Publications by authors named "Xiaoyun Zhu"

53 Publications

A pilot study of the General Movement Optimality Score detects early signs of motor disorder in neonates with arterial ischemic stroke.

Early Hum Dev 2021 Oct 7;163:105484. Epub 2021 Oct 7.

Department of Neonatology, Children's Hospital Fudan University, Shanghai, China. Electronic address:

Aim: To explore whether the General Movement Optimality Score (GMOS) could help to identify asymmetric movement in infants with neonatal arterial ischemic stroke (NAIS) in the early stage.

Method: Twenty-seven infants with NAIS (16 males, 11 females) were enrolled. The general movement video was recorded approximately one month after birth. The GMOS focused separately on the neck and trunk and the upper and lower extremities. The differences between the ipsilesional and contralesional limbs were analyzed.

Results: Eight infants who developed cerebral palsy (CP) had middle cerebral artery (MCA) infarction involving the main branch. By GMOS evaluation, the scores of the contralesional upper and/or lower limbs were lower than those of the ipsilesional side (p < 0.05). In the contralesional limbs, the CP group had a lower GMOS than the non-CP group. Distal rotatory components of the contralesional upper limbs and tremulous movement of the lower limbs showed significant differences.

Interpretation: The GMOS could help to quantitatively find and assess the asymmetric movement of global and contralesional limbs. Distal rotatory movement of the upper limbs could be an early sign of abnormal motor function in infants with NAIS.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105484DOI Listing
October 2021

Early detection relationship of cerebral palsy markers using brain structure and general movements in infants born <32 weeks gestational age.

Early Hum Dev 2021 Aug 25;163:105452. Epub 2021 Aug 25.

Department of Rehabilitation, Children's Hospital, Fudan University, Shanghai 201102, China.

Aim: To detect early brain structural and clinical functional markers of brain injury and development based on a magnetic resonance imaging (MRI) scoring system and a general movement assessment (GMA) for preterm infants later diagnosed with cerebral palsy (CP).

Study Design: Retrospective cohort study. General movements (GMs) were scored according to a semiquantitative scoring system: the GMs optimality score (GMOS) at preterm and term ages and the Motor Optimality Score (MOS) at the corrected age of 3 months after birth. Brain magnetic resonance imaging (MRI) at term-equivalent age was scored using an MRI scoring system. We analyzed the relationship between the early degree of cerebral white matter (WM) abnormality and the GMOS and the MOS for infants born <32 weeks gestational age later diagnosed with CP in a comparison group of neurotypical controls.

Subjects: Sixteen preterm infants were included in this study who underwent MRI and GMs assessment. 8 out of the 16 preterm infants were later diagnosed with CP, while the other 8 infants with normal motor development (N) were placed into the control group. Their median gestational age was 30w6d and 27w6d for each group respectively.

Results: The cerebral WM MRI scores were significantly higher in the CP group than in the control group (p < 0.01). The GMOS and MOS were significantly higher in the control group than in the CP group (p < 0.05). The MOS showed a strong correlation to the cerebral WM MRI score (r = -0.88) and the subscale of cerebral WM items (the cystic degeneration and the focal signal abnormalities) of the MRI score (r = -0.94) in the CP group. The MOS also showed a correlation with corrected biparietal diameter (cBPD) in the preterm infant group with CP (r = 0.75). Results of linear regression analyses between term MRI and GMs measures in preterm infants with CP are presented. Cerebral WM scores were associated with the MOS (β = -0.63; 95%CI = -0.97, -0.29; p < 0.01). Cerebral WM injury, including the subscale of cystic degeneration and focal signal abnormalities was closely associated with the MOS (β = -0.83; 95%CI = -1.13, -0.54; p < 0.001).

Conclusion: Cerebral WM scores show a strong association with a decreased motor performance on the MOS in preterm infants later diagnosed with CP. Severe white matter injury and significantly decreased MOS scores may provide useful early markers and strong evidence to early predict the risk of later development of cerebral palsy in preterm infants.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105452DOI Listing
August 2021

LIX1-like protein drives hepatic stellate cell activation to promote liver fibrosis by regulation of chemokine mRNA stability.

Signal Transduct Target Ther 2021 Sep 1;6(1):319. Epub 2021 Sep 1.

Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

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http://dx.doi.org/10.1038/s41392-021-00665-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408256PMC
September 2021

Astragaloside IV ameliorates diabetic nephropathy in mice by inhibiting NLRP3 inflammasome‑mediated inflammation.

Int J Mol Med 2021 Aug 19;48(2). Epub 2021 Jul 19.

Department of Laboratory of Diabetes, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, P.R. China.

Diabetic nephropathy (DN) is a primary cause of end‑stage renal disease. Despite the beneficial effects of astragaloside IV (AS)‑IV on renal disease, the underlying mechanism of its protective effects against DN has not been fully determined. The aims of the present study were to assess the effects of AS‑IV against DN in mice and to explore the mechanism of AS‑IV involving the NLR family pyrin domain containing 3 (NLRP3), caspase‑1 and interleukin (IL)‑1β pathways. The 8‑week‑old mice received 40 mg/kg AS‑IV once a day for 12 weeks via intragastric administration. Cultured mouse podocytes were used to further confirm the underlying mechanism . AS‑IV effectively reduced weight gain, hyperglycemia and the serum triacylglycerol concentration in mice. AS‑IV also reduced urinary albumin excretion, urinary albumin‑to‑creatinine ratio and creatinine clearance rate, as well as improved renal structural changes, accompanied by the upregulation of the podocyte markers podocin and synaptopodin. AS‑IV significantly inhibited the expression levels of NLRP3, caspase‑1 and IL‑1β in the renal cortex, and reduced the serum levels of tumor necrosis factor (TNF)‑α and monocyte chemoattractant protein‑1. In high glucose‑induced podocytes, AS‑IV significantly improved the expression levels of NLRP3, pro‑caspase‑1 and caspase‑1, and inhibited the cell viability decrease in a dose‑dependent manner, while NLRP3 overexpression eliminated the effect of AS‑IV on podocyte injury and the inhibition of the NLRP3 and caspase‑1 pathways. The data obtained from and experiments demonstrated that AS‑IV ameliorated renal functions and podocyte injury and delayed the development of DN in mice via anti‑NLRP3 inflammasome‑mediated inflammation.
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http://dx.doi.org/10.3892/ijmm.2021.4996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262660PMC
August 2021

A Fusion Protein Complex that Combines IL-12, IL-15, and IL-18 Signaling to Induce Memory-Like NK Cells for Cancer Immunotherapy.

Cancer Immunol Res 2021 Sep 9;9(9):1071-1087. Epub 2021 Jul 9.

Washington University School of Medicine, Division of Oncology, Saint Louis, Missouri.

Natural killer (NK) cells are a promising cellular therapy for cancer, with challenges in the field including persistence, functional activity, and tumor recognition. Briefly, priming blood NK cells with recombinant human (rh)IL-12, rhIL-15, and rhIL-18 (12/15/18) results in memory-like NK cell differentiation and enhanced responses against cancer. However, the lack of available, scalable Good Manufacturing Process (GMP)-grade reagents required to advance this approach beyond early-phase clinical trials is limiting. To address this challenge, we developed a novel platform centered upon an inert tissue factor scaffold for production of heteromeric fusion protein complexes (HFPC). The first use of this platform combined IL-12, IL-15, and IL-18 receptor engagement (HCW9201), and the second adds CD16 engagement (HCW9207). This unique HFPC expression platform was scalable with equivalent protein quality characteristics in small- and GMP-scale production. HCW9201 and HCW9207 stimulated activation and proliferation signals in NK cells, but HCW9207 had decreased IL-18 receptor signaling. RNA sequencing and multidimensional mass cytometry revealed parallels between HCW9201 and 12/15/18. HCW9201 stimulation improved NK cell metabolic fitness and resulted in the DNA methylation remodeling characteristic of memory-like differentiation. HCW9201 and 12/15/18 primed similar increases in short-term and memory-like NK cell cytotoxicity and IFNγ production against leukemia targets, as well as equivalent control of leukemia in NSG mice. Thus, HFPCs represent a protein engineering approach that solves many problems associated with multisignal receptor engagement on immune cells, and HCW9201-primed NK cells can be advanced as an ideal approach for clinical GMP-grade memory-like NK cell production for cancer therapy.
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http://dx.doi.org/10.1158/2326-6066.CIR-20-1002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416787PMC
September 2021

LIX1-like protein promotes liver cancer progression miR-21-3p-mediated inhibition of fructose-1,6-bisphosphatase.

Acta Pharm Sin B 2021 Jun 10;11(6):1578-1591. Epub 2021 Feb 10.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Limb and CNS expressed 1 like (LIX1L) is over-expressed in several types of tumors. However, the function of LIX1L in glucose metabolism and hepatocellular carcinoma (HCC) progression remains elusive. Here we report that LIX1L is over-expressed in human HCC tissues, which predicts unfavorable prognosis. LIX1L deficiency significantly attenuated liver cancer initiation in mice. Functional studies indicated that LIX1L overexpression elevated proliferation, migratory, invasive capacities of HCC cells , and promoted liver cancer growth and metastasis LIX1L knockdown up-regulated fructose-1,6-bisphosphatase (FBP1) expression to reduce glucose consumption as well as lactate production. Mechanistically, LIX1L increased miR-21-3p expression, which targeted and suppressed FBP1, thereby promoting HCC growth and metastasis. MiR-21-3p inhibitor could abrogate LIX1L induced enhancement of cell migration, invasion, and glucose metabolism. Inhibition of miR-21-3p suppressed tumor growth in an orthotopic tumor model. Our results establish LIX1L as a critical driver of hepatocarcinogenesis and HCC progression, with implications for prognosis and treatment.
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http://dx.doi.org/10.1016/j.apsb.2021.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245913PMC
June 2021

Bifunctional TGF-β trap/IL-15 protein complex elicits potent NK cell and CD8 T cell immunity against solid tumors.

Mol Ther 2021 Oct 4;29(10):2949-2962. Epub 2021 Jun 4.

HCW Biologics Inc., Miramar, FL 33025, USA. Electronic address:

Advances in immunostimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. However, novel immunotherapeutics with these dual functions are not frequently reported. Here we describe the creation of a heterodimeric bifunctional fusion molecule, HCW9218, constructed using our soluble tissue factor (TF)-based scaffold technology. This complex comprises extracellular domains of the human transforming growth factor-β (TGF-β) receptor II and a human interleukin-15 (IL-15)/IL-15 receptor α complex. HCW9218 can be readily expressed in CHO cells and purified using antibody-based affinity chromatography in a large-scale manufacturing setting. HCW9218 potently activates mouse natural killer (NK) cells and CD8 T cells in vitro and in vivo to enhance cell proliferation, metabolism, and antitumor cytotoxic activities. Similarly, human immune cells become activated with increased cytotoxicity following incubation with HCW9218. This fusion complex also exhibits TGF-β neutralizing activity in vitro and sequesters plasma TGF-β in vivo. In a syngeneic B16F10 melanoma model, HCW9218 displayed strong antitumor activity mediated by NK cells and CD8 T cells and increased their infiltration into tumors. Repeat-dose subcutaneous administration of HCW9218 was well tolerated by mice, with a half-life sufficient to provide long-lasting biological activity. Thus, HCW9218 may serve as a novel therapeutic to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors.
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http://dx.doi.org/10.1016/j.ymthe.2021.06.001DOI Listing
October 2021

Physalin B attenuates liver fibrosis via suppressing LAP2α-HDAC1-mediated deacetylation of the transcription factor GLI1 and hepatic stellate cell activation.

Br J Pharmacol 2021 09 21;178(17):3428-3447. Epub 2021 May 21.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

Background And Purpose: Liver fibrosis is one of the leading causes of morbidity and mortality worldwide but lacks any acceptable therapy. The transcription factor glioma-associated oncogene homologue 1 (GLI1) is a potentially important therapeutic target in liver fibrosis. This study investigates the anti-fibrotic activities and potential mechanisms of the phytochemical, physalin B.

Experimental Approach: Two mouse models (CCl challenge and bile duct ligation) were used to assess antifibrotic effects of physalin B in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX-2 also served as in vitro liver fibrosis models. Liver fibrogenic genes, GLI1 and GLI1 downstream genes were examined using Western blot and quantitative real-time PCR (qRT-PCR). GLI1 acetylation and LAP2α-HDAC1 interaction were analysed by co-immunoprecipitation.

Key Results: In vivo, physalin B administration attenuated hepatic histopathological injury and collagen accumulation and decreased expression of fibrogenic genes. Physalin B dose-dependently suppressed fibrotic marker expression in LX-2 cells and mouse pHSCs. Mechanistic studies showed that physalin B inhibited GLI activity by non-canonical Hedgehog signalling. Physalin B blocked formation of lamina-associated polypeptide 2α (LAP2α)/histone deacetylase 1 (HDAC1) complexes, thus inhibiting HDAC1-mediated GLI1 deacetylation. Physalin B up-regulated acetylation of GLI1, down-regulated expression of GLI1 and subsequently inhibited HSC activation.

Conclusion And Implications: Physalin B exerted potent antifibrotic effects in vitro and in vivo by disrupting LAP2α/HDAC1 complexes, increasing GLI1 acetylation and inactivating GLI1. This indicates that the phytochemical physalin B may be a potential therapeutic candidate for the treatment of liver fibrosis.
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http://dx.doi.org/10.1111/bph.15490DOI Listing
September 2021

Limb expression 1-like (LIX1L) protein promotes cholestatic liver injury by regulating bile acid metabolism.

J Hepatol 2021 08 18;75(2):400-413. Epub 2021 Mar 18.

Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Background & Aims: Cholestatic liver diseases comprise a variety of disorders of bile formation and/or flow which generally result in progressive hepatobiliary injury. Regulation of bile acid (BA) synthesis and homeostasis is a promising strategy for the treatment of cholestatic liver disease. Limb expression 1-like protein (LIX1L) plays an important role in post-transcriptional gene regulation, yet its role in cholestatic liver injury remains unclear.

Methods: LIX1L expression was studied in patients with primary sclerosing cholangitis (PSC) or primary biliary cholangitis (PBC), and 3 murine models of cholestasis (bile duct ligation [BDL], Mdr2 knockout [Mdr2], and cholic acid [CA] feeding). Lix1l knockout mice were employed to investigate the function of LIX1L in cholestatic liver diseases. Chromatin immunoprecipitation assays were performed to determine whether Egr-1 bound to the Lix1l promoter. MiRNA expression profiling was analyzed by microarray. An adeno-associated virus (AAV)-mediated hepatic delivery system was used to identify the function of miR-191-3p in vivo.

Results: LIX1L expression was increased in the livers of patients with PSC and PBC, and in the 3 murine models, as well as in BA-stimulated primary mouse hepatocytes. BA-induced Lix1l upregulation was dependent on Egr-1, which served as a transcriptional activator. LIX1L deficiency attenuated cholestatic liver injury in BDL and Mdr2 mice. MiR-191-3p was the most reduced miRNA in livers of WT-BDL mice, while it was restored in Lix1l-BDL mice. MiR-191-3p targets and downregulates Lrh-1, thereby inhibiting Cyp7a1 and Cyp8b1 expression. AAV-mediated hepatic delivery of miR-191-3p significantly attenuated cholestatic liver injury in Mdr2 mice.

Conclusions: LIX1L deficiency alleviates cholestatic liver injury by inhibiting BA synthesis. LIX1L functions as a nexus linking BA/Egr-1 and miR-191-3p/LRH-1 signaling. LIX1L and miR-191-3p may be promising targets for the treatment of BA-associated hepatobiliary diseases.

Lay Summary: Bile acid homeostasis can be impaired in cholestatic liver diseases. Our study identified a novel mechanism of positive feedback regulation in cholestasis. LIX1L and miR-191-3p represent potential therapeutic targets for cholestatic liver diseases.
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http://dx.doi.org/10.1016/j.jhep.2021.02.035DOI Listing
August 2021

Tribbles homolog 2 promotes hepatic fibrosis and hepatocarcinogenesis through phosphatase 1A-Mediated stabilization of yes-associated protein.

Liver Int 2021 05 10;41(5):1131-1147. Epub 2021 Jan 10.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

Background & Aims: Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Tribbles homolog 2 (TRIB2) is an oncogene implicated in a variety of cancers, including liver cancer. However, the biological function and regulatory mechanism of TRIB2 in HSCs are poorly understood. In addition, little is known about its role in liver fibrosis progression to HCC. Here, we revealed the clinical significance of TRIB2 in liver fibrosis and HCC development.

Methods: We investigated TRIB2 promoting liver fibrosis in vitro and in vivo. In mouse model of liver fibrosis and HCC, we measured hepatic fibrosis and HCC level through knockdown TRIB2 with shRNA. In addition, we performed western blotting, real-time quantitative PCR, immunofluorescence and co-immunoprecipitation assay to study TRIB2 function in LX-2 cells.

Results: TRIB2 expression was strongly upregulated in human fibrotic liver tissues and HCC tissues. TRIB2 colocalized with α-smooth muscle actin (α-SMA) in fibrotic and HCC liver tissues. Knockdown of TRIB2 inhibited HSC activation and liver fibrosis in vitro and in vivo. TRIB2 promoted Yes-associated protein (YAP) stabilization, nuclear localization, and subsequent fibrotic gene expression independent of the MST-LATS phosphorylation cascade in HSCs. TRIB2 interacted with YAP to recruit phosphatase 1A (PP1A), promoting PP1A-mediated YAP dephosphorylation. TRIB2 knockdown potently attenuated the development of fibrosis-associated liver cancer.

Conclusions: TRIB2 is an attractive target for hepatic fibrosis and fibrosis-associated liver cancer treatment.
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http://dx.doi.org/10.1111/liv.14782DOI Listing
May 2021

Effects of Jianpi Bushen Therapy for Treatment of CKD Anemia: A Meta-Analysis of Randomized Controlled Trials.

Front Pharmacol 2020 15;11:560920. Epub 2020 Sep 15.

Department of Nephropathy, Hubei Provincial Hospital of TCM, Wuhan, China.

Objectives: To evaluate the efficacy of Traditional Chinese Medicine, specifically Jianpi Bushen (JPBS) therapy, for treatment of patients with chronic kidney disease (CKD) anemia.

Methods: Randomized controlled trials of JPBS therapy for CKD anemia were searched and selected from seven electronic databases. The Cochrane collaboration tool was used to conduct methodological quality assessment. RevMan v5.3 software was utilized to perform data analysis.

Results: In total, 12 randomized controlled trials with 799 patients met the meta-analysis criteria. The aggregated results indicated that JPBS therapy is beneficial for CKD anemia by improving the clinical efficacy rate [risk ratio (RR) = 1.23, 95% confidence interval (CI): (1.14, 1.33), < 0.00001] and hemoglobin (Hb) [weighted mean difference (WMD) = 9.55, 95% CI: (7.97, 11.14), < 0.00001], serum ferritin (SF) [WMD = 6.22, 95% CI: (2.65, 9.79), = 0.0006], red blood cell (RBC) [WMD = 0.31, 95% CI: (0.24, 0.38), < 0.00001], hematocrit (HCT) [WMD = 2.95, 95% CI: (2.36, 3.54), < 0.00001], serum creatinine (SCr) [WMD = 64.57, 95% CI: (33.51, 95.64), < 0.0001], and blood urea nitrogen (BUN) levels [WMD = 3.76, 95% CI: (2.21, 5.31), 0.00001]. Furthermore, evidence suggests that JPBS therapy is safe and does not increase adverse reactions compared with western medicine (WM) alone.

Conclusion: This study found that JPBS therapy has a positive effect on the treatment of CKD anemia. However, more well-designed, double-blind, large-scale randomized controlled trials are needed to assess the efficacy of JPBS therapy in the treatment of CKD anemic patients.
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http://dx.doi.org/10.3389/fphar.2020.560920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523512PMC
September 2020

Association of UGT1A1*6 polymorphism with irinotecan-based chemotherapy reaction in colorectal cancer patients: a systematic review and a meta-analysis.

Biosci Rep 2020 10;40(10)

Department of Gastroenterology, Gansu Provincial Hospital, Lanzhou, Gansu 730030, China.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths across the world. Irinotecan (IRI) is commonly used to treat CRC, and IRI-based chemotherapy is linked with adverse reaction and the efficacy of the treatment regimen. The gene UGT1A1 plays a central role in the IRI metabolic pathway. A polymorphism UGT1A1*6 has been widely researched which may be related to response of IRI-based chemotherapy in CRC. All relevant studies were strictly searched from PubMed, Embase, Cochrane Library and Web of Science databases to explore the associations between UGT1A1*6 and response of IRI-based chemotherapy with CRC. Nine articles comprising 1652 patients were included in the final combination. Meta-analysis showed G allele or GG had a lower risk of severe late-onset diarrhea compared with A/AA in allele model and homozygote model (G vs. A: OR = 0.53, 95% CI: 0.28-0.99, P=0.05; GG vs. AA: OR = 0.48, 95% CI: 0.23-0.99, P=0.05), no significant association was observed in other models. In addition, a significant association between UGT1A1*6 and neutropenia was observed in all models (G vs. A: OR = 0.57, 95% CI: 0.46-0.71, P=0.00; GG vs. AA: OR = 0.28, 95% CI: 0.17-0.45, P=0.01; GA vs. AA: OR = 0.42, 95% CI: 0.26-0.70, P=0.00; GG+GA vs. AA: OR = 0.32, 95% CI: 0.20-0.52, P=0.00; GG vs. AA+GA: OR = 0.40, 95% CI: 0.22-0.71, P=0.00), whereas, no relationship was found between UGT1A1*6 and clinical response among the different genotypes. UGT1A1*6 may be considered as a biomarker for IRI-based chemotherapy in CRC.
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http://dx.doi.org/10.1042/BSR20200576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578622PMC
October 2020

Physalin D attenuates hepatic stellate cell activation and liver fibrosis by blocking TGF-β/Smad and YAP signaling.

Phytomedicine 2020 Nov 28;78:153294. Epub 2020 Jul 28.

State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Bioactive Natural Product Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address:

Background: Hepatic fibrosis is considered integral to the progression of chronic liver diseases, as it leads to the development of cirrhosis and hepatocellular carcinoma. The activation of hepatic stellate cells (HSCs) is the dominant event in hepatic fibrogenesis. The transforming growth factor-β1 (TGF-β1) and Yes-associated protein (YAP) pathways play a pivotal role in HSC activation, hepatic fibrosis and cirrhosis progression. Therefore, targeting the TGF-β/Smad and YAP signaling pathways is a promising strategy for antifibrotic therapy.

Purpose: The present study investigated the protective effects of Physalin D (PD), a withanolide isolated from Physalis species (Solanaceae), against liver fibrosis and further elucidated the mechanisms involved in vitro and in vivo.

Study Design/methods: We conducted a series of experiments using carbon tetrachloride (CCl)- and bile duct ligation (BDL)-induced fibrotic mice and cultured LX-2 cells. Serum markers of liver injury, and the morphology, histology and fibrosis of liver tissue were investigated. Western blot assays and quantitative real-time PCR were used to investigate the mechanisms underlying the antifibrotic effects of PD.

Result: PD decreased TGF-β1-induced COL1A1 promoter activity. PD inhibited TGF-β1-induced expression of Collagen I and α-smooth muscle actin (α-SMA) in human hepatic stellate LX-2 cells. PD significantly ameliorated hepatic injury, including transaminase activities, histology, collagen deposition and α-SMA, in CCl- or BDL-induced mice. Moreover, PD markedly decreased the expression of phosphorylated Smad2/3 in vitro and in vivo. Furthermore, PD significantly decreased YAP protein levels, and YAP knockdown did not further enhance the effects of PD, namely α-SMA inhibition, Collagen I expression and YAP target gene expression in LX-2 cells.

Conclusion: These results clearly show that PD ameliorated experimental liver fibrosis by inhibiting the TGF-β/Smad and YAP signaling pathways, indicating that PD has the potential to effectively treat liver fibrosis.
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http://dx.doi.org/10.1016/j.phymed.2020.153294DOI Listing
November 2020

Accurate MRSA identification through dual-functional aptamer and CRISPR-Cas12a assisted rolling circle amplification.

J Microbiol Methods 2020 06 11;173:105917. Epub 2020 Apr 11.

NO. 906 Hospital of People's Liberation Army, Ningbo City, Zhejiang Province 315040, China. Electronic address:

Infectious diseases have become one of the most threatening global challenge with high morbidity and mortality, bringing great difficulties to clinical diagnosis and treatment. New strategy for high-specific and sensitive bacteria detection are urgently needed in facing the crisis of worldwide antibiotic resistance. Herein, a novel method through the integration of dual aptamer technology and CRISPR-Cas12a assisted rolling circle amplification (RCA) was present to obtain both accurate identification and high-sensitive detection of Methicillin-Resistant Staphylococcus Aureus (MRSA). The specificity inherited from the dual functionalized aptamers initiated bioconjugation to specifically recognize the protein targets on the surface of bacteria. Besides the target activity, the functionalized aptamer could also convert the protein recognition to nucleic acids signals. Through the integration of attached RCA and CRISPR-Cas12a assisted trans-cleavage, dual amplification of the nucleic acid signal was obtained. Based on this, we have extended the application of CRISPR-Cas12a from the nucleic acid detection to bacteria detection. As a result, the proposed method was demonstrated to be with significantly improved sensitivity towards MRSA detection. We believe that the novel integrated strategy would diversify the existing pool of bacterial detection and inspire the development of promising drug candidates in the future.
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http://dx.doi.org/10.1016/j.mimet.2020.105917DOI Listing
June 2020

Promoter polymorphisms in the lncRNA-MIAT gene associated with acute myocardial infarction in Chinese Han population: a case-control study.

Biosci Rep 2020 02;40(2)

The Center for Molecular Genetics of Cardiovascular Disease, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China.

Background: Coronary atherosclerotic disease (CAD) is one of the greatest causes of death and disability around the world, and has emerged as a major public health problem. Acute myocardial infarction (AMI) is the most serious type of CAD. Myocardial infarction (MI) association transcript (MIAT) has demonstrated that it plays an important role in AMI.

Purpose: To investigate the association between MIAT promoter polymorphisms and AMI in Chinese Han population.

Methods: A total of 212 AMI patients and 218 healthy controls were recruited. The long non-coding RNA (lncRNA)-MIAT promoter polymorphisms (single nucleotide polymorphisms (SNPs)) were obtained using polymerase chain reaction (PCR) and sequencing techniques. Chi-square test was used to analyze the allele and genotype frequencies of each SNP in two groups. Logistic regression analysis was used to analyze the association of each SNP with AMI. Linkage disequilibrium (LD) and haplotype analysis were performed using SHEsis software. A JASPAR database search predicts transcription factors transition of linked polymorphism in MIAT promoter.

Results: Ten SNPs were found, including rs56371714, rs55892869, rs151057042, rs2157598, rs150465374, rs5761664, rs8142890, rs5752375, rs9608515 and rs1055293700, whereas rs1055293700 was found only in the control group. Single and logistic regression analysis showed that there was a significant correlation between rs5752375 and rs9608515 polymorphisms and AMI, while other sites had no relationship with AMI. These MI association polymorphisms may change the binding sites with transcription factor.

Conclusions: The polymorphisms of lncRNA-MIAT promoter rs5752375 and rs9608515 were significantly associated with AMI in Chinese Han population. This result would be of clinical importance for the early diagnosis of AMI.
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http://dx.doi.org/10.1042/BSR20191203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7040461PMC
February 2020

Detection of colorectal adenomas with a real-time computer-aided system (ENDOANGEL): a randomised controlled study.

Lancet Gastroenterol Hepatol 2020 04 22;5(4):352-361. Epub 2020 Jan 22.

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China. Electronic address:

Background: Colonoscopy performance varies among endoscopists, impairing the discovery of colorectal cancers and precursor lesions. We aimed to construct a real-time quality improvement system (ENDOANGEL) to monitor real-time withdrawal speed and colonoscopy withdrawal time and to remind endoscopists of blind spots caused by endoscope slipping. We also aimed to evaluate the effectiveness of this system for improving adenoma yield of everyday colonoscopy.

Methods: The ENDOANGEL system was developed using deep neural networks and perceptual hash algorithms. We recruited consecutive patients aged 18-75 years from Renmin Hospital of Wuhan University in China who provided written informed consent. We randomly assigned patients (1:1) using computer-generated random numbers and block randomisation (block size of four) to either colonoscopy with the ENDOANGEL system or unassisted colonoscopy (control). Endoscopists were not masked to the random assignment but analysts and patients were unaware of random assignments. The primary endpoint was the adenoma detection rate (ADR), which is the proportion of patients having one or more adenomas detected at colonoscopy. The primary analysis was done per protocol (ie, in all patients having colonoscopy done in accordance with the assigned intervention) and by intention to treat (ie, in all randomised patients). This trial is registered with http://www.chictr.org.cn, ChiCTR1900021984.

Findings: Between June 18, 2019, and Sept 6, 2019, 704 patients were randomly allocated colonoscopy with the ENDOANGEL system (n=355) or unassisted (control) colonoscopy (n=349). In the intention-to-treat population, ADR was significantly greater in the ENDOANGEL group than in the control group, with 58 (16%) of 355 patients allocated ENDOANGEL-assisted colonoscopy having one or more adenomas detected, compared with 27 (8%) of 349 allocated control colonoscopy (odds ratio [OR] 2·30, 95% CI 1·40-3·77; p=0·0010). In the per-protocol analysis, findings were similar, with 54 (17%) of 324 patients assigned ENDOANGEL-assisted colonoscopy and 26 (8%) of 318 patients assigned control colonoscopy having one or more adenomas detected (OR 2·18, 95% CI 1·31-3·62; p=0·0026). No adverse events were reported.

Interpretation: The ENDOANGEL system significantly improved the adenoma yield during colonoscopy and seems to be effective and safe for use during routine colonoscopy.

Funding: Hubei Provincial Clinical Research Center for Digestive Disease Minimally Invasive Incision, Hubei Province Major Science and Technology Innovation Project, and the National Natural Science Foundation of China.
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http://dx.doi.org/10.1016/S2468-1253(19)30413-3DOI Listing
April 2020

An improved mouse model of Graves disease by once immunization with Ad-TSHR289.

Endocr J 2019 Sep 18;66(9):827-835. Epub 2019 Jun 18.

Department of Laboratory of Diabetes, China Academy of Chinese Medical Sciences Guang'anmen Hospital, Beijing 100053, China.

The novel Graves disease (GD) model was established in BALB/c mice with recombinant adenovirus expressing the full-length human TSHR (Ad-TSHR289) by three times immunizations for nearly three months. Reducing the frequency of immunizations may shorten the modeling time to improve the efficiency of the study. In this study, female BALB/c mice were immunized one time with an adenovirus expressing the autoantigen thyroid-stimulating hormone receptor (Ad-TSHR289). At the 3, 6, 12, 17 weeks after the immunization, mice were sacrificed. The blood was collected and thyroids were removed. T3, T4, TRAB and thyroid weight/body weight (TW/BW) were tested. Compared with the Normal control (NC) group, the incidence of hyperthyroidism at 3, 6, 12 and 17 weeks after immunization were about 66.67%, 100%, 100%, and 100%. Meanwhile, the incidences of goiter were nearly 50%, 83.33%, 100% and 100% at the same stages. Therefore, modeling rates of GD were about 50%, 83.33%, 100%, 100% at 3, 6, 12 and 17 weeks after immunization. T3 in serum continues to increase from 3 weeks to 17 weeks after immunization. Serum TRAb reached to peak at 6 weeks and remained from 12 weeks after immunization, while T4 and TW/BW had kept steady from 6 weeks. There are positive correlations between T3, T4 and TRAb, TRAb and TW/BW, as well as T3, T4 and TW/BW. GD model can be constructed by primary immunization with Ad-TSHR289, which could be detected at 3 weeks and at least until the 17 weeks after primary immunization. It would improve the efficiency of GD research.
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http://dx.doi.org/10.1507/endocrj.EJ19-0148DOI Listing
September 2019

Randomised controlled trial of WISENSE, a real-time quality improving system for monitoring blind spots during esophagogastroduodenoscopy.

Gut 2019 12 11;68(12):2161-2169. Epub 2019 Mar 11.

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China.

Objective: Esophagogastroduodenoscopy (EGD) is the pivotal procedure in the diagnosis of upper gastrointestinal lesions. However, there are significant variations in EGD performance among endoscopists, impairing the discovery rate of gastric cancers and precursor lesions. The aim of this study was to construct a real-time quality improving system, WISENSE, to monitor blind spots, time the procedure and automatically generate photodocumentation during EGD and thus raise the quality of everyday endoscopy.

Design: WISENSE system was developed using the methods of deep convolutional neural networks and deep reinforcement learning. Patients referred because of health examination, symptoms, surveillance were recruited from Renmin hospital of Wuhan University. Enrolled patients were randomly assigned to groups that underwent EGD with or without the assistance of WISENSE. The primary end point was to ascertain if there was a difference in the rate of blind spots between WISENSE-assisted group and the control group.

Results: WISENSE monitored blind spots with an accuracy of 90.40% in real EGD videos. A total of 324 patients were recruited and randomised. 153 and 150 patients were analysed in the WISENSE and control group, respectively. Blind spot rate was lower in WISENSE group compared with the control (5.86% vs 22.46%, p<0.001), and the mean difference was -15.39% (95% CI -19.23 to -11.54). There was no significant adverse event.

Conclusions: WISENSE significantly reduced blind spot rate of EGD procedure and could be used to improve the quality of everyday endoscopy.

Trial Registration Number: ChiCTR1800014809; Results.
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http://dx.doi.org/10.1136/gutjnl-2018-317366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872441PMC
December 2019

DEAD Box Protein 5 Inhibits Liver Tumorigenesis by Stimulating Autophagy via Interaction with p62/SQSTM1.

Hepatology 2019 03 8;69(3):1046-1063. Epub 2019 Feb 8.

Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.

In hepatocellular carcinoma (HCC), dysregulated expression of DDX5 (DEAD box protein 5) and impaired autophagy have been reported separately. However, the relationship between them has not been explored. Here we present evidence to show that, by interacting with autophagic receptor p62, DDX5 promotes autophagy and suppresses tumorigenesis. DDX5 inversely correlated with p62/sequestosome 1 (SQSTM1) expression in hepatitis B virus (HBV)-associated and non-HBV-associated HCCs. Patients with low DDX5 expression showed poor prognosis after tumor resection. We found that DDX5 overexpression induced, while DDX5 knockdown attenuated, autophagic flux in HepG2 and Huh7 cells. DDX5 promoted p62 degradation and markedly reduced the half-life of p62. Moreover, DDX5 overexpression dramatically reduced, while DDX5 knockdown promoted, cancer cell growth and tumorigenesis in vitro and in vivo. We found that DDX5 bound to p62 and interfered with p62/TRAF6 (tumor necrosis factor receptor-associated factor 6) interaction. Further findings revealed that the N-terminal domain of DDX5, involved in the interaction with p62, was sufficient to induce autophagy independent of its RNA binding and helicase activity. DDX5 overexpression decreased p62/TRAF6-mediated lysine 63-linked ubiquitination of mammalian target of rapamycin (mTOR) and subsequently inhibited the mTOR signaling pathway. Knockdown of TRAF6 blocked DDX5-induced autophagy. Furthermore, we showed that miR-17-5p downregulated DDX5 and impaired autophagy. Inhibition of miR-17-5p promoted autophagic flux and suppressed tumor growth in HCC xenograft models. Conclusion: Our findings define a noncanonical pathway that links miR-17-5p, DDX5, p62/TRAF6, autophagy, and HCC. These findings open an avenue for the treatment of HCC.
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http://dx.doi.org/10.1002/hep.30300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411283PMC
March 2019

A double-negative feedback loop between DEAD-box protein DDX21 and Snail regulates epithelial-mesenchymal transition and metastasis in breast cancer.

Cancer Lett 2018 11 27;437:67-78. Epub 2018 Aug 27.

Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nan Jing, 210009, China. Electronic address:

DDX21, a DEAD-box protein, implicated in fundamental aspects of RNA metabolism such as gene transcription. DDX21 expression is dysregulated in cancer, but its specific contribution to tumor invasion and metastasis remains to be determined. Here, we demonstrate DDX21 down-regulation is associated with highly metastatic and poor prognosis human breast cancers. DDX21 overexpression inhibited, while DDX21 knockdown promoted epithelial-mesenchymal transition (EMT) in vitro and in vivo. Overexpression of Snail reversed DDX21 mediated inhibition of cell invasion. On the other hand, independent of its helicase activity, DDX21 suppressed Snail transcription by recruiting SUZ12 and EZH2, two core subunits of PRC2 (polycomb-repressive complex 2), to the Snail promoter. Furthermore, down-regulation of DDX21 is mediated by miR-218-5p. Surprisingly, Snail also modulates DDX21 transcription. Snail overexpression decreased DDX21 transcription, whereas Snail knockdown increased DDX21 expression. These novel observations demonstrate firstly, the antagonism/double negative feedback loop between DDX21 and Snail transcription, and secondly, the crucial role of miR-218-5p in promoting EMT, acting by decreasing the ratio of DDX21/Snail. Our results identify DDX21 as a breast cancer metastasis suppressor; blocking miR-218-5p will stabilize DDX21 and epigenetically suppress Snail expression and EMT.
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http://dx.doi.org/10.1016/j.canlet.2018.08.021DOI Listing
November 2018

Design, synthesis, and biological evaluation of 2-(4-(methylsulfonyl)phenyl)pyridine derivatives as GPR119 agonists.

Chem Biol Drug Des 2019 01 12;93(1):67-74. Epub 2018 Sep 12.

School of Pharmaceutical Science, Jiangnan University, Wuxi, Jiangsu, China.

This study describes the design, synthesis, and biological evaluation of a series of novel small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compounds 19 and 20 were obtained with EC values of 75 and 25 nM, respectively, in vitro cAMP assays and effectively decreased blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice. Furthermore, in OGTT with type 2 diabetic mice induced by streptozotocin and high-fat diet, compound 19 also showed significant reduction in blood glucose level compared to vehicle control group, which demonstrated an attractive in vitro and in vivo profile for further development.
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http://dx.doi.org/10.1111/cbdd.13380DOI Listing
January 2019

SCARB1 rs5888 gene polymorphisms in coronary heart disease: A systematic review and a meta-analysis.

Gene 2018 Dec 10;678:280-287. Epub 2018 Aug 10.

The Center for Molecular Genetics of Cardiovascular Disease, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China; Division of Cardiology, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, Shandong 272029, China. Electronic address:

Background: Studies have suggested that high-density lipoprotein (HDL) stimulates scavenger receptor class B type 1 (SR-B1) to promote hepatic uptake of cholesterol. SR-B1 is encoded by scavenger receptor class B member 1 (SCARB1) gene in human. A rare mutation in SCARB1 gene has been associated with coronary heart disease (CHD). A polymorphism rs5888 of SCARB1 gene has been linked to CHD risk in humans.

Objectives: The objective was to investigate the relationship between the SCARB1 gene polymorphism rs5888 and risk of CHD.

Methods: We searched databases of case-control studies and cohort studies on rs5888 polymorphism of SCARB1 gene and risk of CHD. Two reviewers independently screened literature, extracted data, and estimated potential bias of included studies. The quality of the studies was evaluated by recommendation of Newcastle-Ottawa Scale (NOS). Meta-analysis was performed with Stata 12.0 software.

Results: Seven studies including 6360 subjects (cases: 2456, controls: 3904) were included in the final data combination. Meta-analysis showed T allele had a lower risk of CHD as compared to C allele in allele model (T vs. C: OR = 0.87, 95% CI: 0.70 to 1.09, P = 0.229). Moreover, we found that T allele or TT/TC had a lower risk of CHD as compared to C/CC in male in allele model (T vs. C: OR = 0.79, 95% CI: 0.61 to 1.01). However, no significant association was observed in women in all allele models.

Conclusions: Our findings suggested that polymorphism rs5888 had negative association with CHD, especially in male. However, the conclusion needs further verification with high quality studies with larger sample size and rigorous designs.
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http://dx.doi.org/10.1016/j.gene.2018.08.024DOI Listing
December 2018

Dai-Zong-Fang, A Traditional Chinese Herbal Formula, Ameliorates Insulin Resistance in Mice.

Front Physiol 2018 14;9:224. Epub 2018 Mar 14.

Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China.

Intricate health problems, such as insulin resistance (IR) and its associated diseases, call for multi-targeted therapies with few side effects. Based on traditional Chinese medicine (TCM), Dai-Zong-Fang (DZF) is an herbal formula mainly composed of Rhizoma Coptidis (Huanglian) and Fructus Aurantii Immaturus (Zhishi), of which berberine and naringin are the main constituents. Though DZF has been clinically used for treatment of IR and metabolic syndrome for decades, its mechanism remains unknown. In the present study, we observed that both DZF and metformin, the first-line drug for type 2 diabetes, ameliorated insulin resistance with significant improvement of oral glucose tolerance test (OGTT) and homeostasis model assessment of IR (HOMA-IR) level in diabetic C57BL/Ksj-Lepr () mice. Low-density lipoprotein cholesterol (LDL-C) and fatty acids (FAs) also decreased in the blood. Higher dose of DZF (1 g·kg), but not metformin (0.25 g·kg), alleviated hepatic steatosis with reduced liver weight and hepatic lipid accumulation and provided protection from hepatic injury with lower alanine aminotransferase and aspartate aminotransferase and increased hepatic superoxide dismutase activity in mice. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) showed a decrease in FA synthase gene () and an increase in FA oxidation gene expression. Western blot demonstrated that both DZF and metformin activated 5' AMP-activated protein kinase (AMPK) but inhibited Notch intracellular domain (NICD) and Hairy/enhancer-of-split 1 (Hes1) of Notch signaling pathway in the liver. DZF also dramatically improved the ultrastructure of skeletal muscles, AMPK phosphorylation, and GLUT4 translocation. DZF also promoted FA transport and oxidation with and up-regulation in the skeletal muscle. In conclusion, DZF improves insulin sensitivity by reducing hepatic lipids through AMPK activation and Notch signal pathway inhibition and enhancing energy metabolism in the skeletal muscle via AMPK. This study provides insights into the treatment of complex conditions, such as IR, where TCM herbal formulas exert multipronged effects through correlating pathways.
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http://dx.doi.org/10.3389/fphys.2018.00224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5861217PMC
March 2018

Neuroprotective Effect of Chitosan Oligosaccharide on Hypoxic-Ischemic Brain Damage in Neonatal Rats.

Neurochem Res 2017 Nov 28;42(11):3186-3198. Epub 2017 Jul 28.

Department of Pharmacology, Ningxia Medical University, 1160 Shengli Street, Yinchuan, Ningxia Hui Autonomous Region, 750004, People's Republic of China.

Neonatal hypoxic-ischemic brain damage (HIBD) is one of the leading causes of neonatal mortality and permanent neurological disability worldwide and the effective treatment strategies are not yet available. It has been demonstrated that Chitosan oligosaccharide (COS) exerts protective effect in vitro ischemic brain injury. However, no information is available on possible effects of COS on neonatal HIBD. To investigate the hypothesis of the potential neuroprotective effect of COS on the brain injury due to HIBD, 7-day-old Sprague-Dawley rats were treated with left carotid artery ligation followed by exposure to 8% oxygen (balanced with nitrogen) for 2.5 h at 37 °C. After COS treatment, the cerebral damage was measured by behavior tasks, 2,3,5-triphenyltetrazolium chloride(TTC), Hematoxyline-Eosin(HE), Nissl and Fluoro-Jade B(FJB)staining. In addition, the oxidative stress were assayed with ipsilateral hemisphere homogenates. Immunofluorescence staining were used to examine the activation of the astrocyte and microglia. Expression of inflammatory-related proteins were analyzed by western-blot analysis. In this study we found that administration of COS ameliorated early neurological reflex behavior, significantly reduce brain infarct volume and attenuated neuronal cell injury and degeneration. Furthermore, COS markedly decreased the level of MDA, lactic acid and increased SOD, GSH-Px and T-AOC. COS attenuated hypoxic-ischemic induced up-regulation of expressions of interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), meanwhile it dramatically increased the interleukin-10 (IL-10). These results suggest that COS exerts neuroprotection on hypoxic-ischemic brain damage in neonatal rats, it implies COS might be a potential therapeutic for the treatment of HIBD.
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http://dx.doi.org/10.1007/s11064-017-2356-zDOI Listing
November 2017

Coverage and factors associated with influenza vaccination among kindergarten children 2-7 years old in a low-income city of north-western China (2014-2016).

PLoS One 2017 27;12(7):e0181539. Epub 2017 Jul 27.

Institute for Infectious Disease Control and Prevention, Qinghai provincial Center for Disease Control and Prevention, Qinghai, China.

Influenza vaccination has been shown to be the most effective preventive measure to reduce influenza virus infection and its related morbidity and mortality. Young children aged 6-59 months are recommended as one of the priority groups for seasonal influenza vaccination in China. Our study was conducted to evaluate the level of influenza vaccination coverage during 2014-15 and 2015-16 influenza seasons among kindergarten children aged 2-7 years in Xining, a low-income city of north-western China, and to explore potential factors for noncompliance associated with influenza vaccination. The coverage rate of influenza vaccination was 12.2% (95 CI: 10.6-14.2%) in 2014-15 and 12.8% (95 CI: 11.1-14.7%) in 2015-16. The low coverage rate was found to be primarily associated with the lack of knowledge about influenza vaccine in children's parents. The most common reason for vaccine declination was the concern about adverse reactions of vaccine. Therefore tailored information should be provided by clinician and public health doctors for targeted groups through effective methods to improve public understanding of vaccination.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181539PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531459PMC
September 2017

Traditional Chinese medicine Jianpi Bushen therapy suppresses the onset of pre-metastatic niche in a murine model of spontaneous lung metastasis.

Biomed Pharmacother 2017 Feb 22;86:434-440. Epub 2016 Dec 22.

Department of Hematology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China. Electronic address:

Background & Aim: Distinct metastasis accounts for the leading cause of mortality among patients with gastric cancer. The formation of pre-metastatic niche in the target organs provides permissive environments for the adhesion and subsequent growth of metastasized cancer cells. Targeting the pre-metastatic niche is a potential approach to prevent metastasis. Traditional Chinese medicine regimen called Jianpi Bushen therapy (JPBS) has been widely used in clinics to strengthen patients' abilities to fight cancer. The present work is aimed to study the modulating effect of JPBS on the lungs expressions of Rac1, Cdc42, SDF-1, and FN in a murine gastric cancer model showing spontaneous lung metastasis.

Methods: Mice of strain 615 were inoculated with tumor cells derived from mouse forestomach carcinoma (MFC) to induce spontaneous lung metastasis, and were then treated with JPBS, JPBS combined with fluorouracil (5-FU), or 5-FU. Gene and protein expressions of Rac1, Cdc42, SDF-1, and FN in lungs were determined using real-time PCR and immunohistochemistry, respectively. Serum levels of SDF-1 and FN were also measured using ELISA.

Results: Gene and protein expressions of Rac1, Cdc42, SDF-1, and FN were significantly elevated in the lungs of model mice comparing to the counterpart mice received no tumor cell inoculation. JPBS treatment reduced protein expressions of Rac1, Cdc42, SDF-1 and FN in the lungs of model mice. The treatment could also suppress SDF-1 and FN in blood. For serum SDF-1 the level was further lower in model mice treated with combination therapy of JPBS and 5-FU.

Conclusion: The present work identified the potential roles of Rac1, Cdc42, SDF-1 and FN in the early onset of pre-metastatic niche of gastric cancer, and provided insights into the molecular mechanism by which Jianpi Bushen therapy prevent and suppress cancer metastasis.
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http://dx.doi.org/10.1016/j.biopha.2016.12.013DOI Listing
February 2017

A Novel Fusion of ALT-803 (Interleukin (IL)-15 Superagonist) with an Antibody Demonstrates Antigen-specific Antitumor Responses.

J Biol Chem 2016 Nov 20;291(46):23869-23881. Epub 2016 Sep 20.

From the Altor BioScience Corp., Miramar, Florida 33025,

IL-15 and its receptor α (IL-15Rα) are co-expressed on antigen-presenting cells, allowing transpresentation of IL-15 to immune cells bearing IL-2Rβγ and stimulation of effector immune responses. We reported previously that the high-affinity interactions between an IL-15 superagonist (IL-15N72D) and the extracellular IL-15Rα sushi domain (IL-15RαSu) could be exploited to create a functional scaffold for the design of multivalent disease-targeted complexes. The IL-15N72D·IL-15RαSuFc complex, also known as ALT-803, is a multimeric complex constructed by fusing IL-15N72D·IL-15RαSu to the Fc domain of IgG1. ALT-803 is an IL-15 superagonist complex that has been developed as a potent antitumor immunotherapeutic agent and is in clinical trials. Here we describe the creation of a novel fusion molecule, 2B8T2M, using the ALT-803 scaffold fused to four single chains of the tumor-targeting monoclonal antibody rituximab. This molecule displays trispecific binding activity through its recognition of the CD20 molecule on tumor cells, stimulation via IL-2Rβγ displayed on immune effector cells, and binding to Fcγ receptors on natural killer cells and macrophages. 2B8T2M activates natural killer cells to enhance antibody-dependent cellular cytotoxicity, mediates complement-dependent cytotoxicity, and induces apoptosis of B-lymphoma cells. Compared with rituximab, 2B8T2M exhibits significantly stronger antitumor activity in a xenograft SCID mouse model and depletes B cells in cynomolgus monkeys more efficiently. Thus, ALT-803 can be modified as a functional scaffold for creating multispecific, targeted IL-15-based immunotherapeutic agents and may serve as a novel platform to improve the antitumor activity and clinical efficacy of therapeutic antibodies.
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http://dx.doi.org/10.1074/jbc.M116.733600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5104912PMC
November 2016

Tetrahydropalmatine attenuates irradiation induced lung injuries in rats.

Life Sci 2016 May 7;153:74-81. Epub 2016 Apr 7.

Department of Oncology, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong An Road, Xicheng District, Beijing, 100050, China. Electronic address:

Aims: The lung is a major organ targeted by irradiation (R) in cancer radiotherapy of the thoracic region. Irradiation induced lung injury (RILI) is a common major obstacle in thoracic cancer radiotherapy. Tetrahydropalmatine (THP) has been shown to have a protective effect against oxidative stress. This study was designed to investigate the potential radioprotective effect of THP against RILI and to elucidate the underlying mechanisms.

Materials And Methods: Sprague-Dawley rats were treated with THP and R. THP was delivered 1h before R. Using TUNEL staining to explore the effectiveness of THP displayed on R induced pulmonary cells apoptosis. Lung histopathologic findings, bronchoalveolar lavage fluid (BALF) levels of total cell counts, protein and inflammatory cytokines, fibrotic factors (hydroxyproline content), apoptotic mediators (caspase-3 and cytochrome c) and malondialdehyde (MDA) were also evaluated after R.

Key Findings: THP significantly ameliorates the deleterious effects of R. Further studies showed that THP decreased lung injury by inhibiting the pulmonary cells apoptosis; reduced lung inflammation by decreasing BALF cells recruitment and lowering BALF protein levels; reduced pulmonary fibrosis by decreasing collagen content of lung tissues. THP also ameliorated oxidative modification of rat lungs as evidenced by levels of lipid peroxidation. BALF cytokine analysis, moreover, pointed to a mitigation of the chronic inflammatory profile of irradiated lungs as a result of the protective effect of THP treatment.

Significance: THP can effectively attenuate RILI through anti-apoptosis, anti-fibrosis and anti-inflammation mechanisms.
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http://dx.doi.org/10.1016/j.lfs.2016.03.056DOI Listing
May 2016

Phenylbutazone, a New Long-Acting Agent that can Improve the Peptide Pharmacokinetic Based on Serum Albumin as a Drug Carrier.

Chem Biol Drug Des 2016 06 20;87(6):936-45. Epub 2016 Feb 20.

Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China.

As a NPY-2 receptor agonist, PYY24-36- Leu31 is reported to suppress appetite and has a potential in obesity treatment, but its short half-life limits the clinical application. The use of chemical modification to improve interactions with human serum albumin (HSA) is an effective strategy for prolonging the half-lives of peptide analogues. So based on the characteristics that phenylbutazone has a good combination with HSA, we selected a proper linker to link with PYY24-36 -Leu31 to create long-acting and highly biologically active PYY24-36 -Leu31 conjugates, and successfully find a novel, long-acting PYY24-36 -Leu31 conjugate 8 that, when dosed every other day in diet induce obese (DIO) mice for 2 weeks, results in a significant reduction in food intake and body weight and improvement in blood parameter and hepatic steatosis.
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http://dx.doi.org/10.1111/cbdd.12726DOI Listing
June 2016

Comparison of the Superagonist Complex, ALT-803, to IL15 as Cancer Immunotherapeutics in Animal Models.

Cancer Immunol Res 2016 Jan 28;4(1):49-60. Epub 2015 Oct 28.

Altor BioScience Corporation, Miramar, Florida.

IL15, a potent stimulant of CD8(+) T cells and natural killer (NK) cells, is a promising cancer immunotherapeutic. ALT-803 is a complex of an IL15 superagonist mutant and a dimeric IL15 receptor αSu/Fc fusion protein that was found to exhibit enhanced biologic activity in vivo, with a substantially longer serum half-life than recombinant IL15. A single intravenous dose of ALT-803, but not IL15, eliminated well-established tumors and prolonged survival of mice bearing multiple myeloma. In this study, we extended these findings to demonstrate the superior antitumor activity of ALT-803 over IL15 in mice bearing subcutaneous B16F10 melanoma tumors and CT26 colon carcinoma metastases. Tissue biodistribution studies in mice also showed much greater retention of ALT-803 in the lymphoid organs compared with IL15, consistent with its highly potent immunostimulatory and antitumor activities in vivo. Weekly dosing with 1 mg/kg ALT-803 in C57BL/6 mice was well tolerated, yet capable of increasing peripheral blood lymphocyte, neutrophil, and monocyte counts by >8-fold. ALT-803 dose-dependent stimulation of immune cell infiltration into the lymphoid organs was also observed. Similarly, cynomolgus monkeys treated weekly with ALT-803 showed dose-dependent increases of peripheral blood lymphocyte counts, including NK, CD4(+), and CD8(+) memory T-cell subsets. In vitro studies demonstrated ALT-803-mediated stimulation of mouse and human immune cell proliferation and IFNγ production without inducing a broad-based release of other proinflammatory cytokines (i.e., cytokine storm). Based on these results, a weekly dosing regimen of ALT-803 has been implemented in multiple clinical studies to evaluate the dose required for effective immune cell stimulation in humans.
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http://dx.doi.org/10.1158/2326-6066.CIR-15-0093-TDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703482PMC
January 2016
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