Publications by authors named "Yanmin Zhang"

313 Publications

Establishment of iPSC line from a Chinese infant (XACHi012-A) with Jervell and Lange-Nielsen syndrome carrying combined KCNQ1 frameshift c.431delC(p.I145Sfs*92) and nonsense c.1175G > A (p.W392X) variants and two iPSC lines from the parents (XACHi013-A, XACHi014-A).

Stem Cell Res 2021 May 11;53:102391. Epub 2021 May 11.

National Regional Children's Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases; Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, China; Department of Cardiology, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, China. Electronic address:

Induced pluripotent stem cell lines (iPSCs) were generated from peripheral blood mononuclear cells (PBMCs) isolated from the peripheral blood of a two month-old boy and the parents. Jervell and Lange-Nielsen syndrome (JLNS) was diagnosed in the boy carrying combined KCNQ1 frameshift c.431delC (p.I145Sfs*92) and nonsense c.1175G > A(p.W392X) variants inherited from his mother and father respectively. PBMCs were reprogrammed using non-integrative Sendai viral vectors containing reprogramming factors OCT4, SOX2, KLF4 and C-MYC. IPSCs were shown to express pluripotent markers, have trilineage differentiation potential, carrying identified KCNQ1 variants with corresponding PBMC, and have a normal karyotype. Thus we established three iPSC lines as useful tools for studying the pathophysiological mechanism of JLNS and drug testing.
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http://dx.doi.org/10.1016/j.scr.2021.102391DOI Listing
May 2021

Synergistic effect of toosendanin and regorafenib against cell proliferation and migration by regulating WWOX signaling pathway in hepatocellular carcinoma.

Phytother Res 2021 May 31. Epub 2021 May 31.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.

Regorafenib (RGF), a second-line multi-kinase inhibitor in the treatment of HCC (hepatocellular carcinoma) after sorafenib failure, exposes to the risk of drug resistance and subsequent progression of HCC patients. Toosendanin (TSN), a triterpenoid has presented excellent inhibition on several tumors. The purpose of this study is to investigate the inhibitory effect of the combination of TSN and RGF on HCC cells. We identified that TSN and RGF combination (TRC) synergistically inhibited the proliferation and migration of MHCC-97L cells. The upregulation of WWOX (WW-domain containing oxidoreductase) played a vital role in the HCC cell growth treated with TRC. TRC suppressed the phosphorylation of Stat3 and expression of DVL2, negatively regulated the activity of β-catenin by promoting the phosphorylation of GSK3β. In addition, the intranuclear proteins, including MMP2, MMP9, and C-MYC were significantly inhibited by TRC. The in vivo xenograft models confirmed that TRC effectually prevented the tumor growth through upregulating WWOX. Therefore, the treatment of TRC may be a potential solution of RGF resistance and promising therapeutic method in malignant HCC.
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http://dx.doi.org/10.1002/ptr.7174DOI Listing
May 2021

WWOX activation by toosendanin suppresses hepatocellular carcinoma metastasis through JAK2/Stat3 and Wnt/β-catenin signaling.

Cancer Lett 2021 Aug 18;513:50-62. Epub 2021 May 18.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, 710061, PR China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, 710061, PR China. Electronic address:

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide. Loss of WW-domain containing oxidoreductase (WWOX) has been proven to be associated with malignant metastasis in patients with HCC. In this study, by using a non-biased CRISPR knockout genetic screen targeting 19,050 human genes, we found that toosendanin (TSN) is a novel druggable WWOX candidate agonist for metastatic HCC patients. We also found that TSN exhibited significant anti-proliferative and anti-metastatic effects on HCC cells in a WWOX-dependent manner. Overexpression and knockdown of WWOX in vitro and in vivo confirmed that the suppression of HCC by TSN involved WWOX. TSN regulated Stat3, DVL2, and GSK3β by transforming their interactions with WWOX as demonstrated by a Co-IP assay. TSN accelerated the degradation of β-catenin by promoting the function of APC, AXIN1, CK1, and GSK3β complex. Nuclear translocation of p-Stat3 Y705 and β-catenin was impeded by the TSN-induced blockade of JAK2/Stat3 and Wnt/β-catenin signaling, accompanied by the inhibition of MMPs and C-MYC.
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http://dx.doi.org/10.1016/j.canlet.2021.05.010DOI Listing
August 2021

Cephalomannine inhibits hypoxia-induced cellular function via the suppression of APEX1/HIF-1α interaction in lung cancer.

Cell Death Dis 2021 May 14;12(5):490. Epub 2021 May 14.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China.

Lung cancer (LC) is one of the leading causes of cancer-related death. As one of the key features of tumor microenvironment, hypoxia conditions are associated with poor prognosis in LC patients. Upregulation of hypoxic-induced factor-1α (HIF-1α) leads to the activation of various factors that contribute to the increased drug resistance, proliferation, and migration of tumor cells. Apurinic/apyrimidinic endonuclease-1 (APEX1) is a multi-functional protein that regulates several transcription factors, including HIF-1α, that contribute to tumor growth, oxidative stress responses, and DNA damage. In this study, we explored the mechanisms underlying cell responses to hypoxia and modulation of APEX1, which regulate HIF-1α and downstream pathways. We found that hypoxia-induced APEX1/HIF-1α pathways regulate several key cellular functions, including reactive oxygen species (ROS) production, carbonic anhydrase 9 (CA9)-mediated intracellular pH, migration, and angiogenesis. Cephalomannine (CPM), a natural compound, exerted inhibitory effects in hypoxic LC cells via the inhibition of APEX1/HIF-1α interaction in vitro and in vivo. CPM can significantly inhibit cell viability, ROS production, intracellular pH, and migration in hypoxic LC cells as well as angiogenesis of HUVECs under hypoxia through the inhibition of APEX1/HIF-1α interaction. Taken together, CPM could be considered as a promising compound for LC treatment.
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http://dx.doi.org/10.1038/s41419-021-03771-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121842PMC
May 2021

Distinctive Clinicopathologic Features of Monomorphic B-cell Post-transplant Lymphoproliferative Disorders in Children.

Pediatr Dev Pathol 2021 Apr 19:10935266211007254. Epub 2021 Apr 19.

Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Pathology and Laboratory Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Introduction: Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood.

Methods: We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years. Clinical data were reviewed. Pathologic data including histologic types and EBV status were analyzed. Additional immunohistochemical stains, FISH studies, and gene mutational status were performed.

Results: 4 of 18 cases were EBV-negative. All 4 EBV-negative cases were strikingly confined to the gastrointestinal (GI) tract or abdominal lymph nodes, while tumors in EBV-positive cases were found at various anatomic sites; 2 of 4 EBV-negative cases carried mutations in gene. Our cohort also included 2 rare types of PTLD, one plasmablastic lymphoma and one high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS).

Conclusion: We report that monomorphic B-cell PTLDs in children have distinctive clinical and pathological features. More studies are needed to clarify whether and how much these pediatric PTLDs differ from their adult counterparts.
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http://dx.doi.org/10.1177/10935266211007254DOI Listing
April 2021

A potent neutralizing nanobody against SARS-CoV-2 with inhaled delivery potential.

MedComm (Beijing) 2021 Mar 4;2(1):101-113. Epub 2021 Mar 4.

Shanghai Novamab Biopharmaceuticals Co., Ltd Shanghai China.

The coronavirus disease 2019 (COVID-19) pandemic has become a serious burden on global public health. Although therapeutic drugs against COVID-19 have been used in many countries, their efficacy is still limited. We here reported nanobody (Nb) phage display libraries derived from four camels immunized with the SARS-CoV-2 spike receptor-binding domain (RBD), from which 381 Nbs were identified to recognize SARS-CoV-2-RBD. Furthermore, seven Nbs were shown to block interaction of human angiotensin-converting enzyme 2 (ACE2) with SARS-CoV-2-RBD variants and two Nbs blocked the interaction of human ACE2 with bat-SL-CoV-WIV1-RBD and SARS-CoV-1-RBD. Among these candidates, Nb11-59 exhibited the highest activity against authentic SARS-CoV-2 with 50% neutralizing dose (ND) of 0.55 μg/ml. Nb11-59 can be produced on large scale in , with 20 g/L titer and 99.36% purity. It also showed good stability profile, and nebulization did not impact its stability. Overall, Nb11-59 might be a promising prophylactic and therapeutic molecule against COVID-19, especially through inhalation delivery.
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http://dx.doi.org/10.1002/mco2.60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013425PMC
March 2021

Comparison of analgesic activities of aconitine in different mice pain models.

PLoS One 2021 1;16(4):e0249276. Epub 2021 Apr 1.

Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.

Aconitine (AC) is the primary bioactive and secondary metabolite alkaloidin of Aconitum species which is accounted for more than 60% of the total diester-diterpenoid alkaloids in Aconite. To evaluate the analgesic effects of AC, 4 different pain models including hot plate assay, acetic acid writhing assay, formalin and CFA induced pain models were adopted in this study. In hot plate experiment, AC treatment at concentration of 0.3 mg/kg and 0.9 mg/kg improved the pain thresholds of mice similar to the positive drug aspirin at the concentration of 200 mg/kg (17.12% and 20.27% VS 19.21%). In acetic acid writhing experiment, AC significantly reduced the number of mice writhing events caused by acetic acid, and the inhibition rates were 68% and 76%. These results demonstrated that AC treatment revealed significant analgesic effects in both acute thermal stimulus pain model and chemically-induced visceral pain model. The biphasic nociceptive responses induced by formalin were significantly inhibited after AC treatment for 1h or 2h. The inhibition rates were 33.23% and 20.25% of AC treatment for 1h at 0.3 mg/kg and 0.9 mg/kg in phase I. In phase II, the inhibition rates of AC and aspirin were 36.08%, 32.48% and 48.82% respectively, which means AC showed similar analgesic effect to non-steroidal anti-inflammatory compounds. In the chronic CFA-induced nociception model, AC treatment also improved mice pain threshold to 131.33% at 0.3 mg/kg, which was similar to aspirin group (152.03%). Above all, our results verified that AC had obviously analgesic effects in different mice pain models.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249276PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016268PMC
April 2021

Emodin Ameliorates Renal Damage and Podocyte Injury in a Rat Model of Diabetic Nephropathy via Regulating AMPK/mTOR-Mediated Autophagy Signaling Pathway.

Diabetes Metab Syndr Obes 2021 18;14:1253-1266. Epub 2021 Mar 18.

Department of Nephrology, Wuhan No. 1 Hospital, Wuhan, Hubei, 430022, People's Republic of China.

Purpose: The activation of autophagy has potential protective effect on diabetic nephropathy (DN) podocyte injury, and the AMPK/mTOR signaling pathway is an important regulatory pathway of autophagy. Emodin has been reported to effectively delay DN progression; however, the therapeutic mechanisms involved in vivo remain ambiguous. The present study aimed to elucidate the mechanism of emodin in improving renal tissue and podocyte injury in DN by regulating the AMPK/mTOR-autophagy signaling pathway.

Methods: All rats were divided into 4 groups: a Sham group, a Vehicle group, a low-dose emodin (LD-Emo) group (20 mg/kg/day) and a high-dose emodin (HD-Emo) group (40 mg/kg/day). The different doses of Emo and distilled water were daily administrated for 8 weeks after the induction of DN by the unilateral nephrectomy combined with intraperitoneal injections of streptozotocin (STZ). The rats' general status, blood glucose, biochemical parameters, urinary protein excretion, renal histological changes and cell apoptosis in renal tissue, as well as the key protein expressions in the AMPK/mTOR signaling pathway and apoptosis-related proteins were examined, respectively.

Results: Emodin ameliorated the general condition, kidney weight and urinary protein excretion of the rats, but has little influence on serum biochemical parameters and did not lower blood glucose; emodin attenuated renal fibrosis including the cell numbers, extracellular matrix rate and collagen area in glomerulus, simultaneously relieved podocyte foot process fusion, up-regulated the expression of nephrin protein and suppressed glomerular and tubular epithelial cell apoptosis. In addition, emodin can induce and enhance autophagy in podocytes including increased expression of LC3-II/I, Beclin-1, p-AMPK protein and decreased expression of p62, p-mTOR protein, as well as increased autophagosomes in podocytes.

Conclusion: We have demonstrated that emodin, as a natural regulator in vivo, reduced proteinuria and alleviated renal fibrosis without affecting hyperglycemia in DN rats. The potential mechanisms by which emodin exerts its renoprotective effects in vivo are through suppressing cell apoptosis and enhancing autophagy of podocytes via the AMPK/mTOR signaling pathway in the kidney.
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http://dx.doi.org/10.2147/DMSO.S299375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7987270PMC
March 2021

Symmetric Projection Attractor Reconstruction analysis of murine electrocardiograms: Retrospective prediction of Scn5a genetic mutation attributable to Brugada syndrome.

Heart Rhythm O2 2020 Dec;1(5):368-375

Department of Mathematics, University of Surrey, Guildford, United Kingdom.

Background: Life-threatening arrhythmias resulting from genetic mutations are often missed in current electrocardiogram (ECG) analysis. We combined a new method for ECG analysis that uses all the waveform data with machine learning to improve detection of such mutations from short ECG signals in a mouse model.

Objective: We sought to detect consequences of Na channel deficiencies known to compromise action potential conduction in comparisons of Scn5a mutant and wild-type mice using short ECG signals, examining novel and standard features derived from lead I and II ECG recordings by machine learning algorithms.

Methods: Lead I and II ECG signals from anesthetized wild-type and Scn5a mutant mice of length 130 seconds were analyzed by extracting various groups of features, which were used by machine learning to classify the mice as wild-type or mutant. The features used were standard ECG intervals and amplitudes, as well as features derived from attractors generated using the novel Symmetric Projection Attractor Reconstruction method, which reformulates the whole signal as a bounded, symmetric 2-dimensional attractor. All the features were also combined as a single feature group.

Results: Classification of genotype using the attractor features gave higher accuracy than using either the ECG intervals or the intervals and amplitudes. However, the highest accuracy (96%) was obtained using all the features. Accuracies for different subgroups of the data were obtained and compared.

Conclusion: Detection of the Scn5a mutation from short mouse ECG signals with high accuracy is possible using our Symmetric Projection Attractor Reconstruction method.
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http://dx.doi.org/10.1016/j.hroo.2020.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962089PMC
December 2020

A Myocardial Segmentation Method Based on Adversarial Learning.

Biomed Res Int 2021 26;2021:6618918. Epub 2021 Feb 26.

Department of Pediatric Cardiovascular Medicine, Xi'an Children's Hospital, Xi'an 710003, China.

Congenital heart defects (CHD) are structural imperfections of the heart or large blood vessels that are detected around birth and their symptoms vary wildly, with mild case patients having no obvious symptoms and serious cases being potentially life-threatening. Using cardiovascular magnetic resonance imaging (CMRI) technology to create a patient-specific 3D heart model is an important prerequisite for surgical planning in children with CHD. Manually segmenting 3D images using existing tools is time-consuming and laborious, which greatly hinders the routine clinical application of 3D heart models. Therefore, automatic myocardial segmentation algorithms and related computer-aided diagnosis systems have emerged. Currently, the conventional methods for automatic myocardium segmentation are based on deep learning, rather than on the traditional machine learning method. Better results have been achieved, however, difficulties still exist such as CMRI often has, inconsistent signal strength, low contrast, and indistinguishable thin-walled structures near the atrium, valves, and large blood vessels, leading to challenges in automatic myocardium segmentation. Additionally, the labeling of 3D CMR images is time-consuming and laborious, causing problems in obtaining enough accurately labeled data. To solve the above problems, we proposed to apply the idea of adversarial learning to the problem of myocardial segmentation. Through a discriminant model, some additional supervision information is provided as a guide to further improve the performance of the segmentation model. Experiment results on real-world datasets show that our proposed adversarial learning-based method had improved performance compared with the baseline segmentation model and achieved better results on the automatic myocardium segmentation problem.
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http://dx.doi.org/10.1155/2021/6618918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935602PMC
May 2021

Sanguinarine combats hypoxia-induced activation of EphB4 and HIF-1α pathways in breast cancer.

Phytomedicine 2021 Apr 9;84:153503. Epub 2021 Feb 9.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, P.R. China. Electronic address:

Background: Breast cancer is the most common female cancer worldwide. Large hypoxic area is one of the features of tumor microenvironment. Highly activated hypoxia-induced pathways positively correlate with poor clinical response to chemo- and radiotherapy and high mortality in breast cancer patients.

Purpose: We explore the effect of sanguinarine on hypoxia-induced activation of Ephrin type-B receptor 4 (EphB4) and hypoxia inducible factor-1α (HIF-1α) pathways in breast cancer.

Results: Hypoxia-induced expression of a receptor tyrosine kinase EphB4 was observed in hypoxic breast cancer cell models. Sanguinarine, a natural alkaloid, could effectively combat hypoxia-induced EphB4 and HIF-1α expression. Sanguinarine inhibited the activation of downstream protein signal transducer and activator of transcription-3 (STAT3), thereby blocking hypoxia-induced HIF-1α/STAT3 interaction and downregulating the mRNA levels of their target genes. Mechanically, sanguinarine attenuated HIF-1α protein levels via inhibition of MAPK/ERK pathways and promotion of HIF-1α proteasome degradation. Sanguinarine inhibited STAT3 activation through targeting its upstream EphB4 and accelerating STAT3 dephosphorylation. Correspondingly, xenograft models confirmed that sanguinarine treatment disrupted hypoxia-induced pathways and inhibited tumor growth in vivo.

Conclusions: Our results may bring insights to the hypoxia-induced pathways in breast cancers, and suggest sanguinarine as a promising candidate for EphB4 and HIF-1α-targeted inhibition.
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http://dx.doi.org/10.1016/j.phymed.2021.153503DOI Listing
April 2021

Sanguinarine impedes metastasis and causes inversion of epithelial to mesenchymal transition in breast cancer.

Phytomedicine 2021 Apr 10;84:153500. Epub 2021 Feb 10.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, P.R. China. Electronic address:

Background: A large number of breast cancer patients perishes due to metastasis instead of primary tumor, but molecular mechanisms contributing towards cancer metastasis remain poorly understood. Therefore, prompting development of novel treatment is inevitable. A vast variety of plant derived natural substance possesses several therapeutically active constituents, e.g. alkaloids, flavonoids, tannins, resins, terpenoids etc. that exhibit various pharmacological properties e.g. anti-inflammatory, anti-microbial and anti-cancer properties. Sanguinarine (SAN) alkaloid found its place among such naturally occurring substances that exerts several pharmacological activities, including anti-cancer effects.

Purpose: Until now, role of SAN not only against epithelial-mesenchymal transition (EMT) but also against metastasis progression in breast cancer remains indistinct. Thus, aim of the present study was to investigate effects of SAN on EMT process and cancer metastasis in animal model.

Methods: MTT assay was performed to assess SAN effects on proliferation in breast cancer. Scratch assay was performed to evaluate effects of SAN on migration in breast cancer. Colony formation assay was performed to determine effects of SAN on colonization characteristics of breast cancer. Western blotting was performed to measure EMT regulating protein expression as well as major pathway protein expression induced against TGF-β treatment in breast cancer. Tail vein method of injecting breast cancer cells in bulb/c mice was conducted to study metastasis progression and thereafter assessing effects of SAN against metastasis in mice.

Results: In vivo results: MTT assay performed, demonstrated dose dependent inhibition of cell proliferation in breast cancer. Scratch assay results showed, SAN played a major role as migration inhibitor in estrogen receptor positive (ER+) breast cancer. Colony forming assay results demonstrated that SAN constrains ability of breast cancer to develop into well-defined colonies. Western blotting results for EMT regulating protein expression, after TGF-β treatment showed, SAN inhibited cadherin switch in ER+ breast cancer. Moreover, expression of pathway proteins involved in EMT process after TGF-β treatment i.e. Smad, PI3K/Akt and MAP kinase were significantly masked against SAN treatment.

In Vivo Results: The appearance of metastatic nodules in lung tissues of mice model, helps to study the effects of SAN against metastasis in bulb/c mice. The obtained results have confirmed that SAN impeded lung metastasis. The macroscopic examination has confirmed metastasis inhibitory role of SAN in breast cancer. The Hematoxylin and eosin (H&E) staining results further advocate anti-metastatic characteristics of SAN, presented by fewer metastatic nodule and lesions appearance in SAN treated mice compared to untreated metastasis mice.

Conclusion: In summary, SAN displayed prominent anti-metastatic effects in animal model and anti-proliferation effects together with significant inhibitory potential on EMT regulating protein expression against TGF-β treatment in ER+ breast cancer. So, overall findings of our study highlighted the pre-clinical significance of SAN in animal model therefore, further studies in humans as a part of clinical trial will be needed to establish pharmacokinetics and other effects of SAN, so that it can be a potential candidate for future treatment of metastatic breast cancer (MBC).
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http://dx.doi.org/10.1016/j.phymed.2021.153500DOI Listing
April 2021

Serum and Tissue Levels of Advanced Glycation End Products and Risk of Mortality in Patients on Maintenance Hemodialysis.

Am J Nephrol 2021 17;52(1):8-16. Epub 2021 Feb 17.

Division of Nephrology, Nanfang Hospital, Southern Medical University, National Clinical Research Center for Kidney Disease, State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Guangdong Provincial Key Laboratory of Renal Failure Research, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou, China,

Background: The relation of tissue and circulating advanced glycation end products (AGEs) with mortality in hemodialysis (HD) patients remains inconclusive. We aimed to investigate the association of serum AGEs (CML) and tissue AGEs estimated by skin autofluorescence (SAF) with all-cause and cardiovascular disease (CVD) mortality, and examine the possible modifiers for the association in HD patients with by far the largest sample size in any similar studies.

Methods: A total of 1,634 HD patients were included from the China Cooperative Study on Dialysis (CCSD), a multicenter prospective cohort study. The primary and secondary outcomes were all-cause mortality and CVD mortality, respectively.

Results: The median follow-up duration was 5.2 years. Overall, there was a positive relation of baseline SAF levels with the risk of all-cause mortality (per 1 AU increment, adjusted hazard ratio (HR), 1.30; 95% confidence interval (CI): 1.12, 1.50) and CVD mortality (per 1 AU increment, adjusted HR, 1.36; 95% CI: 1.14, 1.62). Moreover, a stronger positive association between baseline SAF (per 1 AU increment) and all-cause mortality was found in participants with shorter dialysis vintage, or lower C-reactive protein levels (Both p interactions <0.05). Nevertheless, there was no significant association between serum CML and the risk of mortality.

Conclusions: In patients undergoing long-term HD, baseline SAF, but not serum CML, was significantly associated with the risk of all-cause and CVD death.
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http://dx.doi.org/10.1159/000512385DOI Listing
February 2021

1α,25-dihydroxyvitamin D3 promotes early osteogenic differentiation of PDLSCs and a 12-year follow-up case of early-onset vitamin D deficiency periodontitis.

J Steroid Biochem Mol Biol 2021 04 21;208:105805. Epub 2021 Jan 21.

The Affiliated Stomatology Hospital, Zhejiang University School of Medicine, Yan'an Road, Hangzhou, 310000, Zhejiang Province, China; Key Laboratory of Oral Biomedical Research of Zhejiang Province, Zhejiang University School of Stomatology, China. Electronic address:

Periodontitis is a chronic periodontal disease that contributes to tooth loss. In recent years, many animal studies have reported that vitamin D (VitD) deficiency results in chronic periodontitis. However, no studies have reported cases of early-onset periodontitis with VitD deficiency. This study reports a 5-year-old male patient with early-onset periodontitis, VitD deficiency and VitD receptor (VDR) mutation. The patient was treated with VitD and calcium, and received systematic periodontal treatment. During the 12-year treatment, the periodontal conditions of this patient were stable. Our in vitro study found that VitD could promote the expression of alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), bone morphogenetic protein 2 (BMP2), bone gamma-carboxyglutamate protein (BGLAP), and VDR in the early osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Meanwhile, VitD could downregulate mRNA expression levels of Interleukin-6 (IL-6), Interleukin-8 (IL-8), Interleukin-1β (IL-1β) and protein levels of IL-6 in the tumor necrosis factor-α (TNF-α) -induced inflammation of PDLSCs. Therefore, sufficient VitD supply can be a potential treatment for VitD deficiency induced early-onset periodontitis.
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http://dx.doi.org/10.1016/j.jsbmb.2020.105805DOI Listing
April 2021

Baseline serum triglyceride predicts early-onset peritonitis and prognosis in incident CAPD patients.

Medicine (Baltimore) 2021 Jan;100(2):e23673

Department of Nephrology, Wuhan first hospital, Wuhan, China.

Abstract: We aimed to investigate the hypothesis that serum triglyceride (TG) may be an independent predictor of early-onset peritonitis and prognosis in incident continuous ambulatory peritoneal dialysis (CAPD) patients.In this retrospective, observational study, we screened 291 adults admitted to the PD center of the Wuhan No. 1 hospital from August 1, 2013 to November 31, 2017. All biochemical data were collected at the first 1 to 3 months after the initiation of CAPD. Early-onset peritonitis was defined as peritonitis occurring within 6 months after the initiation of PD. All of PD patients were followed up to July 31, 2018. The primary endpoint was the incidence of early-onset peritonitis while the second endpoints included overall mortality and technical failure.A total of 38 patients occurred early-onset PD peritonitis and the Lasso logistic regression selected TG and age in the final model for early-onset peritonitis. We divided patients into two groups based on the median baseline TG levels: TG ≥ 1.4mmo/L group (n = 143) and TG < 1.4mmol/L group (n = 148). There were 34 (11.7%) patients died and 33 (11.3%) patients transferred to hemodialysis during the follow-up, Moreover, a level of TG ≥ 1.4mmol/L at the initiation of CAPD was associated with a significantly increased probability of technical failure (hazard ratio, HR, 1.30; 95% confidence interval, 95% CI, 1.09 to 2.19, P = .043) and overall mortality (HR, 2.33; 95% CI, 1.16-4.72, P = .018).Serum TG levels measured at the initiation of PD therapy is an independent predictor of early-onset peritonitis and prognosis of CAPD patients.
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http://dx.doi.org/10.1097/MD.0000000000023673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808518PMC
January 2021

Multiple Intravenous Injections of Valproic Acid-Induced Mesenchymal Stem Cell from Human-Induced Pluripotent Stem Cells Improved Cardiac Function in an Acute Myocardial Infarction Rat Model.

Biomed Res Int 2020 17;2020:2863501. Epub 2020 Dec 17.

Peking University Shenzhen Hospital, Ultrasound Department, China.

Mounting evidence indicates that the mesenchymal stem cell (MSC) injection is safe and efficacious for treating cardiomyopathy; however, there is limited information relating to multiple intravenous injections of human-induced pluripotent stem cell-derived mesenchymal stem cell (hiPSC-MSC) and long-term evaluation of the cardiac function. In the current study, MSC-like cells were derived from human-induced pluripotent stem cells through valproic acid (VPA) induction and continuous cell passages. The derived spindle-like cells expressed MSC-related markers, secreted angiogenic and immune-regulatory factors, and could be induced to experience chondrogenic and adipogenic differentiation. During the induction process, expression of epithelial-to-mesenchymal transition- (EMT-) related gene N-cadherin and vimentin was upregulated to a very high level, and the expression of pluripotency-related genes Sox2 and Oct4 was downregulated or remained unchanged, indicating that VPA initiated EMT by upregulating the expression of EMT promoting genes and downregulating that of pluripotency-related genes. Two and four intravenous hiPSC-MSC injections (10 cells/per injections) were provided, respectively, to model rats one week after acute myocardial infarction (AMI). Cardiac function parameters were dynamically monitored during a 12-week period. Two and four cell injections significantly the improved left ventricular ejection fraction and left ventricular fractional shortening; four-injection markedly stimulated angiogenesis reduced the scar size and cell apoptosis number in the scar area in comparison with that of the untreated control model rats. Although the difference was insignificant, the hiPSC-MSC administration delayed the increase of left ventricular end-diastolic dimension to different extents compared with that of the PBS-injection control. No perceptible immune reaction symptom or hiPSC-MSC-induced tumour formation was found over 12 weeks. Compared with the PBS-injection control, four injections produced better outcome than two injections; as a result, at least four rounds of MSC injections were suggested for AMI treatment.
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http://dx.doi.org/10.1155/2020/2863501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759411PMC
May 2021

Structure-based discovery of 1H-indole-2-carboxamide derivatives as potent ASK1 inhibitors for potential treatment of ulcerative colitis.

Eur J Med Chem 2021 Feb 25;211:113114. Epub 2020 Dec 25.

School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, PR China. Electronic address:

Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase (MAPK) family, is implicated in many human diseases. Here, we describe the structural optimization of hit compound 7 and conduct further structure-activity relationship (SAR) studies that result in the development of compound 19 with a novel indole-2-carboxamide hinge scaffold. Compound 19 displays potent anti-ASK1 kinase activity and stronger inhibitory effect on ASK1 in AP1-HEK293 cells than previously described ASK1 inhibitor GS-4997. Besides improved in vitro activity, compound 19 also exhibits an appropriate in vivo PK profile. In a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis (UC), compound 19 shows significant anti-UC efficacy and markedly attenuates DSS-induced body weight loss, colonic shortening, elevation in disease activity index (DAI) and inflammatory cell infiltration in colon tissues. Mechanistically, compound 19 represses the phosphorylation of ASK1-p38/JNK signaling pathways and suppresses the overexpression of inflammatory cytokines. Together, these findings suggest that ASK1 inhibitors can potentially be used as a therapeutic strategy for UC.
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http://dx.doi.org/10.1016/j.ejmech.2020.113114DOI Listing
February 2021

Early Onset of Combined Oxidative Phosphorylation Deficiency in Two Chinese Brothers Caused by a Homozygous (Leu275Phe) Mutation in the Gene.

Front Pediatr 2020 2;8:583047. Epub 2020 Dec 2.

Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Xi'an, China.

Mitochondrial diseases constitute a group of heterogeneous hereditary diseases caused by impairments in mitochondrial oxidative phosphorylation and abnormal cellular energy metabolism. C1QBP plays an important role in mitochondrial homeostasis. In this study, clinical, laboratory examinations, 12-lead electrocardiographic, ultrasonic cardiogram, and magnetic resonance imaging data were collected from four members of a Chinese family. Whole exome were amplified and sequenced for the proband. The structure of protein encoded by the mutation was predicted using multiple software programs. The proband was a 14-year old boy with myocardial hypertrophy, exercise intolerance, ptosis, and increased lactate. His 9-year old brother exhibited similar clinical manifestations while the phenomenon of ptosis was not as noticeable as the proband. The onset of this disease was in infancy in both cases. They were born after uneventful pregnancies of five generation blood relative Chinese parents. A homozygous mutation (Leu275Phe) in the gene was identified in both brothers in an autosomal recessive inherited pattern. Their parents were heterozygous mutation carriers without clinical manifestations. We demonstrated that a homozygous C1QBP- P.Leu275Phe mutation in an autosomal recessive inherited mode of inheritance caused early onset combined oxidative phosphorylation deficiency 33 (COXPD 33) (OMIM:617713) in two brothers from a Chinese family.
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http://dx.doi.org/10.3389/fped.2020.583047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738465PMC
December 2020

MiRNAs directly targeting the key intermediates of biological pathways in pancreatic cancer.

Biochem Pharmacol 2021 Jul 3;189:114357. Epub 2020 Dec 3.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China. Electronic address:

Pancreatic Cancer (PC) is a severe form of malignancy all over the world. Delayed diagnosis and chemoresistance are the major factors contributing to its poor prognosis and high mortality rate. The genetic and epigenetic regulations of biological pathways further complicate the progression and chemotherapy response to this cancer. MicroRNAs (MiRNAs) involvement has been observed in all types of cancers including PC. The understanding and categorization of miRNAs according to their specific targets are very important to develop early diagnostic and therapeutic interventions. The current review, emphasizing recent research findings, has categorized miRNAs that directly target the potential onco-factors that act as central converging signal-nodes in five major cancer-related pathways i.e., MAPK/ERK, JAK/STAT, Wnt/β-catenin, AKT/mTOR, and TGFβ in PC. The therapeutic perspectives of miRNAs in PC have also been discussed. This will help to understand the interplay of various miRNAs within foremost signaling pathways and develop a multifactorial approach to treat difficult-to-treat PC.
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http://dx.doi.org/10.1016/j.bcp.2020.114357DOI Listing
July 2021

The discovery of quinoline derivatives, as NF-κB inducing kinase (NIK) inhibitors with anti-inflammatory effects in vitro, low toxicities against T cell growth.

Bioorg Med Chem 2021 01 7;29:115856. Epub 2020 Nov 7.

School of Sciences, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China. Electronic address:

NIK is a critical regulatory protein of the non-classical NF-kB pathway, and its dysregulated activation has been proved to be one of the pathogenic factors in a variety of autoimmune diseases and inflammatory diseases. Nevertheless, its corresponding development of inhibitors faces many obstacles, including the lack of structure types of known inhibitors, immature activity evaluation methods of compounds in vitro. In this study, a series of quinoline derivatives were obtained through rational design and chemical synthesis. Among them, the representative compounds 17c and 24c have excellent inhibitory activities on LPS-induced macrophage (J774) nitric oxide release and anti-Con A-stimulated primary T cell proliferation. This evaluation method has good universality and overcomes the obstacles mentioned above, which are faced by the current inhibitor research to a certain extent. Besides, the compound's toxicity against the growth of T cells under non-stress conditions was evaluated, for the first time, as an indicator for the investigation to avoid potential safety risks. Pharmacokinetic properties evaluation of the less toxic compound 24c confirmed its good metabolic behavior (especially oral properties, F% = 21.7%), and subsequent development value.
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http://dx.doi.org/10.1016/j.bmc.2020.115856DOI Listing
January 2021

[Clinical and genetic analysis of a Chinese pedigree affected with Smith-Lemli-Opitz syndrome].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2020 Nov;37(11):1272-1275

Department of Rehabilitation Medicine, Children' Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou, Henan 450018, China.

Objective: To explore the clinical phenotype and pathogenic variants in a Chinese pedigree affected with Smith-Lemli-Opitz syndrome.

Methods: Peripheral blood samples were collected from five members, including two affected ones, from the pedigree for the extraction of genomic DNA. Whole exome sequencing was carried out, and candidate variants were verified by Sanger sequencing as well as reverse transcription sequencing at the RNA level.

Results: The proband and another affected child from the pedigree showed mental retardation, dyskinesia, microcephaly, micrognathia, anteverted nares, and 2/3 toe syndactyly. The proband also had hypospadia, single upper incisor, and lower serum cholesterol level. Both children were found to harbor a paternally derived c.278C>T (p.T93M) variant and a maternally derived c.907G>A (p.G303R) variant of the DHCR7 gene. Both were known pathogenic mutations.

Conclusion: The compound heterozygous mutations of c.278C>T (p.T93M) and c.907G>A (p.G303R) of the DHCR7 gene probably underlay the disease in this pedigree. Above finding has enabled early diagnosis and treatment of Smith-Lemli-Opitz syndrome.
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http://dx.doi.org/10.3760/cma.j.cn511374-20190929-00502DOI Listing
November 2020

Independent Prognostic Potential of GNPNAT1 in Lung Adenocarcinoma.

Biomed Res Int 2020 29;2020:8851437. Epub 2020 Oct 29.

Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and The Berlin Institute of Health, Berlin, Germany.

Background: Glucosamine-Phosphate N-Acetyltransferase 1 (GNPNAT1) is a critical enzyme in the biosynthesis of uridine diphosphate-N-acetylglucosamine. It has many important functions, such as protein binding, monosaccharide binding, and embryonic development and growth. However, the role of GNPNAT1 in lung adenocarcinoma (LUAD) remains unclear.

Methods: In this study, we explored the expression pattern and prognostic value of GNPNAT1 in LUAD across TCGA and GEO databases and assessed its independent prognostic value via Cox analysis. LinkedOmics and GEPIA2 were applied to investigate coexpression and functional networks associated with GNPNAT1. The TIMER web tool was deployed to assess the correlation between GNPNAT1 and the main six types of tumor-infiltrating immune cells. Besides, the correlations between GNPNAT1 and the LUAD common genetic mutations, TMB, and immune signatures were examined.

Results: GNPNAT1 was validated upregulated in tumor tissues in TCGA-LUAD and GEO cohorts. Moreover, in both TCGA and GEO cohorts, high GNPNAT1 expression was found to be associated with poor overall survival. Cox analysis showed that high GNPNAT1 expression was an independent risk factor for LUAD. Functional network analysis suggested that GNPNAT1 regulates cell cycle, ribosome, proteasome, RNA transport, and spliceosome signaling through pathways involving multiple cancer-related kinases and E2F family. In addition, GNPNAT1 correlated with infiltrating levels of B cells, CD4+ T cells, and dendritic cells. B cells and dendritic cells could predict the outcome of LUAD, and B cells and CD4+ T cells were significant independent risk factors. The TMB and mutations of KRAS, EGFR, STK11, and TP53 were correlated with GNPNAT1. At last, the correlation analysis showed GNPNAT1 correlated with most of the immune signatures we performed.

Conclusion: Our findings showed that GNPNAT1 was correlated to the prognosis and immune infiltration of LUAD. In particular, the tight relationship between GNPNAT1 and B cell marker genes may be the epicenter of the immune response and one of the key factors affecting the prognosis. Our findings laid the foundation for further research on the immunomodulatory role of GNPNAT1 in LUAD.
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http://dx.doi.org/10.1155/2020/8851437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7648248PMC
May 2021

Activity Prediction of Small Molecule Inhibitors for Antirheumatoid Arthritis Targets Based on Artificial Intelligence.

ACS Comb Sci 2020 12 4;22(12):873-886. Epub 2020 Nov 4.

Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.

Rheumatoid arthritis (RA) is a chronic autoimmune disease, which is compared to "immortal cancer" in industry. Currently, SYK, BTK, and JAK are the three major targets of protein tyrosine kinase for this disease. According to existing research, marketed and research drugs for RA are mostly based on single target, which limits their efficacy. Therefore, designing multitarget or dual-target inhibitors provide new insights for the treatment of RA regarding of the specific association between SYK, BTK, and JAK from two signal transduction pathways. In this study, machine learning (XGBoost, SVM) and deep learning (DNN) models were combined for the first time to build a powerful integrated model for SYK, BTK, and JAK. The predictive power of the integrated model was proved to be superior to that of a single classifier. In order to accurately assess the generalization ability of the integrated model, comprehensive similarity analysis was performed on the training and the test set, and the prediction accuracy of the integrated model was specifically analyzed under different similarity thresholds. External validation was conducted using single-target and dual-target inhibitors, respectively. Results showed that our model not only obtained a high recall rate (97%) in single-target prediction, but also achieved a favorable yield (54.4%) in dual-target prediction. Furthermore, by clustering dual-target inhibitors, the prediction performance of model in various classes were proved, evaluating the applicability domain of the model in the dual-target drug screening. In summary, the integrated model proposed is promising to screen dual-target inhibitors of SYK/JAK or BTK/JAK as RA drugs, which is beneficial for the clinical treatment of rheumatoid arthritis.
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http://dx.doi.org/10.1021/acscombsci.0c00169DOI Listing
December 2020

Identification of a Novel Tumor Microenvironment-Associated Eight-Gene Signature for Prognosis Prediction in Lung Adenocarcinoma.

Front Mol Biosci 2020 23;7:571641. Epub 2020 Sep 23.

Department of Laboratory Medicine, the Second Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China.

Background: Lung cancer has become the most common cancer type and caused the most cancer deaths. Lung adenocarcinoma (LUAD) is one of the major types of lung cancer. Accumulating evidence suggests the tumor microenvironment is correlated with the tumor progress and the patient's outcome. This study aimed to establish a gene signature based on tumor microenvironment that can predict patients' outcomes for LUAD.

Methods: Dataset TCGA-LUAD, downloaded from the TCGA portal, were taken as training cohort, and dataset GSE72094, obtained from the GEO database, was set as validation cohort. In the training cohort, ESTIMATE algorithm was applied to find intersection differentially expressed genes (DEGs) among tumor microenvironment. Kaplan-Meier analysis and univariate Cox regression model were performed on intersection DEGs to preliminarily screen prognostic genes. Besides, the LASSO Cox regression model was implemented to build a multi-gene signature, which was then validated in the validation cohorts through Kaplan-Meier, Cox, and receiver operating characteristic curve (ROC) analyses. In addition, the correlation between tumor mutational burden (TMB) and risk score was evaluated by Spearman test. GSEA and immune infiltrating analyses were conducted for understanding function annotation and the role of the signature in the tumor microenvironment.

Results: An eight-gene signature was built, and it was examined by Kaplan-Meier analysis, revealing that a significant overall survival difference was seen. The eight-gene signature was further proven to be independent of other clinico-pathologic parameters via the Cox regression analyses. Moreover, the ROC analysis demonstrated that this signature owned a better predictive power of LUAD prognosis. The eight-gene signature was correlated with TMB. Furthermore, GSEA and immune infiltrating analyses showed that the exact pathways related to the characteristics of eight-genes signature, and identified the vital roles of Mast cells resting and B cells naive in the prognosis of the eight-gene signature.

Conclusion: Identifying the eight-gene signature (INSL4, SCN7A, STAP1, P2RX1, IKZF3, MS4A1, KLRB1, and ACSM5) could accurately identify patients' prognosis and had close interactions with Mast cells resting and B cells naive, which may provide insight into personalized prognosis prediction and new therapies for LUAD patients.
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http://dx.doi.org/10.3389/fmolb.2020.571641DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546815PMC
September 2020

Stem-cell-derived ECM sheet-implant complexes for enhancing osseointegration.

Biomater Sci 2020 Dec 19;8(23):6647-6656. Epub 2020 Oct 19.

Department of Implantology, Affiliated Hospital of Stomatology, Medical College, Zhejiang University, No. 395, Yan'an Road, Xia-Cheng Region, Hangzhou, Zhejiang 310006, China.

Numerous treatment methods have been developed to modify the surface of dental implants to improve cell migration and proliferation, removal torque, and osseointegration. Recent studies have constructed cell sheet-implant complexes with enhanced osteogenic capabilities. However, these complexes have some limitations, such as requirements for complex preparation processes, cell vitality maintenance, strict preservation conditions, and the induction of immunogenicity. Extracellular matrix (ECM) sheets without cells may be a more desirable material. To date, the effect of ECM sheets on implant osseointegration has not been reported. In this study, we fabricated ECM sheet-implant complexes through the combination of rat bone marrow mesenchymal stem cell (BMSC)-derived ECM sheets with sandblasted, large-grit, acid-etched (SLA) implants. These complexes were characterized by light microscopy, scanning electron microscopy (SEM), and immunofluorescence (IF) assays. The adhesion, proliferation, and osteogenic differentiation of BMSCs cultured on ECM sheets were detected in vitro. Then, the ECM sheet-implant complexes were transplanted into the metaphysis of the tibias of rats to evaluate the implant osseointegration in vivo. The results showed that ECM sheets were successfully constructed and showed significantly improved adhesion and proliferation. BMSCs cultured on ECM sheets upregulated the expression levels of the osteogenic-related genes alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), and runt-related transcription factor 2 (Runx2) compared to controls. In vivo, ECM sheet-implant complexes demonstrated superior new bone formation. Our findings proved that the BMSC-derived ECM sheets promoted osseointegration in vitro and in vivo. The current study indicated that the ECM sheet could be an ideal tissue engineering material, and ECM sheet-implant complexes could provide a strategy with low immunogenicity and easy storage and transportation. This research provides a novel strategy for the development of implant surface modification approaches.
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http://dx.doi.org/10.1039/d0bm00980fDOI Listing
December 2020

Association between blood copper and nonalcoholic fatty liver disease according to sex.

Clin Nutr 2021 Apr 29;40(4):2045-2052. Epub 2020 Sep 29.

Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences; School of Basic Medicine Peking Union Medical College, Beijing, China. Electronic address:

Background & Aims: Nonalcoholic fatty liver disease (NAFLD) is a common disease with potential sex-based difference in the prevalence and prognosis. Copper deficiency may affect the antioxidant defense system and lead to the progression of NAFLD. This study aimed to evaluate the association between blood copper and NAFLD according to sex difference.

Methods: A case-control study of 1816 cases of NAFLD and 1111 sex- and age-matched control cases was conducted in Tangshan, China, from January 1, 2016, to December 31, 2017, based on the Kailuan cohort. In men and women, logistic regression analysis was separately applied to determine the risk of NAFLD, severity of NAFLD based on hepatic steatosis, the NAFLD fibrosis score, and fibrosis-4 score, for each quartile of blood copper with the lowest quartile as the reference. In addition, the effect of metabolic syndrome on the association between copper and NAFLD was assessed.

Results: In men, blood copper concentration was lower in the NAFLD group (mean ± SD: 0.617 ± 0.117 μg/mL) than in the control group (mean ± SD: 0.655 ± 0.133 μg/mL) (P < 0.001). After adjustment for possible confounders, the odds ratio of NAFLD at the highest quartile of copper compared to the lowest quartile was 0.57 (95% CI: 0.41-0.80) and the protective effect of higher blood copper was increased with the severity of NAFLD. In the results of stratified analysis, lower copper concentration was a significant additional factor that contributed to higher risk of NAFLD in male subjects with metabolic syndrome. However, no significant association was observed between copper and NAFLD in women with different characteristics, except an NAFLD fibrosis score < -1.455 and moderate hepatic steatosis.

Conclusions: Higher copper levels achieved significant protective effect against NAFLD in men but not in women. Sex-specific intervention is a potential tool for the prevention of development of NAFLD.
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http://dx.doi.org/10.1016/j.clnu.2020.09.026DOI Listing
April 2021

Novel diphenyl urea derivative serves as an inhibitor on human lung cancer cell migration by disrupting EMT via Wnt/β-catenin and PI3K/Akt signaling.

Toxicol In Vitro 2020 Dec 15;69:105000. Epub 2020 Sep 15.

School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an 710061, PR China; State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an 710061, PR China. Electronic address:

Targeted anti-tumor small molecules are considered to be promising candidates for cancer treatment. The novel diphenyl urea derivative (DUD) was synthesized by the molecular docking based on the structure optimization of Taspine (a natural product). In this study, we explored the anti-metastatic potential of DUD for NSCLC in vitro. DUD significantly suppressed A549 cell migration by reversing EMT. The inhibition was reflected on upregulation of E-cadherin and downregulation of N-cadherin, vimentin, Snail and HIF-1α. Meanwhile, DUD inhibited the β-catenin nuclear translocation by upregulating Axin and downregulating the expression of APC, CK1 and phosphorylation of GSK3β, and simultaneously decreasing MMP9 and MMP13 expression. Moreover, it was associated with the downregulation of the PI3K/Akt/mTOR signaling. Furthermore, we used XAV939, an β-catenin inhibitor, to verify the mechanism of DUD. These results suggested that DUD inhibited A549 cells migration by reversing EMT via Wnt/β-catenin and PI3K/Akt signaling. DUD might be a potential therapeutic drug candidate for NSCLC treatment.
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http://dx.doi.org/10.1016/j.tiv.2020.105000DOI Listing
December 2020

Discovery of Dual FGFR4 and EGFR Inhibitors by Machine Learning and Biological Evaluation.

J Chem Inf Model 2020 10 23;60(10):4640-4652. Epub 2020 Sep 23.

Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, China.

Kinase inhibitors are widely used in antitumor research, but there are still many problems such as drug resistance and off-target toxicity. A more suitable solution is to design a multitarget inhibitor with certain selectivity. Herein, computational and experimental studies were applied to the discovery of dual inhibitors against FGFR4 and EGFR. A quantitative structure-property relationship (QSPR) study was carried out to predict the FGFR4 and EGFR activity of a data set consisting of 843 and 5088 compounds, respectively. Four different machine learning methods including support vector machine (SVM), random forest (RF), gradient boost regression tree (GBRT), and XGBoost (XGB) were built using the most suitable features selected by the mutual information algorithm. As for FGFR4 and EGFR, SVM showed the best performance with = 0.80 and = 0.75, demonstrating excellent model stability, which was used to predict the activity of some compounds from an in-house database. Finally, compound was selected, which exhibits inhibitory activity against FGFR4 (IC = 86.2 nM) and EGFR (IC = 83.9 nM) kinase, respectively. Furthermore, molecular docking and molecular dynamics simulations were performed to identify key amino acids for the interaction of compound with FGFR4 and EGFR. In this paper, the machine-learning-based QSAR models were established and effectively applied to the discovery of dual-target inhibitors against FGFR4 and EGFR, demonstrating the great potential of machine learning strategies in dual inhibitor discovery.
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http://dx.doi.org/10.1021/acs.jcim.0c00652DOI Listing
October 2020

Nanocomposite hydrogel with NIR/magnet/enzyme multiple responsiveness to accurately manipulate local drugs for on-demand tumor therapy.

Biomaterials 2020 12 2;262:120357. Epub 2020 Sep 2.

Department of Chemical Engineering, Shaanxi Key Laboratory of Energy Chemical Process Intensification, Institute of Polymer Science in Chemical Engineering, School of Chemical Engineering and Technology, Xi'an Jiao Tong University, Xi'an, 710049, China. Electronic address:

Chemotherapy is one of the most commonly utilized approaches to treat malignant tumor. However, the well-controlled chemotherapy able to accurately manipulate local drugs for on-demand tumor treatment is still a challenge. Herein, a magnet and light dual-responsive hydrogel combining thermosensitive poly(N-acryloyl glycinamide) (PNAGA), doxorubicin (DOX) loaded and polyester (PE) capped mesoporous silica nanocarriers (MSNs) as well as FeO nanoparticles (FeO NPs) grafted graphene oxide (GO) was fabricated to address above issue. The FeO NPs and GO respectively serve as magnetothermal agent and photothermal agent to perform hyperthermia, meanwhile to generate chain motion of PNAGA with varying degrees under different conditions of magnetic field and/or NIR irradiation. This strategy not only allowed the gel-sol transition of the hydrogel by prior heating for tumor injection, but performed controllable release routes of DOX-MSNs-PE (DMP for short) nanocarriers to meet various requirements from different patients and the changing states of tumor. Furthermore, these escaped DMP nanocarriers could be taken by surrounding tumor cells, and then deliver their drug to these cells after rapid hydrolysis of the PE cap triggered by esterase, resulting in accurate chemotherapy. Both in vitro and in vivo results indicated that the [email protected] hydrogel combining well-controllable chemotherapy and hyperthermia can eliminate more than 90% tumor cells and effectively inhibit the tumor growth in mice model, demonstrating the great candidate of our hydrogel for accurate tumor therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120357DOI Listing
December 2020

Hepatitis B virus infection and diabetes mellitus: the Kailuan prospective cohort study in China.

Hepatol Int 2020 Sep 3;14(5):743-753. Epub 2020 Sep 3.

Department of Epidemiology and Biostatistics, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, 100005, China.

Background And Aims: The effect of hepatitis B virus (HBV) infection on diabetes has remained unclear. We thus conducted a prospective cohort study to investigate the association between different HBV infection status and new-onset diabetes in a Chinese population.

Methods: We enrolled 55,520 participants with HBV serological markers and diabetes free in 2010 in Kailuan cohort. Cox regression models were used to analyze the relationship between different HBV infection status and incidence of diabetes after adjusting different confounders.

Results: During an average follow-up of 5.6 years, we identified 6008 incident patients with diabetes. Compared to the participants with hepatitis B surface antigen (HBsAg) negative/hepatitis B surface antibody (anti-HBs) negative/hepatitis B core antibody (anti-HBc) negative, those with chronic HBV infection or with HBsAg negative/anti-HBc positive had a higher risk to occur diabetes. The hazard ratios were 1.18 (95% CI 0.99-1.40, p = 0.0588) and 1.22 (95% CI 1.08-1.36, p = 0.0009), respectively. The association between chronic HBV infection, anti-HBc positive and diabetes was different between those with different levels of high density lipoprotein cholesterol, blood pressure, body mass index, and age.

Conclusion: The individuals with chronic HBV infection or anti-HBc positive may have an increased risk of diabetes, and the association may be modified by the different status of metabolism related variables and age. Effective management of HBV infection may contribute to the reduction of the burden of both hepatitis B and diabetes.
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http://dx.doi.org/10.1007/s12072-020-10086-2DOI Listing
September 2020