. Epub 2021 Feb 18.

UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London, EC1V 9EL, UK.

Background: The integrin VLA-4 (α4β1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical α4β1 integrin inhibitor (GW559090, GW) in a mouse model for non-infectious posterior uveitis (experimental autoimmune uveitis; EAU) and its effect on intraocular leukocyte subsets.

Methods: Mice (female; B10.RIII or C57Bl/6; aged 6-8 weeks) were immunized with specific interphotoreceptor retinoid-binding protein (IRBP) peptides to induce EAU. Topically administered GW (3, 10, and 30 mg/ml) were given twice daily either therapeutically once disease was evident, or prophylactically, and compared with vehicle-treated (Veh) and 0.1% dexamethasone-treated (Dex) controls. Mice were sacrificed at peak disease. The retinal T cell subsets were investigated by immunohistochemistry and immunofluorescence staining. The immune cells within the retina, blood, and draining lymph nodes (dLNs) were phenotyped by flow cytometry. The effect of GW559090 on non-adherent, adherent, and migrated CD4 T cell subsets across a central nervous system (CNS) endothelium was further assayed in vitro and quantitated by flow cytometry.

Results: There was a significant reduction in clinical and histological scores in GW- and Dex-treated groups as compared to controls either administered therapeutically or prophylactically. There were fewer CD45 leukocytes infiltrating the retinae and vitreous fluids in the treated GW group (P < 0.05). Immunofluorescence staining and flow cytometry data identified decreased levels of retinal Th17 cells (P ≤ 0.001) in the GW-treated eyes, leaving systemic T cell subsets unaffected. In addition, fewer Ly6C inflammatory monocyte/macrophages (P = 0.002) and dendritic cells (P = 0.017) crossed the BRB following GW treatment. In vitro migration assays confirmed that Th17 cells were selectively suppressed by GW559090 in adhering to endothelial monolayers.

Conclusions: This α4β1 integrin inhibitor may exert a modulatory effect in EAU progression by selectively blocking Th17 cell migration across the blood-retinal barrier without affecting systemic CD4 T cell subsets. Local α4β1 integrin-directed inhibition could be clinically relevant in treating a Th17-dominant form of uveitis.
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http://dx.doi.org/10.1186/s12974-021-02080-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893745PMC
February 2021

Prognosis of Ocular Tuberculosis Following Long-Term Antitubercular Therapy.

J Ocul Pharmacol Ther 2021 05 1;37(4):241-247. Epub 2021 Feb 1.

Department of Ophthalmology, Eye Institute, Eye and ENT Hospital, Fudan University, Shanghai, China.

This study presents clinical features and prognosis after long-term (12-18 months) antitubercular therapy (ATT) in patients with ocular tuberculosis (OTB) in East China, an endemic area of tuberculosis. This retrospective study reviewed data from OTB patients treated at the Eye and ENT Hospital of Fudan University from 2008 to 2018. All the patients completed a minimum follow-up of 6 months after the cessation of ATT. Sixty-six patients with OTB were studied. The ocular manifestations included retinal vasculitis (51.6%), choroiditis (24.2%), panuveitis (23.2%), intermediate uveitis (7.4%), scleritis (5.3%), anterior uveitis (2.1%), and optic neuropathy (1%). Except for two patients (ATT for 6 months), all other patients (64/66, 96.97%) received ATT for at least 12 months (6 patients for 12 months, 30 patients for 15 months, and 28 patients for 18 months). Treatment in conjunction with oral corticosteroids was used in 48 patients (72.7%). The average initial best-corrected visual acuity (BCVA) was 0.8 ± 0.64 (LogMAR), which improved to 0.31 ± 0.35 (LogMAR) at the last follow-up ( < 0.05). The final BCVA was significantly associated with the initial BCVA and the duration of clinical symptoms. A complete remission of uveitis was achieved in 97% of the patients. This study observed a favorable prognosis with long-term ATT regimens. Patients with better baseline visual acuity and a shorter duration of clinical symptoms before diagnosis had a better prognosis.
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http://dx.doi.org/10.1089/jop.2020.0100DOI Listing
May 2021

Untargeted Metabolomic Characterization of Ovarian Tumors.

Cancers (Basel) 2020 Dec 4;12(12). Epub 2020 Dec 4.

Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

Diagnosis of ovarian cancer is difficult due to the lack of clinical symptoms and effective screening algorithms. In this study, we aim to develop models for ovarian cancer diagnosis by detecting metabolites in urine and plasma samples. Ultra-high-performance liquid chromatography and quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) in positive ion mode was used for metabolome quantification in 235 urine samples and 331 plasma samples. Then, Urine and plasma metabolomic profiles were analyzed by univariate and multivariate statistics. Four groups of samples: normal control, benign, borderline and malignant ovarian tumors were enrolled in this study. A total of 1330 features and 1302 features were detected from urine and plasma samples respectively. Based on two urine putative metabolites, five plasma putative metabolites and five urine putative metabolites, three models for distinguishing normal-ovarian tumors, benign-malignant (borderline + malignant) and borderline-malignant ovarian tumors were developed respectively. The AUC (Area Under Curve) values were 0.987, 0876 and 0.943 in discovery set and 0.984, 0.896 and 0.836 in validation set for three models. Specially, the diagnostic model based on 5 plasma putative metabolites had better early-stage diagnosis performance than CA125 alone. The AUC values of the model were 0.847 and 0.988 in discovery and validation set respectively. Our results showed that normal and ovarian tumors have unique metabolic signature in urine and plasma samples, which shed light on the ovarian cancer diagnosis and classification.
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http://dx.doi.org/10.3390/cancers12123642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761955PMC
December 2020

High sensitivity and specificity feature detection in liquid chromatography-mass spectrometry data: A deep learning framework.

Talanta 2021 Jan 28;222:121580. Epub 2020 Aug 28.

CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 106023, China. Electronic address:

Feature detection is a crucial pre-processing step for high-resolution liquid chromatography-mass spectrometry (LC-MS) data analysis. Typical practices based on thresholds or rigid mathematical assumptions can cause ineffective performance in detecting low abundance and non-ideal distributed compounds. We herein introduce a novel feature detection method based on deep learning named SeA-M2Net that considers feature detection as an image-based object detection task. By fully employing raw data directly, and integrating all related factors (e.g., LC elution, charge state, and isotope distribution) with two-dimensional pseudo color images to calculate the probability of the presence of the compound, low abundance compounds can be well preserved and observed. More importantly, SeA-M2Net, with deep multilevel and multiscale structures focuses on compound pattern detection in a learned method instead of assuming a mathematical parametric model. All parameters in SeA-M2Net are learned from data in the training procedure, thus allowing for maximum flexibility of pattern distribution deformation. The algorithm is tested on several LC-MS datasets of multiple biological samples obtained from different instruments with varied experimental settings. We demonstrate the superiority of the new approach in handling complex compound patterns (e.g., low abundance, overlapping regions, LC shifts, and missing values). Our experiments indicate that SeA-M2Net outperforms widely used detection methods in terms of detection accuracy.
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http://dx.doi.org/10.1016/j.talanta.2020.121580DOI Listing
January 2021

Quinetides: diverse posttranslational modified peptides of ribonuclease-like storage protein from as markers for differentiating ginseng species.

J Ginseng Res 2020 Sep 29;44(5):680-689. Epub 2019 May 29.

CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.

Background: Peptides have diverse and important physiological roles in plants and are ideal markers for species identification. It is unclear whether there are specific peptides in L. (PQ). The aims of this study were to identify Quinetides, a series of diverse posttranslational modified native peptides of the ribonuclease-like storage protein (ginseng major protein), from PQ to explore novel peptide markers and develop a new method to distinguish PQ from

Methods: We used different fragmentation modes in the LTQ Orbitrap analysis to identify the enriched Quinetide targets of PQ, and we discovered Quinetide markers of PQ and using ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry analysis. These "peptide markers" were validated by simultaneously monitoring Rf and F11 as standard ginsenosides.

Results: We discovered 100 Quinetides of PQ with various post-translational modifications (PTMs), including a series of glycopeptides, all of which originated from the protein ginseng major protein. We effectively distinguished PQ from using new "peptide markers." Four unique peptides (Quinetides TP6 and TP7 as markers of PQ and Quinetides TP8 and TP9 as markers of ) and their associated glycosylation products were discovered in PQ and .

Conclusion: We provide specific information on PQ peptides and propose the clinical application of peptide markers to distinguish PQ from .
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http://dx.doi.org/10.1016/j.jgr.2019.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471211PMC
September 2020

Cinnamic Aldehyde Inhibits Lipopolysaccharide-Induced Chondrocyte Inflammation and Reduces Cartilage Degeneration by Blocking the Nuclear Factor-Kappa B Signaling Pathway.

Front Pharmacol 2020 5;11:949. Epub 2020 Aug 5.

Department of Orthopedics, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, China.

Osteoarthritis (OA), as one of the top 10 causes of physical disability, is characterized by inflammation of the synovial membrane and progressive destruction of the articular cartilage. Cinnamic aldehyde (CA), an α,β-unsaturated aldehyde extracted from the traditional Chinese herbal medicine cinnamon ( J.Presl), has been reported to have anti-inflammatory, antioxidant, and anticancer properties. However, the anti-inflammatory effect of CA on OA remains unclear. The purpose of the present study was to investigate the effects of CA on inflammation, and cartilage degeneration in OA. A CCK-8 assay was performed to assess the potential toxicity of CA on cultured human OA chondrocytes. Following treatment with lipopolysaccharide (LPS) and CA, the expression of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alfa (TNF-α), was evaluated using quantitative real-time polymerase chain reaction (RT-qPCR) analysis, enzyme-linked immunosorbent assay, and Western blotting (WB). The production of matrix metalloproteinase-13 (MMP-13) and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) was also examined using RT-qPCR and WB. Furthermore, to investigate the potential anti-inflammatory mechanism of CA, biomarkers of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway (p65, IKB-α) were detected using WB. The results demonstrated that CA significantly inhibited the expressions of IL-1β, IL-6, TNF-α, MMP-13, and ADAMTS-5 in LPS-induced OA chondrocytes. CA dramatically suppressed LPS-stimulated NF-κB activation. Collectively, these results suggest that CA treatment may effectively prevent OA.
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http://dx.doi.org/10.3389/fphar.2020.00949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419651PMC
August 2020

Functionally distinct IFN-γ IL-17A Th cells in experimental autoimmune uveitis: T-cell heterogeneity, migration, and steroid response.

Eur J Immunol 2020 12 31;50(12):1941-1951. Epub 2020 Aug 31.

UCL Institute of Ophthalmology, University College London, London, UK.

Immunopathogenic roles for both Th1 (CD4 IFN-γ ) and Th17 (CD4 IL-17A ) cells have been demonstrated in experimental autoimmune uveitis (EAU). However, the role for Th17/Th1 (CD4 T cells co-expressing IFN-γ and IL-17A) cells in EAU is not yet understood. Using interphotoreceptor retinoid-binding protein peptide-induced EAU in mice, we found increased levels of Th17/Th1 cells in EAU retinae (mean 9.6 ± 4.2%) and draining LNs (mean 8.4 ± 3.9%; p = 0.01) relative to controls. Topical dexamethasone treatment effectively reduced EAU severity and decreased retinal Th1 cells (p = 0.01), but had no impact on retinal Th17/Th1 or Th17 cells compared to saline controls. Using in vitro migration assays with mouse CNS endothelium, we demonstrated that Th17/Th1 cells were significantly increased within the migrated population relative to controls (mean 15.6 ± 9.5% vs. 1.9 ± 1.5%; p = 0.01). Chemokine receptor profiles of Th17/Th1 cells (CXCR3 and CCR6) did not change throughout the transendothelial migration process and were unaffected by dexamethasone treatment. These findings support a role for Th17/Th1 cells in EAU and their resistance to steroid inhibition suggests the importance of targeting both Th17 and Th17/Th1 cells for improving therapy.
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http://dx.doi.org/10.1002/eji.202048616DOI Listing
December 2020

Mobile Bearing versus Fixed Bearing for Total Knee Arthroplasty: Meta-analysis of Randomized Controlled Trials at Minimum 10-Year Follow-up.

J Knee Surg 2020 Jun 26. Epub 2020 Jun 26.

Department of Orthopaedic Surgery, Beijing University of Chinese Medicine Third Affiliated Hospital, Beijing, People's Republic of China.

This meta-analysis aimed to compare the clinical and radiographic outcomes between mobile-bearing total knee arthroplasty (MB-TKA) and fixed-bearing total knee arthroplasty (FB-TKA) at a minimum 10-year follow-up. PubMed, EMBASE, and Cochrane databases were searched. All included articles were evaluated by two trained reviewers according to the guidelines of the Cochrane Collaboration Handbook for potential risk, and the Consolidated Standards on Reporting Trials (CONSORT) checklist and scoring system was also used to assess the methodological quality of each study. The extracted data included function scores, range of motion (ROM) of the knee, incidence of adverse events or revision, survivorship analysis, and radiographic outcomes. Seven randomized controlled trials (RCTs) were included in this meta-analysis, and all RCTs had a follow-up period longer than 10 years. This meta-analysis shows no significant difference between the two groups with respect to the Keen Society Score (KSS;  = 0.38), KSS function score ( = 0.30), the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC;  = 0.59), ROM ( = 0.71), radiolucent line ( = 0.45), femoral and tibial component positions in the coronal plane ( = 0.55 and 0.35, respectively), revision incidence ( = 0.77), and survivorship rates ( = 0.39). Meanwhile, it showed a slight difference between the two groups in the tibial component position in the sagittal plane ( = 0.003). According to this meta-analysis, the current best available evidence suggests no significant difference between the MB-TKA and FB-TKA groups with respect to the clinical outcomes, radiographic outcomes, revision, and survivorship at a minimum 10-year follow-up. This is a Level II, meta-analysis study.
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http://dx.doi.org/10.1055/s-0040-1713356DOI Listing
June 2020

Alpha-Synuclein Dopaminylation Presented in Plasma of Both Healthy Subjects and Parkinson's Disease Patients.

Proteomics Clin Appl 2020 09 12;14(5):e1900117. Epub 2020 Jul 12.

Division of Biological Technology, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China, 116023.

Purpose: Alpha-synuclein (α-syn) dopaminylation can lead to the death of dopaminergic neurons in the brain and is a risk factor of Parkinson's disease (PD). This study aims to examine whether such a posttranslational modification (PTM) is presented in human blood plasma.

Experimental Design: In vitro reaction simulation between α-syn and dopamine (DA) is conducted to study the biochemical mechanism. Then α-syn from human blood plasma samples is detected by using immunoprecipitation-mass spectrometry (IP-MS). Lastly the levels of endogenous α-syn and α-syn dopaminylation in 88 blood plasma samples from patients with PD, major depressive disorder (MDD), and healthy control (HC) are compared.

Results: DA modifies α-syn with the addition of dopamine-quinone (DAQ) into lysine sites of α-syn in vitro and the addition of DAQ and 3,4-dihydroxyphenylacetaldehyde (DOPAL) in plasma samples. The unmodified α-syn between the PD and HC groups showed similar levels. The levels of two peptides, one with lysine 34 ( K) DAQ modification and the other with lysine 23 ( K) ubiquitination, are significantly higher in PD and MDD compared with HC.

Conclusions And Clinical Relevance: Thus, α-syn dopaminylation is measurable and might be used to indicatethe presence and progression of neurological disorders.
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http://dx.doi.org/10.1002/prca.201900117DOI Listing
September 2020

Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate-mediated regulation of cullin-RING ligase and sensitize cancer cells to MLN4924/pevonedistat.

J Biol Chem 2020 07 3;295(30):10281-10292. Epub 2020 Jun 3.

Department of Biology, Southern University of Science and Technology, Shenzhen, Guangdong, China

Inositol hexakisphosphate (IP) is an abundant metabolite synthesized from inositol 1,3,4,5,6-pentakisphosphate (IP) by the single IP 2-kinase (IP5K). Genetic and biochemical studies have shown that IP usually functions as a structural cofactor in protein(s) mediating mRNA export, DNA repair, necroptosis, 3D genome organization, HIV infection, and cullin-RING ligase (CRL) deneddylation. However, it remains unknown whether pharmacological perturbation of cellular IP levels affects any of these processes. Here, we performed screening for small molecules that regulate human IP5K activity, revealing that the antiparasitic drug and polysulfonic compound suramin efficiently inhibits IP5K and The results from docking experiments and biochemical validations suggested that the suramin targets IP5K in a distinct bidentate manner by concurrently binding to the ATP- and IP-binding pockets, thereby inhibiting both IP phosphorylation and ATP hydrolysis. NF449, a suramin analog with additional sulfonate moieties, more potently inhibited IP5K. Both suramin and NF449 disrupted IP-dependent sequestration of CRL by the deneddylase COP9 signalosome, thereby affecting CRL activity cycle and component dynamics in an IP5K-dependent manner. Finally, nontoxic doses of suramin, NF449, or NF110 exacerbate the loss of cell viability elicited by the neddylation inhibitor and clinical trial drug MLN4924/pevonedistat, suggesting synergistic ef-fects. Suramin and its analogs provide structural templates for designing potent and specific IP5K inhibitors, which could be used in combination therapy along with MLN4924/pevonedistat. IP5K is a potential mechanistic target of suramin, accounting for suramin's therapeutic effects.
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http://dx.doi.org/10.1074/jbc.RA120.014375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383383PMC
July 2020

Outcome and risk of ocular complications of managing children with chronic anterior uveitis with topical rimexolone 1.

Int Ophthalmol 2020 May 21;40(5):1061-1068. Epub 2020 Apr 21.

Institute of Ophthalmology, University College of London, London, UK.

Purpose: To investigate the efficacy and safety of 1% rimexolone ophthalmic suspension in children with chronic anterior uveitis under real-life conditions in a tertiary center.

Methods: This is a retrospective longitudinal study. Medical records were analyzed at baseline, 1, 3, 6 and 12 months before and after switching to rimexolone for best-corrected visual acuity (BCVA), oral steroid use, number of flares, IOP and anti-glaucoma management.

Results: Twenty-four patients (41 eyes) diagnosed with either anterior uveitis (n = 25, 60.0%) or panuveitis (n = 16, 40%) were enrolled. The mean age was 10.5 years (4-16 years). The number of patients requiring oral prednisolone reduced from 8 patients (32.0%) at baseline to 3 patients (20.0%) at 12 months (P < 0.001). Following baseline, the median number of uveitis flares reduced from 2.0 (inter-quartile range (IQR) 1.0-2.75) to 1.0 (IQR 0.0-1.0) compared to the 12 months before baseline (P < 0.001). The mean IOP reduced from baseline (22.0 ± 7.3 mmHg) to 1 month (18.8 ± 8.7 mmHg, P = 0.01) and remained stable up to 12 months (15.9 ± 5.0 mmHg, P < 0.001). Average BCVA, dose of oral prednisolone and anti-glaucoma treatments did not change compared to the baseline. The development for IOP ≥ 30 mmHg was associated with a known corticosteroid response [odds ratio (OR) 6.8, P = 0.003] and a dose > 7.5 mg/day oral prednisolone (OR 4.4, P = 0.033).

Conclusions: Rimexolone 1% ophthalmic suspension is an effective and safe topical steroid for pediatric anterior uveitis.
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http://dx.doi.org/10.1007/s10792-020-01358-9DOI Listing
May 2020

Discovery and validation of biomarkers for Zhongning goji berries using liquid chromatography mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2020 Apr 17;1142:122037. Epub 2020 Feb 17.

CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address:

Daodi medicinal material (DMM), which is traditional Chinese herbal medicine that has been used for long periods and have gained credibility in clinical practice, is part of the Chinese culture. However, Zhongning Goji berries (ZNG), a DMM, are illegally adulterated in the market by adding non Zhongning goji berries (NZNG). Consequently, the development of biomarker(s) is necessary for proper identification of ZNG and NZNG. In this study, a nontargeted metabolomics approach based on ultra high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) was used to find the differential composition between ZNG and NZNG. Using a combination of single-factor and multivariate statistical analyses, seven compounds with significant differences were discovered and identified, one of which was an unreported compound (a glycoside of pyrrolidine alkaloid). These compounds could be used as single biomarkers for receiver operating characteristic (ROC) analysis. In particular, the binary logistic regression result showed that two sets of combinative biomarkers to distinguish ZNG from NZNG with good sensitivity and specificity. Moreover, there was a significant positive correlation between the two combinative biomarkers and the glycoside of pyrrolidine alkaloid. The results of this study provide new ideas on the developments of ZNG identification, authenticity control and against adulteration in the Chinese circulation market.
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http://dx.doi.org/10.1016/j.jchromb.2020.122037DOI Listing
April 2020

Performance of Multiparametric Functional Imaging and Texture Analysis in Predicting Synchronous Metastatic Disease in Pancreatic Ductal Adenocarcinoma Patients by Hybrid PET/MR: Initial Experience.

Front Oncol 2020 25;10:198. Epub 2020 Feb 25.

Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

To assess the imaging biomarkers of glucose metabolic activity and diffusion-weighted imaging (DWI) derived from pretreatment integrated F-fluorodeoxyglucose positron emission tomography-magnetic resonance (F-FDG PET/MR) imaging as potential predictive factors of metastasis in patients with pancreatic ductal adenocarcinoma (PDAC). We retrospectively included 17 consecutive patients with pathologically confirmed PDAC by pretreatment F-FDG PET/MR. The study subjects were divided into a non-metastatic group (M0, six cases) and a metastatic group (M1, 11 cases). The F-FDG PET/MR images were reviewed independently by two board certificated nuclear medicine physicians and one radiologist. Conventional characteristics and quantitative parameters from both PET and apparent diffusion coefficient (ADC) were assessed. The texture features were extracted from LIFEx packages (www.lifexsoft.org), and a 3D tumor volume of interest was manually drawn on fused PET/ADC images. Chi-square tests, independent-samples -tests and Mann-Whitney -tests were used to compare the differences in single parameters between the two groups. A logistic regression analysis was performed to determine independent predictors. A receiver operating characteristic (ROC) curve analysis was performed to assess the discriminatory power of the selected parameters. Correlations between metabolic parameters and ADC features were calculated with Spearman's rank correlation coefficient test. For conventional parameters, univariable analysis demonstrated that the M1 group had a significantly larger size and a higher peak of standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) than those of the M0 group ( < 0.05 for all). TLG remained significant predictor in the multivariable analysis, but there were no significant differences for the area under the ROC curve (AUC) among the four conventional features in differential diagnoses ( > 0.05 for all). For the texture features, there were four features from the PET image and 13 from the ADC map that showed significant differences between the two groups. Multivariate analysis indicated that one feature from PET and three from the ADC were significant predictors. TLG was associated with ADC-GLRLM_GLNU ( = 0.659), ADC-GLRLM_LRHGE ( = 0.762), and PET-GLRLM_LRHGE ( = 0.806). Multiple parameters and texture features of primary tumors from F-FDG PET/MR images maybe reliable biomarkers to predict synchronous metastatic disease for the pretreatment PDAC.
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http://dx.doi.org/10.3389/fonc.2020.00198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052324PMC
February 2020

Extraction and identification of synovial tissue-derived exosomes by different separation techniques.

J Orthop Surg Res 2020 Mar 9;15(1):97. Epub 2020 Mar 9.

Department of Orthopaedic Surgery, Beijing University of Chinese Medicine Third Affiliated Hospital, No. 51, Xiaoguan Street, Anding Gate, Chaoyang District, Beijing, China.

Objective: The aim of this study is to compare the efficiency of different separation techniques for extracting synovial tissue-derived exosomes.

Methods: The synovial tissue discarded during knee arthroscopy or total knee arthroplasty surgery was collected from the Third Affiliated Hospital of Beijing University of Chinese Medicine. Ultracentrifugation (UC), filtration combined with size exclusion chromatography (SECF), and 8% polyethylene glycol (PEG) were used to extract synovial tissue-derived exosomes. Transmission electron microscopy (TEM), nanoparticle tracer analysis (NTA), and Western Blot (WB) were used to detect the morphology, particle size, and biomarker proteins (CD9, CD63, Flotillin-1, and calnexin) of exosomes.

Results: The extracts of enriched round and discoid vesicles were successfully extracted with UC, SECF, and PEG. The results of TEM have shown that all three extraction methods can extract circular or elliptical vesicles with disc- and cup-shaped structures from the synovial tissue, with the diameter is about 30-150 nm. NTA suggested the main peaks of three groups of exosomes are around 100-120 nm, and the concentration of the three groups of exosomes was greater than 1 × 10/ml. The results of WB showed that three positive protein markers (CD9, CD63, and Flotillin-1) were highly expressed in the suspension extracted by the three methods and low in the synovial tissue. However, the negative protein (calnexin) was highly expressed in synovial tissues and PEG group, while low in UC and SECF group.

Conclusion: Morphology, particle size, and labeled protein marker detection confirmed that UC, SECF, and PEG can extract exosomes derived from synovial tissue; UC and SECF are more recommended for the extraction of synovial tissue-derived exosomes, which provides a methodological basis for studying the function and mechanism of synovial tissue exosomes in the future.
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http://dx.doi.org/10.1186/s13018-020-01604-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063768PMC
March 2020

Basis for metabolite-dependent Cullin-RING ligase deneddylation by the COP9 signalosome.

Proc Natl Acad Sci U S A 2020 02 11;117(8):4117-4124. Epub 2020 Feb 11.

Department of Biology, Southern University of Science and Technology, Shenzhen, 518055 Guangdong, China;

The Cullin-RING ligases (CRLs) are the largest family of ubiquitin E3s activated by neddylation and regulated by the deneddylase COP9 signalosome (CSN). The inositol polyphosphate metabolites promote the formation of CRL-CSN complexes, but with unclear mechanism of action. Here, we provide structural and genetic evidence supporting inositol hexakisphosphate (IP) as a general CSN cofactor recruiting CRLs. We determined the crystal structure of IP in complex with CSN subunit 2 (CSN2), based on which we identified the IP-corresponding electron density in the cryoelectron microscopy map of a CRL4A-CSN complex. IP binds to a cognate pocket formed by conserved lysine residues from CSN2 and Rbx1/Roc1, thereby strengthening CRL-CSN interactions to dislodge the E2 CDC34/UBE2R from CRL and to promote CRL deneddylation. IP binding-deficient knockin mice are embryonic lethal. The same mutation disabled Csn2 from rescuing UV-hypersensitivity of -null yeast. These data suggest that CRL transition from the E2-bound active state to the CSN-bound sequestered state is critically assisted by an interfacial IP small molecule, whose metabolism may be coupled to CRL-CSN complex dynamics.
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http://dx.doi.org/10.1073/pnas.1911998117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049131PMC
February 2020

Peptides as Potential Biomarkers for Authentication of Mountain-Cultivated Ginseng and Cultivated Ginseng of Different Ages Using UPLC-HRMS.

J Agric Food Chem 2020 Feb 5;68(7):2263-2275. Epub 2020 Feb 5.

CAS Key Laboratory of Separation Sciences for Analytical Chemistry , Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Zhongshan Road 457 , Dalian 116023 , China.

The growth conditions and age of are vital for determining the quality of the ginseng plant. However, the considerable difference in price according to the cultivation method and period of leads to its adulteration in the trade market. We herein focused on ginseng peptides and the possibility of these peptides to be used as biomarker(s) for discrimination of . We applied an ultraperformance liquid chromatography-high resolution mass spectrometry-based peptidomics approach to characterize ginseng peptides and discover novel peptide biomarkers for authentication of mountain-cultivated ginseng (MCG). We identified 52 high-confidence peptides and screened 20 characteristic peptides differentially expressed between MCG and cultivated ginseng (CG). Intriguingly, 6 differential peptides were expressed significantly in MCG and originated from dehydrins that accumulated during cold or drought conditions. In addition, 14 other differential peptides that were significantly expressed in CG derived from ginseng major protein, an essential protein for nitrogen storage. These biological associations confirmed the reliability and credibility of the differential peptides. Additionally, we determined several robust peptide biomarkers for discrimination of MCG through a precise selection process. These findings demonstrate the potential of peptide biomarkers for identification and quality control of in addition to ginsenoside analysis.
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http://dx.doi.org/10.1021/acs.jafc.9b05568DOI Listing
February 2020

Intra-articular platelet-rich plasma injection for knee osteoarthritis: a summary of meta-analyses.

J Orthop Surg Res 2019 Nov 27;14(1):385. Epub 2019 Nov 27.

Department of Orthopaedic Surgery, Beijing University of Chinese Medicine Third Affiliated Hospital, No. 51, XiaoGuan street, AnDing gate, ChaoYang district, Beijing, China.

Objective: The purpose of this study was (1) to perform a summary of meta-analyses comparing platelet-rich plasma (PRP) injection with hyaluronic acid (HA) and placebo injection for KOA patients, (2) to determine which meta-analysis provides the best available evidence to making proposals for the use of PRP in the treatment of KOA patients, and (3) to highlight gaps in the literature that require future investigation.

Material And Methods: PubMed, EMBASE, and Cochrane databases search were performed for meta-analyses which compared PRP injection with HA or placebo. Clinical outcomes and adverse events were extracted from these meta-analyses. Meta-analysis quality was assessed using the Quality of Reporting of Meta-analyses (QUOROM) systems and the Oxman-Guyatt quality appraisal tool. The Jadad decision algorithm was also used to determine which meta-analysis provided the best available evidence.

Results: Four meta-analyses were included in our study, and all of these articles were Level I evidence. The QUOROM score of each included meta-analysis range from 14 to 17 points (mean score 15, maximum score 18), and the Oxman-Guyatt score range from 4 to 6 points (mean score 5, maximum score 7). Three meta-analyses indicated PRP showed more benefit in pain relief and functional improvement than the control group, and the other one suggested no difference between these groups. All included meta-analyses found no statistical difference in adverse events between these groups. In addition, a meta-analysis conducted by Shen et al. got the highest methodological quality score and suggested that PRP provided better pain relief and function improvement in the treatment of KOA.

Conclusions: For short-term follow-up (≤1 year), intra-articular PRP injection is more effective in terms of pain relief and function improvement in the treatment of KOA patients than HA and placebo, and there is no difference in the risk of an adverse event between PRP and HA or placebo.

Level Of Evidence: Level I evidence, a summary of meta-analyses TRIAL REGISTRATION: PROSPERO ID CRD42018116168.
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http://dx.doi.org/10.1186/s13018-019-1363-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880602PMC
November 2019

In situ derivatization of Au nanoclusters via aurophilic interactions of a triphenylphosphine gold(i) salt with neurotransmitters and their rapid MALDI-TOF-MS detection in mice brain tissue extracts.

J Mater Chem B 2020 01 25;8(1):38-44. Epub 2019 Nov 25.

CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, No. 457 Zhongshan Road, Dalian, 116023, China.

Matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) has attracted much attention for the detection of small molecules such as neurotransmitters due to its softness, high sensitivity, extensive compatibility and diverse mass analyzers. However, it has been really a difficult challenge to develop a highly specific organic compound as a matrix for the rapid, sensitive and selective detection of neurotransmitters. Herein, we report tris(triphenylphosphine)gold oxonium tetrafluoroborate ([PhPAu]OBF) for the first time as an efficient matrix for the rapid and simultaneous MALDI-MS detection of neurotransmitters. [PhPAu]OBF facilitates the in situ derivatization of gold nanoclusters (Au NCLs) during the interaction with neurotransmitters, which increases their ionization energy by absorbing more ultra-violet (UV) radiation during MALDI-TOF-MS detection. The results show that this [PhPAu]OBF matrix can exhibit a 10-fold faster response time compared to previously reported pyrylium matrices. In addition, [PhPAu]OBF can also provide the simultaneous derivatization of various neurotransmitters, including dopamine (DA), noradrenaline (NAd), serotonin (5-HT), γ-aminobutyric acid (GABA), histamine (H) and tyramine (TY), in mice brain tissue extracts, which can be detected in the MALDI-TOF-MS spectra.
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http://dx.doi.org/10.1039/c9tb01800jDOI Listing
January 2020

Stiffer, Stronger and Centrosymmetrical Class of Pentamodal Mechanical Metamaterials.

Materials (Basel) 2019 Oct 23;12(21). Epub 2019 Oct 23.

School of Science, Xi' an Jiaotong University, Xi'an 710049, China.

Pentamode metamaterials have been used as a crucial element to achieve elastical unfeelability cloaking devices. They are seen as potentially fragile and not simple for integration in anisotropic structures due to a non-centrosymmetric crystalline structure. Here, we introduce a new class of pentamode metamaterial with centrosymmetry, which shows better performances regarding stiffness, toughness, stability and size dependence. The phonon band structure is calculated based on the finite element method, and the pentamodal properties are evaluated by analyzing the single band gap and the ratio of bulk and shear modulus. The Poisson's ratio becomes isotropic and close to 0.5 in the limit of small double-cone connections. Stability and scalability analysis results show that the critical load factor of this structure is obviously higher than the classical pentamode structure under the same static elastic properties, and the Young's modulus gradually converges to a stable value (the infinite case) with an increasing number of unit cells.
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http://dx.doi.org/10.3390/ma12213470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861979PMC
October 2019

Are Inositol Polyphosphates the Missing Link in Dynamic Cullin RING Ligase Regulation by the COP9 Signalosome?

Biomolecules 2019 08 7;9(8). Epub 2019 Aug 7.

Department of Biology, Institute of Neuroscience, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen 518055, China.

The E3 ligase activity of Cullin RING Ligases (CRLs) is controlled by cycles of neddylation/deneddylation and intimately regulated by the deneddylase COP9 Signalosome (CSN), one of the proteasome lid-CSN-initiation factor 3 (PCI) domain-containing "Zomes" complex. Besides catalyzing the removal of stimulatory Cullin neddylation, CSN also provides a docking platform for other proteins that might play a role in regulating CRLs, notably protein kinases and deubiquitinases. During the CRL activity cycle, CRL-CSN complexes are dynamically assembled and disassembled. Mechanisms underlying complex dynamics remain incompletely understood. Recently, the inositol polyphosphate metabolites (IP6, IP7) and their metabolic enzymes (IP5K, IP6K) have been discovered to participate in CRL-CSN complex formation as well as stimulus-dependent dissociation. Here we discuss these mechanistic insights in light of recent advances in elucidating structural basis of CRL-CSN complexes.
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http://dx.doi.org/10.3390/biom9080349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722667PMC
August 2019

Measurement of ultra-trace level of intact oxytocin in plasma using SALLE combined with nano-LC-MS.

J Pharm Biomed Anal 2019 Sep 13;173:62-67. Epub 2019 Apr 13.

CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian, 116023, China. Electronic address:

Measurement of peptides such as oxytocin in plasma is a critical challenge in clinical research because of their extreme low concentrations as well as the tremendous interferencing substances co-presented in plasma. In this study, we developed an efficient salt-out assisted liquid-liquid extraction (SALLE) to treat plasma, and then analyzed the samples using nano-LC-MS to quantify intact oxytocin (OT) in human and rat plasmas. Our results showed that the use of SALLE (Isopropanol/KHPO (4 M)) allows efficient removal of various disrupters, including proteins, inorganic salts, and lipids, which helps avoid the risk of blocked capillary columns and matrix effects. Moreover, instant SALLE can reduce the possible binding between OT and proteins, thus allowing high repeatability of OT extraction from the original plasma. This combination of SALLE and nano-LC-MS method provided in the end a 1 pg/m L of detection limit. Comparative analysis showed that the concentration of OT in the plasma taken from 12 volunteers ranged from 3 to 214 pg/m L, about one order less than those in the plasma of rats. Compared to the previously reported LC-MS and immunoassay methods, the combination of SALLE and nano-LC-MS permits reliable measurement of intact OT even in human plasma. Our approach may be an alternative method for quantitative determination of other ultra-trace peptides in plasma, which would help the investigators understand the role of peptides in behaviours and diseases.
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http://dx.doi.org/10.1016/j.jpba.2019.04.023DOI Listing
September 2019

Various Multicharged Anions of Ginsenosides in Negative Electrospray Ionization with QTOF High-Resolution Mass Spectrometry.

J Am Soc Mass Spectrom 2019 Mar 14;30(3):403-418. Epub 2019 Jan 14.

CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road 457, 116023, Dalian, People's Republic of China.

When characterizing components from ginseng, we found a vast number of multicharged anions presented in the liquid chromatography-mass spectrometry (LC-MS) chromatograms. The source of these anions is unclear yet, while ginsenosides, the major components of ginseng, are the main suspected type of molecules because of their sugar moiety. Our investigation using 14 pure ginsenosides affirmed that the multicharged anions were formed by ginsenosides rather than other types of ingredients in ginseng. Various anions could be observed for each ginsenoside. These anions contain ions ([M-2H], [M+Adduct]), as well as those formed by polymerization of at least two ginsenosides, such as [nM-2H], [nM-H+Adduct], and [nM-3H]. The presence of so different types of ions from a ginsenoside explains the reason for the large number of anions in the LC-MS analysis of ginseng. We further found that formation of [nM-2H] ions was influenced by the number of sugar chains: ginsenosides containing two sugar chains produced all [nM-2H] ion types, whereas ginsenosides containing one sugar chain did not produce [2M-2H]. Thus, [2M-2H] and [3M-2H] can be utilized to rapidly identify monodesmosidic and/or bidesmosidic ginsenosides as joint diagnostic anions. The position of the glycosyl radical might be the key factor affecting the formation of multicharged multimer ions from monodesmosidic ginsenosides. Consequently, three groups of ginsenoside isomers were differentiated by characteristic [nM-2H] anions. Using concentration-dependent characteristics and collision-induced dissociation (CID), we confirmed that [nM-2H] ions are non-covalently bound multimers whose aggregation has marked distinction between monodesmosidic and bidesmosidic ginsenosides, accounting for the differentiated formation of [nM-2H] between them. Graphical Abstract.
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http://dx.doi.org/10.1007/s13361-018-2089-5DOI Listing
March 2019

Magnetotransport Anomaly in Room-Temperature Ferrimagnetic NiCo O Thin Films.

Adv Mater 2019 Jan 29;31(4):e1805260. Epub 2018 Nov 29.

Department of Physics and Astronomy & Nebraska Center for Materials and Nanoscience, University of Nebraska-Lincoln, Lincoln, NE, 68588-0299, USA.

The inverse spinel ferrimagnetic NiCo O presents a unique model system for studying the competing effects of crystalline fields, magnetic exchange, and various types of chemical and lattice disorder on the electronic and magnetic states. Here, magnetotransport anomalies in high-quality epitaxial NiCo O thin films resulting from the complex energy landscape are reported. A strong out-of-plane magnetic anisotropy, linear magnetoresistance, and robust anomalous Hall effect above 300 K are observed in 5-30 unit cell NiCo O films. The anomalous Hall resistance exhibits a nonmonotonic temperature dependence that peaks around room temperature, and reverses its sign at low temperature in films thinner than 20 unit cells. The scaling relation between the anomalous Hall conductivity and longitudinal conductivity reveals the intricate interplay between the spin-dependent impurity scattering, band intrinsic Berry phase effect, and electron correlation. This study provides important insights into the functional design of NiCo O for developing spinel-based spintronic applications.
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http://dx.doi.org/10.1002/adma.201805260DOI Listing
January 2019

Rapid discrimination between red and white ginseng based on unique mass-spectrometric features.

J Pharm Biomed Anal 2019 Feb 3;164:202-210. Epub 2018 Oct 3.

CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, PR China. Electronic address:

Red ginseng (RG) and white ginseng (WG), two processed products of Panax ginseng C. A. Meyer, are in high demand due to their unique features. In this study, some of these unique features were identified and confirmed as biomarkers of RG by using ultra-high-performance liquid chromatography-mass spectrometry, data mining, support vector machine, and artificial neural network. Principal component analysis showed clear separation between the RG and WG extracts, indicating the presence of potential discriminators. In addition, 20 features that are dominant in RG were found by data mining. Samples of Panax quinquefolium (PQ) and Panax notoginseng (PN), close relatives of Panax ginseng C.A.Meyer, were investigated and it was found that 17 features which were absent in PQ and PN samples, were present in RG and WG. Five of these markers were identified as nitrogen-containing compounds that have not been previously reported. Finally, we found that RG can be identified among different ginseng medicinal herbs including RG, WG, PQ, and PN samples, by loading four feature markers corresponding to nitrogen-containing compounds into a discriminating model, based on a support vector machine or an artificial neural network. Thus, this study provides an efficient tool to identify RG during pharmacological research.
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http://dx.doi.org/10.1016/j.jpba.2018.10.007DOI Listing
February 2019

Extensive characterization and differential analysis of endogenous peptides from Bombyx batryticatus using mass spectrometric approach.

J Pharm Biomed Anal 2019 Jan 18;163:78-87. Epub 2018 Sep 18.

CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Zhongshan Road 457, Dalian 116023, China. Electronic address:

Bombyx batryticatus, the dried larva of Bombyx mori L. (4th-5th instars) infected with Beauveria bassiana Vuill, is an important animal-derived medicine effective against several diseases. The metamorphosis of silkworm can result insignificant changes in the levels of proteins and polypeptides in the 4 and 5 instar larvae. Here, we performed extensive characterization of Bombyx batryticatus peptides, including polypeptides containing cysteines, using an MS-based data mining strategy. A total of 779 peptides with various PTMs (post-translational modifications) were identified through database search and de novo sequencing. Some of these peptides might have important biological activities. Besides, the differential analysis of polypeptides between the head and body of Bombyx batryticatus was performed to provide a clinical basis for rational use of the drugs derived from it. This study illustrates the abundance and sequences of endogenous Bombyx batryticatus polypeptides, and thus, provides potential candidates for the screening of active compounds for future biological research and drug discovery studies.
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http://dx.doi.org/10.1016/j.jpba.2018.09.033DOI Listing
January 2019

Cajanine promotes osteogenic differentiation and proliferation of human bone marrow mesenchymal stem cells.

Adv Clin Exp Med 2019 Jan;28(1):45-50

Department of Orthopedics, Dongzhimen Hospital, Beijing University of Chinese Medicine, China.

Background: Seed cells - mesenchymal stem cells (MSCs) - appear to be an attractive tool in the context of tissue engineering. Bone marrow represents the main source of MSCs for both experimental and clinical studies. However, the number limitation of bone marrow MSCs (BMSCs) and decreased function caused by proliferation make the search for adequate alternative sources of these cells for autologous and allogenic transplant necessary.

Objectives: This study was aimed to investigate the roles of cajanine isolated from the extracts of Cajanus cajan L. Millsp. in the proliferation and differentiation of BMSCs, and to discover the mechanism of proliferation of BMSCs promoted by cajanine.

Material And Methods: Bone marrow mesenchymal stem cells were cultured in high-glucose Dulbecco's Modified Eagle's Medium (DMEM) and osteogenic differentiation was induced by adding dexamethasone, ascorbic acid and β-glycerophosphate supplements. Bone marrow MSCs were cultured in medium without cajanine or supplemented with cajanine. The information about the proliferation and osteogenic differentiation of BMSCs was collated. The osteogenic differentiation potential of BMSCs was also assessed at the 3rd passage by Von Kossa staining. To observe cell signal transduction changes of BMSCs after culturing them with cajanine for 24 h, the western blot analysis was performed to detect phosphorylated cell cycle proteins and activated cyclins.

Results: After osteogenic induction, the differentiation of BMSCs was accelerated by cajanine treatment. Osteogenesis markers were upregulated by cajanine treatment at both protein and mRNA levels. Cajanine obviously promoted the proliferation of BMSCs. After BMSCs were cultured with cajanine for 24 h, the cell cycle regulator proteins were phosphorylated or upregulated.

Conclusions: Cajanine can promote the expansion efficiency of BMSCs, at the same time keeping their multi-differentiation potential. Cajanine can activate the cell cycle signal transduction pathway, thus inducing cells to enter the G1/S phase and accelerating cells entering the G2/M phase. This study can contribute to the development of cajanine-based drugs in tissue engineering.
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http://dx.doi.org/10.17219/acem/76638DOI Listing
January 2019

Clinical Remission of Sight-Threatening Non-Infectious Uveitis Is Characterized by an Upregulation of Peripheral T-Regulatory Cell Polarized Towards T-bet and TIGIT.

Front Immunol 2018 3;9:907. Epub 2018 May 3.

Ocular Immunology, Institute of Ophthalmology, University College London (UCL), London, United Kingdom.

Background: Non-infectious uveitis can cause chronic relapsing and remitting ocular inflammation, which may require high dose systemic immunosuppression to prevent severe sight loss. It has been classically described as an autoimmune disease, mediated by pro-inflammatory Th1 and Th17 T-cell subsets. Studies suggest that natural immunosuppressive CD4CD25FoxP3 T-regulatory cells (Tregs) are involved in resolution of inflammation and may be involved in the maintenance of clinical remission.

Objective: To investigate whether there is a peripheral blood immunoregulatory phenotype associated with clinical remission of sight-threatening non-infectious uveitis by comparing peripheral blood levels of Treg, Th1, and Th17, and associated DNA methylation and cytokine levels in patients with active uveitic disease, control subjects and patients (with previously active disease) in clinical remission induced by immunosuppressive drugs.

Methods: Isolated peripheral blood mononuclear cells (PBMC) from peripheral blood samples from prospectively recruited subjects were analyzed by flow cytometry for CD3, CD4, FoxP3, TIGIT, T-bet, and related orphan receptor γt. Epigenetic DNA methylation levels of FOXP3 Treg-specific demethylated region (TSDR), FOXP3 promoter, TBX21, RORC2, and TIGIT loci were determined in cryopreserved PBMC using a next-generation sequencing approach. Related cytokines were measured in blood sera. Functional suppressive capacity of Treg was assessed using T-cell proliferation assays.

Results: Fifty patients with uveitis (intermediate, posterior, and panuveitis) and 10 control subjects were recruited. The frequency of CD4CD25FoxP3 Treg, TIGIT Treg, and T-bet Treg and the ratio of Treg to Th1 were significantly higher in remission patients compared with patients with active uveitic disease; and TIGIT Tregs were a significant predictor of clinical remission. Treg from patients in clinical remission demonstrated a high level of suppressive function compared with Treg from control subjects and from patients with untreated active disease. PBMC from patients in clinical remission had significantly lower methylation levels at the FOXP3 TSDR, FOXP3 promoter, and TIGIT loci and higher levels at RORC loci than those with active disease. Clinical remission was also associated with significantly higher serum levels of transforming growth factor β and IL-10, which positively correlated with Treg levels, and lower serum levels of IFNγ, IL-17A, and IL-22 compared with patients with active disease.

Conclusion: Clinical remission of sight-threatening non-infectious uveitis has an immunoregulatory phenotype characterized by upregulation of peripheral Treg, polarized toward T-bet and TIGIT. These findings may assist with individualized therapy of uveitis, by informing whether drug therapy has induced phenotypically stable Treg associated with long-term clinical remission.
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http://dx.doi.org/10.3389/fimmu.2018.00907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943505PMC
June 2019