Publications by authors named "Wen Jie Zheng"

102 Publications

Risk of Autoimmune Diseases Following Optic Neuritis: A Nationwide Population-Based Cohort Study.

Front Med (Lausanne) 2022 13;9:903608. Epub 2022 Jun 13.

Department of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.

Objectives: Optic neuritis is (ON) is believed to be an immune-mediated disease; however, the association between optic neuritis and autoimmune diseases remains unclear. This study aimed to identify the incidence rate and adjusted hazard ratio (aHR) of autoimmune diseases in patients with optic neuritis.

Methods: This nationwide, population-based, retrospective cohort study collected patients' data between 1999 and 2013 from the National Health Insurance Research Database in Taiwan. A total of 9,235 patients were included. Using 1:4 propensity scoring, 1,847 patients were enrolled in the optic neuritis group and 7,388 in the non-optic neuritis group according to age, sex, comorbidities, and corticosteroid use. Follow-up was started from the index date and the endpoint was a diagnosis of new-onset autoimmune diseases including, myasthenia gravis (MG), psoriatic arthritis (PsA), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and ankylosing spondylitis (AS).

Results: The Kaplan-Meier curves depicted that patients with optic neuritis had a higher cumulative incidence of autoimmune diseases than patients without optic neuritis. Cox proportional hazard regression showed that patients with optic neuritis were at a high risk of autoimmune diseases (aHR: 1.40; 95% C.I., 1.05-1.87), including MG (aHR: 4.16, 95% C.I.: 1.33-12.94), SLE (aHR: 3.33, 95% C.I.: 1.24-8.97), and AS (aHR: 2.86, 95% C.I.: 1.54-5.31). Subgroup analysis provided that patients with optic neuritis aged below 65 years (aHR: 1.42, 95% C.I.: 1.03-1.96) or who were females (aHR: 1.59, 95% C.I.: 1.11-2.27) had a significantly increased risk of autoimmune diseases compared to respective controls. The use of corticosteroids reduced the risk of autoimmune diseases in patients with optic neuritis (aHR for corticosteroids non-users: 1.46, 95% C.I.: 1.03-2.07).

Conclusion: Patients with optic neuritis presented with a high risk of autoimmune diseases such as MG, SLE, and AS, especially patients with optic neuritis who were young or females. Corticosteroids attenuated the link between optic neuritis and subsequent autoimmune diseases.
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http://dx.doi.org/10.3389/fmed.2022.903608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9234206PMC
June 2022

Clinical characteristics of multicentric reticulohistiocytosis and distinguished features from rheumatoid arthritis: a single-center experience in China.

Orphanet J Rare Dis 2022 04 12;17(1):164. Epub 2022 Apr 12.

Department of Rheumatology and Clinical Immunology, Peking Union Medical College, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, National Clinical Research Center for Dermatologic and Immunologic Diseases, Ministry of Science& Technology, State Key Laboratory of Complex Severe and Rare Diseases, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100730, China.

Objective: To investigate the clinical features of multicentric reticulohistiocytosis (MRH).

Methods: The clinical manifestations, laboratory examination results and histologic characteristics of eleven patients with MRH were collected and compared with those of 33 patients with rheumatoid arthritis.

Results: In total, 72.7% of the MRH patients were women. The median age was 46 years (range 33-84 years). Diagnosed by specific pathologic features, all MRH patients exhibited cutaneous involvement. The dorsa of the hands, arms, face and auricle were the most commonly affected areas. Nodules were also located on the legs, scalp, trunk, neck, and even the hypoglossis and buccal mucosa. Ten MRH patients (90.9%) had symmetric polyarthritis. Compared with rheumatoid arthritis (RA) patients, MRH patients were more likely to have distal interphalangeal joint (DIP) involvement (63.6% vs 24.2%, P = 0.017) and less likely to have elbow (36.4% vs 72.7%, P = 0.003), ankle (45.5% vs 93.9%, P < 0.001) and metacarpophalangeal joint (MCP) (36.4% vs 78.8%, P = 0.009) involvement. Positivity for rheumatoid factor (RF) (36.4% vs 84.6%, P = 0.001) and anti-CCP antibody (9.1% vs 81.8%, P = 0.000), as well as the median RF titer [43.8 (31.7-61.0) vs 175.4 (21.3-940.3), P = 0.021], in MRH patients was lower than in RA patients. Elevation of the erythrocyte sedimentation rate (ESR) was also less common in MRH patients than in RA patients (36.4% vs 72.7%, P = 0.030). After treatment with median- to large-dose corticosteroids and disease-modifying antirheumatic drugs, 8 patients achieved complete remission and 2 patients partial remission (skin lesions ameliorated, joint lesions not ameliorated).

Conclusion: Always pathologically diagnosed, MRH is a systemic disease involving RA-like erosive polyarthritis and a specific distribution of skin nodules characterized by "coral beads". More DIP involvement and less elbow, ankle and MCP involvement are seen in MRH than in RA. In addition, less positivity and lower-titer RF, uncommon presence of anti-CCP antibodies and ESR elevation may be helpful to distinguish MRH from RA.
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http://dx.doi.org/10.1186/s13023-022-02311-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9004099PMC
April 2022

The accuracy and effectiveness of automatic pedicle screw trajectory planning based on computer tomography values: an in vitro osteoporosis model study.

BMC Musculoskelet Disord 2022 Feb 21;23(1):165. Epub 2022 Feb 21.

Department of Orthopaedics, Xinqiao Hospital, Amy Medical University (Third Military Medical University), Chongqing, 400037, People's Republic of China.

Background: Pedicle screw placement in patients with osteoporosis is a serious clinical challenge. The bone mineral density (BMD) of the screw trajectory has been positively correlated with the screw pull-out force, while the computer tomography (CT) value has been linearly correlated with the BMD. The purpose of this study was to establish an in vitro osteoporosis model and verify the accuracy and effectiveness of automated pedicle screw planning software based on CT values in this model.

Methods: Ten vertebrae (L1-L5) of normal adult pigs were randomly divided into decalcification and control groups. In the decalcification group, the vertebral bodies were decalcified with Ethylenediaminetetraacetic acid (EDTA) to construct an in vitro osteoporosis model. In the decalcification group, automatic planning (AP) and conventional manual planning (MP) were used to plan the pedicle screw trajectory on the left and right sides of the pedicle, respectively, and MP was used on both sides of the control group. CT values of trajectories obtained by the two methods were measured and compared. Then, 3D-printed guide plates were designed to assist pedicle screw placement. Finally, the pull-out force of the trajectory obtained by the two methods was measured.

Results: After decalcification, the BMD of the vertebra decreased from - 0.03 ± 1.03 to - 3.03 ± 0.29 (P < 0.05). In the decalcification group, the MP trajectory CT value was 2167.28 ± 65.62 Hu, the AP trajectory CT value was 2723.96 ± 165.83 Hu, and the MP trajectory CT value in the control group was 2242.94 ± 25.80 Hu (P < 0.05). In the decalcified vertebrae, the screw pull-out force of the MP group was 48.6% lower than that of the control group (P < 0.05). The pull-out force of the AP trajectory was 44.7% higher than that of the MP trajectory (P < 0.05) and reached 97.4% of the MP trajectory in the control group (P > 0.05).

Conclusion: Automatic planning of the pedicle screw trajectory based on the CT value can obtain a higher screw pull-out force, which is a valuable new method of pedicle screw placement in osteoporotic vertebre.
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http://dx.doi.org/10.1186/s12891-022-05101-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8862578PMC
February 2022

Oncogenic tuftelin 1 as a potential molecular-targeted for inhibiting hepatocellular carcinoma growth.

World J Gastroenterol 2021 Jun;27(23):3327-3341

Department of Medical Immunology, Medical School of Nantong University, Nantong 226001, Jiangsu Province, China.

Background: Abnormal tuftelin 1 (TUFT1) has been reported in multiple cancers and exhibits oncogenic roles in tumor progression. However, limited data are available on the relationship between TUFT1 and hepatocellular carcinoma (HCC), and the exact biological mechanism of TUFT1 is still poorly understood in HCC.

Aim: To investigate TUFT1 expression in HCC and how interfering transcription affects HCC growth.

Methods: TUFT1 in HCC and non-HCC tissues based on databases of the Cancer Genome Atlas and Oncomine were analyzed, and TUFT1 in human HCC tissues on microarray were detected by immunohistochemistry for clinicopathological features, overall survival, and disease-free survival. HCC cells were transfected with constructed vectors of that interfere or over-express TUFT1 for analyzing the biological behaviors of HCC cells. Proliferation, invasion, migration, and apoptosis of cells were detected by cell counting kit-8, scratch assay, transwell tests, and flow cytometry and confirmed by Western blotting, respectively.

Results: Abnormal TUFT1 levels in databases expressed in HCC at messenger RNA (mRNA) level and HCC tissues were mainly located in cytoplasm and membrane. The level of TUFT1 expression in the HCC group was significantly higher ( = 18.563, < 0.001) than that in the non-cancerous group, closely related to clinical staging, size, vascular invasion of tumor, hepatitis B e-antigen positive, and ascites ( < 0.01) of HCC patients, and negatively to HCC patients' overall survival and disease-free survival ( < 0.001). After interfering with transcription at mRNA level in the MHCC-97H cells by the specific TUFT1-short hairpin RNA, cell proliferation, invasion, and metastasis were significantly inhibited with increasing apoptosis rate. In contrast, proliferation, invasion, and migration were significantly enhanced after over-expression of TUFT1 mRNA in Hep3B cells .

Conclusion: Oncogenic TUFT1 was associated with the progression of HCC and could be a potential molecular-target for inhibiting HCC growth.
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http://dx.doi.org/10.3748/wjg.v27.i23.3327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8218352PMC
June 2021

New strategy of color and power doppler sonography combined with DMSA in the assessment of acute pyelonephritis in infants.

BMC Nephrol 2021 05 17;22(1):181. Epub 2021 May 17.

Department of Rheumatology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang Province, China.

Background: The purpose of this study was to evaluate the clinical value of color and power doppler sonography (CPDS) when combined it with 99mTc-dimercaptosuccinic acid scintigraphy (DMSA) in assessment of acute pyelonephritis (APN) in infants.

Methods: A total of 79 children with APN admitted to our hospital from June 2016 to Jan 2019 were enrolled, including 52 boys and 27 girls, age range 1 month to 3 years old. All cases followed the diagnostic criteria for acute pyelonephritis and excluded anatomical abnormalities of urinary system. All 79 patients were examined by urinary ultrasonography (US), CPDS, and DMSA within 48 h of fever and analyzed the clinical value of combining the two methods in the assessment of APN in infants.

Results: Among 79 children, urinary ultrasonography revealed 2 cases of renal cortical echo changes, both located in the upper pole of the kidney, 24 cases of kidney enlargement, and 1 case of left kidney shrinkage. Ninety-five kidneys were shown to be diseased with DMSA, while 105 kidneys abnormal by CPDS. The sensitivity of CPDS was 69.4%, and the specificity was 38.1%. In children younger than 6 months, the sensitivity of CPDS was 56.9%, which was 84.2% in childeren between 6 months to 1 year, and 94.4% from 1 to 3 years old, respectively. The corresponding specificity of CPDS was 44.1, 26.7, and 35.7%. There was no significant correlation between CPDS levels and DMSA positive results. The abnormal rate of intermediate part in the kidneys was significantly lower than that in the upper and lower poles. Children with abnormal CPDS have a greater risk of renal scarring(p < 0.05).

Conclusion: Abnormalities detected by CPDS in a cohort of infants with APN poorly correlated with DMSA findings. But the sensitivity of CPDS is highly age-related, it can be used as a non-invasive helpful tool for early diagnosis of acute pyelonephritis in infants older than 6 months old.
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http://dx.doi.org/10.1186/s12882-021-02390-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130442PMC
May 2021

Application of DNA barcoding and metabarcoding for species identification in salmon products.

Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2021 May 30;38(5):754-768. Epub 2021 Mar 30.

Agro-product Safety Research Center, Chinese Academy of Inspection and Quarantine, Beijing, China.

Mislabelling is a significant manifestation of food fraud. Traditional Sanger sequencing technology is the gold standard for seafood species identification. However, this method is not suitable for analysing processed samples that may contain more than one species. This study tested the feasibility of next-generation sequencing in identifying mixed salmon products. Salmon samples containing up to eight species were amplified using mini-barcode primers, and sequenced on an Illumina HiSeq2500 platform. All species were accurately identified, and mixtures as low as 1% (w/w) could be detected. Furthermore, this study conducted a market survey of 32 products labelled as salmon. For pure and mixed fish products, Sanger and next-generation sequencing techniques were respectively used for species identification, and for NGS results, we also used real-time PCR method to cross-validate the mixed products to further verify the accuracy of the DNA metabarcoding technology established in this study. DNA barcoding and metabarcoding of commercial salmon food products revealed the presence of mislabelling in 16 of 32 (50%) samples. The developed DNA barcoding and metabarcoding methods are useful for the identification of salmon species in food and can be used for quality control of various types of salmon products.
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http://dx.doi.org/10.1080/19440049.2020.1869324DOI Listing
May 2021

[Clinical features of children with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: an analysis of 13 cases].

Zhongguo Dang Dai Er Ke Za Zhi 2021 Feb;23(2):143-147

Department of Pediatric Rheumatology, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, China.

Objective: To study the clinical features of children with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, a polygenic and multifactorial autoinflammatory disease with unknown pathogenesis.

Methods: A retrospective analysis was performed on the medical data of 13 children with PFAPA syndrome.

Results: All 13 children had disease onset within the age of 3 years, with a mean age of onset of (14±10) months. They all had periodic fever, with 8-18 attacks each year. The mean interictal period of fever was (30±5) days. Pharyngitis, cervical adenitis, and aphthous stomatitis were the three cardinal symptoms, with incidence rates of 100% (13/13), 85% (11/13), and 38% (5/13) respectively. There were increases in white blood cells, C-reactive protein, and erythrocyte sedimentation rate during fever. Of all the 13 children, 6 underwent whole exome sequencing and 7 underwent panel gene detection for autoinflammatory disease, and the results showed single heterozygous mutations in the gene in 6 children (46%). Recurrent fever in all children gradually returned to normal without antibiotics. Ten children were treated with a single dose of glucocorticoids, and fever was relieved after treatment. Of all the children, 4 were treated with cimetidine, among whom 2 had response; 4 children were treated with colchicine, among whom 2 had response and 2 were withdrawn from the drug due to adverse reactions. Tonsillectomy was performed for 2 children, among whom 1 was followed up for 3 years without recurrence and 1 still had recurrence.

Conclusions: For children with unexplained periodic fever with early onset accompanied by pharyngitis, cervical adenitis, aphthous stomatitis, elevated inflammatory indices, and good response to glucocorticoids, PFAPA syndrome should be considered. This disorder has good prognosis, and early diagnosis can avoid the long-term repeated use of antibiotics.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921540PMC
February 2021

mir-22-3p/KLF6/MMP14 axis in fibro-adipogenic progenitors regulates fatty infiltration in muscle degeneration.

FASEB J 2020 09 27;34(9):12691-12701. Epub 2020 Jul 27.

Department of Orthopaedics, the Second Affiliated Xinqiao Hospital of Army Medical University, Chongqing, China.

Fibro/adipogenic progenitors (FAPs) are the main cellular source of fatty degeneration in muscle injury; however, the underlying mechanism of FAP adipogenesis in muscle degeneration needs to be further examined. Matrix metalloproteinase 14 (MMP-14) has been reported to induce the adipogenesis of 3T3-L1 preadipocytes, but whether MMP-14 also regulates the differentiation of FAPs remains unclear. To investigate whether and how MMP-14 regulates FAP adipogenesis and fatty infiltration in muscle degeneration, we examined MMP-14 expression in degenerative muscles and tested the effect of MMP-14 on FAP adipogenesis in vitro and in vivo. As expected, MMP-14 enhanced FAP adipogenesis and fatty infiltration in degenerative muscles; moreover, blocking endogenous MMP-14 in injured muscles facilitated muscle repair. Further investigations revealed that Kruppel-like factor 6 (KLF6) was a transcription factor associated with MMP-14 and acted as an "on-off" switch in the differentiation of FAPs into adipocytes or myofibroblasts. Moreover, KLF6 was the target gene of miR-22-3p, which was downregulated during FAP adipogenesis both in vitro and in vivo, and overexpression of miR-22-3p markedly prevented FAP adipogenesis and attenuated fatty degeneration in muscles. Our study revealed that miR-22-3p/KLF6/MMP-14 is a novel pathway in FAP adipogenesis and that inhibiting KLF6 is a potential strategy for the treatment of muscular degenerative diseases.
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http://dx.doi.org/10.1096/fj.202000506RDOI Listing
September 2020

Combined Use of Recombinant Human BMP-7 and Osteogenic Media May Have No Ideal Synergistic Effect on Leporine Bone Regeneration of Human Umbilical Cord Mesenchymal Stem Cells Seeded on Nanohydroxyapatite/Collagen/Poly (l-Lactide).

Stem Cells Dev 2020 09 13;29(18):1215-1228. Epub 2020 Aug 13.

Department of Chemistry, Jinan University, Guangzhou, China.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) are a promising alternative source of mesenchymal stem cells (MSCs) that are enormously attractive for clinical use. This study was designed to investigate the effect of recombinant human bone morphogenetic protein-7 (rhBMP-7) and/or osteogenic media (OMD) on bone regeneration of hUC-MSCs seeded on nanohydroxyapatite/collagen/poly(l-lactide) (nHAC/PLA) in a rabbit model. The characteristics of stem cells were analyzed by plastic adherence, cell phenotype, and multilineage differentiation potential. Cell proliferation was examined using cell counting kit-8 assay. Osteogenic differentiation was evaluated by quantitative Ca concentration, PO concentration, alkaline phosphatase (ALP) activity, osteocalcin (OCN) secretion, and mineralized matrix formation. Bone regeneration was investigated in jaw bone defect repair in rabbit by microcomputed tomography, fluorescent labeling, and hematoxylin and eosin staining. Except for initial stress response, OMD and OMD + rhBMP-7 inhibited the proliferation of hUC-MSCs seeded on nHAC/PLA; rhBMP-7 inhibited cell proliferation in the nonlogarithmic phase and attenuated the inhibitory effect of OMD on cell proliferation. The inhibitory effects of OMD, rhBMP-7, and OMD + rhBMP-7 on cell proliferation were ranked as OMD > OMD + rhBMP-7 > rhBMP-7. OMD, rhBMP-7, and OMD + rhBMP-7 promoted Ca concentration, PO concentration, ALP activity, OCN secretion, and mineralized matrix formation of hUC-MSCs seeded on nHAC/PLA. The promoting effects of OMD, rhBMP-7, and OMD+rhBMP-7 on Ca concentration, PO concentration, ALP activity, OCN secretion, and mineralized matrix formation were ranked as rhBMP-7 > OMD > OMD + rhBMP-7, OMD > OMD + rhBMP-7 > rhBMP-7, OMD > rhBMP-7 > OMD + rhBMP-7, rhBMP-7 > OMD + rhBMP-7 > OMD, and OMD > rhBMP-7 > OMD + rhBMP-7, respectively. In rabbit jaw bone defect repair, OMD, rhBMP-7, and OMD + rhBMP-7 enhanced bone regeneration of hUC-MSCs seeded on nHAC/PLA, but the largest bone mineral apposition rate and bone formation were presented in cultures with rhBMP-7. These findings suggested that the combined use of rhBMP-7 and OMD may have no ideal synergistic effect on bone regeneration of hUC-MSCs seeded on nHAC/PLA in rabbit jaw bone defect.
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http://dx.doi.org/10.1089/scd.2020.0066DOI Listing
September 2020

Dynamic expression of hepatic GP73 mRNA and protein and circulating GP73 during hepatocytes malignant transformation.

Hepatobiliary Pancreat Dis Int 2020 Oct 29;19(5):449-454. Epub 2020 Feb 29.

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China. Electronic address:

Background: Hepatic Golgi protein-73 (GP73) expression is related to hepatocellular carcinoma (HCC) progression. The aim of this study was to investigate the dynamic expression of GP73 mRNA and protein during hepatocytes malignant transformation.

Methods: Human GP73 expressions in 88 HCC tissues and their self-control surrounding tissues were examined by immunohistochemistry, and survival time of HCC patients was evaluated by the Kaplan-Meier method. HCC model of Sprague-Dawley rats was made by diet containing 2-fluorenylacetamide. The rats were divided into the control, hepatocyte degeneration, precanceration, and HCC groups to observe GP73 protein and mRNA alterations during hepatocytes malignant transformation.

Results: The GP73 expression was significantly higher in the cancerous tissues than that in the surrounding tissues, with shorter survival time, and the positive rates of GP73 protein in human HCC tissues were 53.3% at stage I, 84.0% at stage II, 84.6% at stage III, and 60.0% at stage IV, respectively. The positive rates of hepatic GP73 protein and mRNA in the rat models were none in the control group, 66.7% and 44.4% in the hepatocytes degeneration group, 88.9% and 77.8% in the hepatocytes precanceration group, and 100% in the HCC group, respectively. There was a positive correlation (r = 0.91, P<0.01) between hepatic GP73 and serum GP73 during rat hepatocytes malignant transformation.

Conclusions: Abnormal GP73 expression may be a sensitive and valuable biomarker in hepatocarcinogensis.
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http://dx.doi.org/10.1016/j.hbpd.2020.02.009DOI Listing
October 2020

Chiral Ru(ii) complexes act as a potential non-viral gene carrier for directional transportation to the nucleus and cytoplasm.

Metallomics 2020 04 13;12(4):504-513. Epub 2020 Feb 13.

Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou 510632, China.

Guanine-rich DNA sequences can spontaneously fold into four-stranded structures called G-quadruplexes (G4s). G4s have been identified extensively in the promoter regions of several proto-oncogenes, including c-myc, as well as telomeres. G4s have attracted an increasing amount of attention in the field of nanotechnology because of their use as versatile building blocks of DNA-based nanostructures. In this study, we report the self-assembly of c-myc G-quadruplex DNA controlled by a pair of chiral ruthenium(ii) complexes coordinated by 2-(4-phenyacetylenephenyl)-1H-imidazo[4,5f][1,10]phenanthroline (PBEPIP), Λ-[Ru(bpy)(PBEPIP)](ClO) (Λ-RM0627, bpy = bipyridine) and Δ-[Ru(bpy)(PBEPIP)](ClO) (Δ-RM0627). Λ-RM0627 could promote the high-order self-assembly of c-myc G-quadruplex DNA into a nanowire structure, whereas Δ-RM0627 could induce DNA condensation into G-quadruplex aggregates. Moreover, in vitro studies on human liver carcinoma HepG2 cells showed that the nanowire of c-myc G-quadruplex DNA promoted by Λ-RM0627 could be localized in the nuclei of cells, whereas the nanoparticle of c-myc G-quadruplex DNA generated by Δ-RM0627 was taken up and localized in the cytoplasm. This study provides examples of the enantioselective self-assembly of G4 DNA molecules controlled by chiral ruthenium(ii) complexes and suggests the potential applications of assembled nanostructures as non-viral DNA vectors for gene therapy.
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http://dx.doi.org/10.1039/c9mt00192aDOI Listing
April 2020

Abnormal CD44 activation of hepatocytes with nonalcoholic fatty accumulation in rat hepatocarcinogenesis.

World J Gastrointest Oncol 2020 Jan;12(1):66-76

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China.

Background: Prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing, and NAFLD has become one of the most common chronic liver diseases worldwide. With abnormal CD44 activation, the severe form of NAFLD can progress to liver cirrhosis and hepatocellular carcinoma (HCC). Thus, the molecular mechanism of CD44 in NAFLD needs to be identified.

Aim: To investigate the relationship between CD44 activation and malignant transformation of rat hepatocytes under nonalcoholic lipid accumulation.

Methods: Sprague-Dawley rats were fed a high-fat (HF) for 12 wk to entice NAFLD and then with HF plus 2-fluorenylacetamide (0.05%) to induce HCC. Rats were sacrificed every 2 wk, and subsequently divided into the groups based on liver pathological examination (hematoxylin and eosin staining): NAFLD, denaturation, precancerosis, HCC, and control. Liver CD44 mRNA was detected by OneArray. Liver fat as assessed by Oil red O staining or CD44 by immunohistochemical assay was compared with their integral optic density. Serum CD44, alanine aminotransferase, aspartate aminotransferase, triglyceride, total cholesterol, and AFP levels were quantitatively tested.

Results: Elevated CD44 was first reported in hepatocarcinogenesis, with increasing expression from NAFLD to HCC at the protein or mRNA level. The CD44 integral optic density values were significantly different between the control group and the NAFLD ( = 25.433, < 0.001), denaturation ( = 48.822, < 0.001), precancerosis ( = 27.751, < 0.001), and HCC ( = 16.239, < 0.001) groups, respectively. Hepatic CD44 can be secreted into the blood, and serum CD44 levels in HCC or precancerous rats were significantly higher ( < 0.001) than those in any of the other rats. Positive correlations were found between liver CD44 and CD44 mRNA ( = 0.373, = 0.043) and serum CD44 ( = 0.541, = 0.002) and between liver CD44 mRNA and serum CD44 ( = 0.507, = 0.004). Moreover, significant correlations were found between liver CD44 and liver AFP ( = 0.572, = 0.001), between serum CD44 and serum AFP ( = 0.608, < 0.001), and between CD44 mRNA and AFP mRNA ( = 0.370, = 0.044).

Conclusion: The data suggested that increasing CD44 expression is associated with the malignant transformation of hepatocytes in NAFLD.
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http://dx.doi.org/10.4251/wjgo.v12.i1.66DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6960074PMC
January 2020

Metagenomic profiling of the pro-inflammatory gut microbiota in ankylosing spondylitis.

J Autoimmun 2020 02 2;107:102360. Epub 2019 Dec 2.

Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China.

Objective: Gut dysbiosis has been reported implicated in ankylosing spondylitis (AS), a common chronic inflammatory disease mainly affects sacroiliac joints and spine. Utilizing deep sequencing on the feces of untreated AS patients, our study aimed at providing an in-depth understanding of AS gut microbiota.

Methods: We analyzed the fecal metagenome of 85 untreated AS patients and 62 healthy controls by metagenomic shotgun sequencing, and 23 post-treatment feces of those AS patients were collected for comparison. Comparative analyses among different cohorts including AS, rheumatoid arthritis and Behcet's disease were performed to uncover some common signatures related to inflammatory arthritis. Molecular mimicry of a microbial peptide was also demonstrated by ELISpot assay.

Results: We identified AS-enriched species including Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri. Pathway analysis revealed increased oxidative phosphorylation, lipopolysaccharide biosynthesis and glycosaminoglycan degradation in AS gut microbiota. Microbial signatures of AS gut selected by random forest model showed high distinguishing accuracy. Some common signatures related to autoimmunity, such as Bacteroides fragilis and type III secretion system (T3SS), were also found. Finally, in vitro experiments demonstrated an increased amount of IFN-γ producing cells triggered by a bacterial peptide of AS-enriched species, mimicking type II collagen.

Conclusions: These findings collectively indicate that gut microbiota was perturbed in untreated AS patients with diagnostic potential, and some AS-enriched species might be triggers of autoimmunity by molecular mimicry. Additionally, different inflammatory arthritis shared some common microbial signatures.
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http://dx.doi.org/10.1016/j.jaut.2019.102360DOI Listing
February 2020

Complement C1q synergizes with PTX3 in promoting NLRP3 inflammasome over-activation and pyroptosis in rheumatoid arthritis.

J Autoimmun 2020 01 7;106:102336. Epub 2019 Oct 7.

Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China; Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China. Electronic address:

Excessive inflammatory cytokines play crucial roles in the pathogenesis of rheumatoid arthritis (RA), however, the underlying mechanism remains unclear. In this study, we demonstrated that pentaxin 3 (PTX3), an essential component of innate immunity, was elevated in RA and preferentially bound to CD14 monocytes. C1q promoted the binding and resulted in increased cell proliferation, activation and caspase-1-related late apoptotic cells (7-AADannexin V), as well as enhanced release of inflammatory cytokines including TNF-α, IL-1β and IL-6. Serum from RA patients, compared with healthy controls, induced gasdermin D (GSDMD)-dependent pyroptosis in monocytes, and this ability was associated with disease activity. Moreover, PTX3 synergized with C1q to promote pyroptosis in RA-serum pre-incubated monocytes by coordinately enhancing NLRP3 inflammasome over-activation and inducing GSDMD cleavage, cell swelling with large bubbles, caspase-1-dependent cell death and inflammatory cytokine release including IL-6. On the other hand, IL-6 promoted PTX3 plus C1q-induced pyroptosis in both normal and RA serum pre-incubated monocytes. These findings collectively implicated an important role of IL-6 in driving PTX3 plus C1q-mediated pyroptosis in RA and shed lights on a potential new treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.
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http://dx.doi.org/10.1016/j.jaut.2019.102336DOI Listing
January 2020

Alteration of oncogenic IGF-II gene methylation status associates with hepatocyte malignant transformation.

Hepatobiliary Pancreat Dis Int 2019 Apr 21;18(2):158-163. Epub 2019 Jan 21.

Department of Oncology, Affiliated Hospital of Nantong University, Nantong 226001, China. Electronic address:

Background: Oncogenic insulin-like growth factor-II (IGF-II) is overexpressed in hepatocellular carcinoma (HCC). The present study aimed to analyze the dynamic alteration of IGF-II CpG site methylation status and its molecular mechanism in HCC progression.

Methods: IGF-II alterations were observed in rat hepatocarcinogenesis models induced by 2-acetylaminofluorene. Liver IGF-II expression was compared by immunohistochemistry or tissue IGF-II specific concentration (nmol/mg protein). Status of human IGF-II promoter 3 (P3) or rat IGF-II P2 CpG site methylation was amplified by methylation-specific polymerase chain reaction (MSP). Serum IGF-II levels were quantitatively detected by an enzyme-linked immunosorbent assay.

Results: The levels of hepatic IGF-II expression were significantly elevated in the HCC group (P < 0.001). The unmethylation rate of IGF-II P3 CpG sites was 100% in the HCC-, 52.5% in the paracancerous-, and none (0%) in the distal noncancerous-tissues. Abnormal IGF-II expression was related to differentiation degree, tumor invasion, and positive HBV-DNA (all P < 0.001), with a negative correlation between P3 methylation degree and IGF-II expression. There was a positive correlation between liver IGF-II specific concentration and circulating IGF-II level (r = 0.97, P < 0.001). Significantly negative correlation was found between IGF-II P2 CpG site methylation and circulating IGF-II (r = -0.89, P < 0.001) or liver IGF-II level (r = -0.84, P < 0.001).

Conclusions: The increase of serum IGF-II and the alteration of oncogenic gene IGF-II methylation may be biomarkers for HCC diagnosis and DNA methylation may be the therapeutic target of HCC.
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http://dx.doi.org/10.1016/j.hbpd.2019.01.003DOI Listing
April 2019

Abnormal expression of is significantly associated with malignant transformation of hepatocytes.

World J Gastroenterol 2018 Aug;24(32):3650-3662

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China.

Aim: To explore the relationship between dynamic expression of high mobility group box-3 (HMGB3) and malignant transformation of hepatocytes.

Methods: Expression of HMGB family proteins were observed in rat hepatocarcinogenesis models induced with 2-acetylaminofluorene. Alterations of HMGB3 were analyzed at the mRNA level by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and at the protein level by immunohistochemistry or Western blotting. HMGB3 in human liver cancer tissues were evaluated using bioinformatics databases from GEO, TCGA, and Oncomine. A specific HMGB3-shRNA was used to knock down HMGB3 expression in order to investigate its effects on proliferation and cell cycle and .

Results: Elevated HMGB3 levels were first reported in hepatocarcinogenesis, with increasing expression from normal liver to cancer. Bioinformatic databases showed that HMGB3 expression in hepatocellular carcinoma tissues was significantly higher than that in normal liver tissues. Higher HMGB3 expression was discovered in liver cancer cells compared with LO2 cells . According to gene set enrichment analysis, HMGB3 mRNA levels were correlated with cell cycle and DNA replication pathways. Knocking down HMGB3 by specific shRNA significantly inhibited proliferation of HepG2 cells by cell cycle arrest and downregulating DNA replication related genes (cyclin B1, FEN1, and PCNA) at the mRNA and protein level. Furthermore, silencing HMGB3 significantly inhibited xenograft tumor growth (measured by Ki67) .

Conclusion: HMGB3 is involved in malignant transformation of hepatocytes and could be a useful biomarker for diagnosis and a potential target for therapy of liver cancer.
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http://dx.doi.org/10.3748/wjg.v24.i32.3650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6113724PMC
August 2018

Preparation of Ru(ii)@oligonucleotide nanosized polymers as potential tumor-imaging luminescent probes.

RSC Adv 2018 Aug 30;8(53):30573-30581. Epub 2018 Aug 30.

School of Chemistry, Jinan University Guangzhou 510632 China.

The development of Ru(ii) complexes as luminescent probes has attracted increasing attention in recent decades. In this study, the nanosized polymers of two Ru(ii) complexes [Ru(phen)(dppz)](ClO) (1, phen = 1,10-phenanthrolin; dppz = dipyrido[3,2-:2',3'-]phenazine) and [Ru(phen)(Br-dppz)](ClO) (2, Br-dppz = 11-bromodipyrido[3,2-:2',3'-]phenazine) with oligonucleotides were prepared and investigated as potential tumor-imaging probes. The formation of the nanosized polymers, which had an average width of 125-438 nm and an average height of 3-6 nm, for 1 and [email protected] were observed through atomic force microscopy. The emission spectra indicated that the luminescence of 1 and 2 markedly increased after binding to oligonucleotides and double-strand DNA (calf thymus DNA), respectively. Moreover, further studies indicated that [email protected] and [email protected] can easily enter into tumor cells and selectively highlight the tumor area in the zebrafish bear xenograft tumor (MDA-MB-231). In summary, this study demonstrated that [email protected] and [email protected] could be developed as potential tumor-imaging luminescent probes for clinical diagnosis and therapy.
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http://dx.doi.org/10.1039/c8ra05454aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9085494PMC
August 2018

Correction: Chiral ruthenium polypyridyl complexes as mitochondria-targeted apoptosis inducers.

Medchemcomm 2018 Apr 19;9(4):745. Epub 2018 Mar 19.

Department of Chemistry , Jinan University , Guangzhou , 510632 , China . Email: ; ; Tel: +86 20 8522 1263.

[This corrects the article DOI: 10.1039/C0MD00060D.].
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http://dx.doi.org/10.1039/c8md90010hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072508PMC
April 2018

Expression of hepatic Wnt5a and its clinicopathological features in patients with hepatocellular carcinoma.

Hepatobiliary Pancreat Dis Int 2018 Jun 13;17(3):227-232. Epub 2018 Mar 13.

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, No. 20 West Temple Rd, Nantong 226001, China. Electronic address:

Backgroud: Wingless-type MMTV integration site family member 5a (Wnt5a) is involved in carcinogenesis. However, little data are available in Wnt5a signaling with hepatocellular carcinoma (HCC). In the present study, we investigated the expression of hepatic Wnt5a in HCC and the role of Wnt5a in HCC progression and outcome.

Methods: Wnt5a expression and cellular distribution in HCCs and their matched paracancerous tissues from 87 patients were analyzed with tissue microarray and immunohistochemistry and compared with hepatic Wnt3a signaling. Wnt5a expression was categorized into low or high based on immunohistochemistry. Overall survival rate of HCC patients was estimated in correlation with the hepatic Wnt5a level using Kaplan-Meier method; the survival difference between patients with low and those with high Wnt5a was compared with log-rank test; and prognostic analysis was carried out with Cox regression.

Results: Total incidence of Wnt5a expression in the HCC tissues was 70.1%, which was significantly lower (χ= 13.585, P < 0.001) than that in their paracancerous tissues (88.5%). Significant difference of Wnt5a intensity was found between HCC and their paracancerous tissues (Z = 8.463, P < 0.001). Wnt5a intensity was inversely correlated with Wnt3a signaling (r = -0.402, P < 0.001) in HCC tissues. A decrease of Wnt5a expression in relation to the clinical staging from stage I to IV and low or no staining at advanced HCC were observed. Wnt5a level was related to periportal embolus (χ= 11.069, P < 0.001), TNM staging (χ= 8.852, P < 0.05), 5-year survival (χ= 4.961, P < 0.05), and confirmed as an independent prognosis factor of HCC patients (hazard ratio: 1.957; 95% confidence interval: 1.109-3.456; P < 0.05).

Conclusions: The decrease of hepatic Wnt5a signaling is associated with HCC progression and poor prognosis.
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http://dx.doi.org/10.1016/j.hbpd.2018.03.005DOI Listing
June 2018

Comparison of the impact of Tripterygium wilfordii Hook F and Methotrexate treatment on radiological progression in active rheumatoid arthritis: 2-year follow up of a randomized, non-blinded, controlled study.

Arthritis Res Ther 2018 04 10;20(1):70. Epub 2018 Apr 10.

Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing, 100730, China.

Background: Tripterygium wilfordii Hook F (TwHF) alone or in combination with methotrexate (MTX) has been shown to be more effective than MTX monotherapy in controlling the manifestations in subjects with disease-modifying antirheumatic drug (DMARD)-naïve active rheumatoid arthritis (RA) over a 6-month period. The long-term impact of these therapies on disease activity and radiographic progression in RA has not been examined.

Methods: Patients with DMARD-naïve RA enrolled in the "Comparison of Tripterygium wilfordii Hook F with methotrexate in the Treatment of Active Rheumatoid Arthritis" (TRIFRA) study were randomly allocated into three arms with TwHF or MTX or the two in combination. Clinical indexes and radiographic data at baseline and year 2 was collected and compared using an intent-to-treat (ITT) and a per-protocol (PP) analysis. Two radiologists blinded to the treatment scored the images independently.

Results: Of 207 subjects 109 completed the 2-year follow up. The number of subjects withdrawing from the study and the number adhering to the initial regimens were similar among the three groups (p > = 0.05). In the ITT analysis, proportions of patients reaching American College of Rheumatology 50% (ACR50) response criteria were 46.4%, 58.0% and 50.7% in the MTX, TwHF and MTX + TwHF groups (TwHF vs MTX monotherapy, p = 0.004). Similar patterns were found in ACR20, ACR70, Clinical Disease Activity Index good responses, European League Against Rheumatism good response, remission rate and low disease activity rate at year 2. The results of the PP analysis agreed with those in the ITT analysis. The changes in total Sharp scores and joint erosion and joint space narrowing during the 2 years were associated with changes in disease activity measured by the 28-joint count Disease Activity Score and were comparable among the three groups (p > 0.05). Adverse events were similar in the three treatment groups.

Conclusions: During the 2-year therapy period, TwHF monotherapy was not inferior to MTX monotherapy in controlling disease activity and retarding radiological progression in patients with active RA.

Trial Registration: This is a follow-up study. Original trial registration: ClinicalTrials.gov , NCT01613079 . Registered on 4 June 2012.
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http://dx.doi.org/10.1186/s13075-018-1563-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5894170PMC
April 2018

4-Phenylbutyric acid presents therapeutic effect on osteoarthritis via inhibiting cell apoptosis and inflammatory response induced by endoplasmic reticulum stress.

Biotechnol Appl Biochem 2018 Jul 7;65(4):540-546. Epub 2018 Feb 7.

Department of Orthopedics, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, 311201, Zhejiang, People's Republic of China.

Osteoarthritis (OA) is a common bone and joint disease with a wild range of risk factors, which is associated with endoplasmic reticulum (ER) stress. The aim of our study was to discuss the possible mechanism of ER stress associated with OA in vivo and explore novel therapeutic method against OA. OA-induced damages in cartilage tissues were evaluated by HE, Safranin O/fast green, and TUNEL staining. The inflammatory factors concentration and the expression of FAP, MMP2, MMP9, Bax, Bcl-2, CHOP, and GRP78 were evaluated by ELISA, real-time PCR, and Western blot analyses. As results, 4-phenylbutyric acid (4-PBA)-treated OA cartilage tissues presented alleviated tissue damage with less apoptotic cells and cytokine production in comparison with advanced-OA tissues. Downregulation of Bax/Bcl-2, CHOP, GRP78, inflammatory factors, and reactive oxygen species generation, and the increase of MMP level detected after 4-PBA treatment indicated an inhibitory effect of 4-PBA on cell apoptosis, inflammatory response, and ER stress in OA. In conclusion, we indicate that ER stress causes cell apoptosis and inflammatory response, resulting in the tissue damage within OA. At the same time, 4-PBA exhibited protective effect on cartilage cells against OA through the inhibition of ER stress.
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http://dx.doi.org/10.1002/bab.1642DOI Listing
July 2018

Chemotaxis of Vδ2 T cells to the joints contributes to the pathogenesis of rheumatoid arthritis.

Ann Rheum Dis 2017 Dec 2;76(12):2075-2084. Epub 2017 Sep 2.

Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Ministry of Education Key Laboratory, Beijing, China.

Objectives: To explore the role of Vδ2 T cells in the pathogenesis of rheumatoid arthritis (RA).

Methods: Sixty-eight patients with RA, 21 patients with osteoarthritis and 21 healthy controls were enrolled in the study. All patients with RA fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA. Peripheral Vδ2T population, chemokine receptor expression and proinflammatory cytokine secretion were quantified by flow cytometry. The infiltration of Vδ2 T cells within the synovium was examined by immunohistochemistry and flow cytometry. The effect of tumour necrosis factor (TNF)-α and interleukin (IL)-6 on Vδ2 T migration was determined by flow cytometry and transwell migration assay.

Results: Peripheral Vδ2T cells, but not Vδ1 T cells, were significantly lower in patients with RA, which was negatively correlated with disease activity gauged by Disease Activity Score in 28 joints. Vδ2 T cells from RA accumulated in the synovium and produced high levels of proinflammatory cytokines including interferon-γ and IL-17. Phenotypically, Vδ2 T cells from RA showed elevated chemotaxis potential and expressed high levels of chemokine receptors CCR5 and CXCR3, which was driven by increased serum TNF-α through nuclear factor kappa B signalling. In vivo, TNF-α neutralising therapy dramatically downregulated CCR5 and CXCR3 on Vδ2 T cells and repopulated the peripheral Vδ2 T cells in patients with RA.

Conclusions: High levels of TNF-α promoted CCR5 and CXCR3 expression in Vδ2 T cells from RA, which potentially infiltrated into the synovium and played crucial roles in the pathogenesis of RA. Targeting Vδ2 T cells might be a potential approach for RA.
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http://dx.doi.org/10.1136/annrheumdis-2016-211069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705844PMC
December 2017

Preliminary study of diffusion kurtosis imaging in thyroid nodules and its histopathologic correlation.

Eur Radiol 2017 Nov 14;27(11):4710-4720. Epub 2017 Jun 14.

Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, No. 160, Pujian Road, Shanghai, 200127, China.

Objectives: To evaluate the utility of diffusion kurtosis imaging (DKI) of patients with thyroid nodules and to assess the probable correlation with histopathological factors.

Methods: The study included 58 consecutive patients with thyroid nodules who underwent magnetic resonance imaging (MRI) examination, including DKI and diffusion-weighted imaging (DWI). Histopathological analysis of paraffin sections included cell density and immunohistochemical analysis of Ki-67 and vascular endothelial growth factor (VEGF). Statistical analyses were performed using Student's t-test, receiver operating characteristic (ROC) curves and Spearman's correlation.

Results: The diffusion parameters, cell density and immunohistochemistry analysis between malignant and benign lesions showed significant differences. The largest area under the ROC curve was acquired for the D value (AUC = 0.797). The highest sensitivity was shown with the use of K (threshold = 0.832, sensitivity = 0.917). The Ki-67 expression generally stayed low. A moderate correlation was found between ADC, D and cell density (r = -0.536, P = 0.000; r = -0.570, P = 0.000) and ADC, D and VEGF expression (r = -0.451, P = 0.000; r = -0.522, P = 0.000).

Conclusion: The DKI-derived parameters D and K demonstrated an advantage compared to conventional DWI for thyroid lesion diagnosis. While the histopathological study indicated that the D value correlated better with extracellular change than the ADC value, the K value probably changed relative to the intracellular structure.

Key Points: • DWI and DKI parameters can identify PTC from benign thyroid nodules. • Correlations were found between diffusion parameters and histopathological analysis. • DKI obtains better diagnostic accuracy than conventional DWI.
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http://dx.doi.org/10.1007/s00330-017-4874-0DOI Listing
November 2017

Microwave-Assisted Synthesis of Imidazo[4,5-f][1,10]phenanthroline Derivatives as Apoptosis Inducers in Chemotherapy by Stabilizing Bcl-2 G-quadruplex DNA.

Molecules 2017 May 20;22(5). Epub 2017 May 20.

Department of Chemistry, Jinan University, Guangzhou 510006, China.

Herein, a series of imidazo[4,5-][1,10] phenanthroline derivatives RPIP (PIP = imidazo [4,5-][1,10] phenanthroline, R = NO₂, ; CF₃, ; Cl, ; OH, ) have been synthesized in yields of 82.3-94.7% at 100 °C under the irradiation of microwave. MTT assay has been utilized to evaluate the inhibitory activity (IC) of these compounds against the growth of various tumor cells, and the results revealed that these compounds, especially , exhibited excellent inhibitory activity against the growth of A549 cells with IC of 15.03 μM. Moreover, it's also confirmed that can penetrate into the membrane of tumor cells and distribute in mitochondria when observed under microscopy, resulting apoptosis of tumor cells. The further studies showed that can bind to G-quadruplex DNA, which demonstrated by the increase of melting point of G4 DNA in the presence of , as well as electronic titration and emission spectra. In a word, this kind of compound may develop as a potential apoptosis inducer in cancer chemotherapy via binding and stabilizing to the G-quadruplex DNA.
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http://dx.doi.org/10.3390/molecules22050829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154642PMC
May 2017

Mitochondrial carnitine palmitoyl transferase-II inactivity aggravates lipid accumulation in rat hepatocarcinogenesis.

World J Gastroenterol 2017 Jan;23(2):256-264

Juan-Juan Gu, Wen-Jie Zheng, Deng-Fu Yao, Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China.

Aim: To investigate the dynamic alteration of mitochondrial carnitine palmitoyl transferase II (CPT-II) expression during malignant transformation of rat hepatocytes.

Methods: Sprague-Dawley male rats were fed with normal, high fat (HF), and HF containing 2-fluorenylacetamide (2-FAA) diet, respectively. According to the Hematoxylin and Eosin staining of livers, rats were divided into control, fatty liver, degeneration, precancerous, and cancerous groups. Liver lipids were dyed with Oil Red O, CPT-II alterations were analyzed by immunohistochemistry, and compared with CPT-II specific concentration (μg/mg protein). Levels of total cholesterol (Tch), triglyceride (TG), and amino-transferases [alanine aminotransferase (ALT), aspartate aminotransferase (AST)] were determined by the routine methods.

Results: After intake of HF and/or HF+2-FAA diets, the rat livers showed mass lipid accumulation. The lipid level in the control group was significantly lower than that in other groups. The changes of serum TG and Tch levels were abnormally increasing, 2-3 times more than those in the controls ( < 0.05). During the rat liver morphological changes from normal to cancer development process with hepatocyte injury, serum AST and ALT levels were significantly higher (4-8 times, < 0.05) than those in the control group. The specific concentration of CPT-II in liver tissues progressively decreased during hepatocyte malignant transformation, with the lowest CPT-II levels in the cancer group than in any of the other groups ( < 0.05).

Conclusion: Low CPT-II expression might lead to abnormal hepatic lipid accumulation, which should promote the malignant transformation of hepatocytes.
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http://dx.doi.org/10.3748/wjg.v23.i2.256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5236505PMC
January 2017

Mechanisms underlying the antiapoptotic and anti-inflammatory effects of monotropein in hydrogen peroxide-treated osteoblasts.

Mol Med Rep 2016 Dec 31;14(6):5377-5384. Epub 2016 Oct 31.

Department of Orthopedic Surgery, Xiaoshan Traditional Chinese Medical Hospital, Hangzhou, Zhejiang 311200, P.R. China.

Monotropein, the primary iridoid glycoside isolated from Morindacitrifolia, has been previously reported to possess potent antioxidant and antiosteoporotic properties. However, there is no direct evidence correlating the antiosteoporotic effect of monotropein with its observed antioxidant capacity, and the molecular mechanisms involved in mediating these processes remain unclear. Therefore, the aim of the present study was to investigate the protective effects of monotropein against oxidative stress in osteoblasts and the mechanisms involved in mediating this process. Osteoblast viability was evaluated using the MTT assay. The mitochondrial membrane potential and reactive oxygen species were detected by flow cytometry analyses. Western blotting and enzyme‑linked immunosorbent assays were performed to detect protein expression levels. A significant reduction in osteoblast viability was observed at 24 h following exposure to various concentrations (100‑1,000 µM) of H2O2 compared with untreated osteoblasts. The cytotoxic effect of H2O2 was notably reversed when osteoblasts were pretreated with 1‑10 µg/ml monotropein. Pretreatment with 1-10 µg/ml monotropein increased the mitochondrial membrane potential and reduced the generation of reactive oxygen species in osteoblasts following exposure to H2O2. In addition, the H2O2‑induced increase in apoptotic markers (caspase-3 and caspase-9) and H2O2-induced reduction in sirtuin 1 levels were significantly reversed following pretreatment of cells with monotropein. Furthermore, monotropein significantly reduced H2O2‑induced stimulation of NF‑κB expression, in addition to the expression of a number of proinflammatory mediators. These results indicate that monotropein suppresses apoptosis and the inflammatory response in H2O2‑induced osteoblasts through the activation of the mitochondrial apoptotic signaling pathway and inhibition of the NF‑κB signaling pathway.
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http://dx.doi.org/10.3892/mmr.2016.5908DOI Listing
December 2016

Contribution and underlying mechanisms of CXCR4 overexpression in patients with systemic lupus erythematosus.

Cell Mol Immunol 2017 Oct 26;14(10):842-849. Epub 2016 Sep 26.

Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Clinical Immunology Center, Chinese Academy of Medical Sciences and Peking Union Medical College, The Ministry of Education Key Laboratory, Beijing 100730, China.

Aberrant expression of CXCR4 has been indicated to play a role in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanism of CXCR4 dysregulation in SLE is unclear. This study is aimed to explore the clinical significance and possible mechanisms of abnormal CXCR4 expression on B cells from patients with untreated SLE. Expression of CXCR4 on peripheral B cells was determined by flow cytometry and western blotting. Freshly isolated B cells were cultured with exogenous interleukin 21(IL-21) in the presence or absence of CD40 ligand (CD40L) plus anti-IgM antibody (aIgM), and changes in CXCR4 expression were detected. Involvement of phosphatidylinositol 3 kinase (PI3K)/Akt and Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways was assessed by adding blocking agents Ly294002 and AG490. Since CD63 is reported to mediate endosomal recruitment of CXCR4 and BCL6 is capable of silencing CD63 gene transcription, we also measured BCL6 and CD63 gene transcription with real-time PCR. It was shown that CXCR4 expression on B cells was significantly upregulated in SLE patients, especially in those with lupus nephritis, and was positively correlated with SLE Disease Activity Index scores and negatively with the serum complement 3 levels (P<0.05). Downregulation of CXCR4 by IL-21 was intact. In contrast, a similar effect of aIgM plus CD40L in downregulating CXCR4 expression was defective in SLE patients but was restored by co-stimulation with IL-21 in vitro. Both Ly294002 and AG490 promoted downregulation of surface CXCR4 expression on B cells from SLE patients (P=0.078 and P=0.064). Furthermore, B cells from SLE patients exhibited diminished CD63 mRNA and enhanced BCL6 mRNA expression (both P<0.05). To sum up, CXCR4 was overexpressed on SLE B cells, positively correlating with disease activity and kidney involvement. Overactivation of the PI3K/Akt and JAK/STAT pathways as well as defective CD63 synthesis may contribute to CXCR4 dysregulation in SLE.
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http://dx.doi.org/10.1038/cmi.2016.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649106PMC
October 2017

Facile synthesis of S-Ag nanocomposites and Ag2S short nanorods by the interaction of sulfur with AgNO3 in PEG400.

Nanotechnology 2016 Jun 25;27(22):225602. Epub 2016 Apr 25.

Department of Chemistry, Jinan University, Guangzhou 510632, People's Republic of China.

A facile, eco-friendly and inexpensive method to prepare Ag2S short nanorods and S-Ag nanocomposites using sublimed sulfur, AgNO3, PVP and PEG400 was studied. According to x-ray diffraction and scanning electron microscopy of the Ag2S, the products are highly crystalline and pure Ag2S nanorods with diameters of 70-160 nm and lengths of 200-360 nm. X-ray diffraction of the S-Ag nanocomposites shows that we obtained cubic Ag and S nanoparticles. Transmission electron microscopy shows that the molar ratio of PVP to Ag(+) plays an important role in controlling the size and morphology of the S-Ag nanocomposites. When the molar ratio of PVP to Ag(+) was 10:1, smaller sizes, better dispersibility and narrower distribution of S-Ag nanocomposites with diameters of 10-40 nm were obtained. The formation mechanism of the S-Ag nanocomposites was studied by designing a series of experiments using ultraviolet-visible measurement, and it was found that S nanoparticles are produced first and act as seed crystals; then Ag(+) becomes Ag nanocrystals on the surfaces of the S nanoparticles by the reduction of PVP. PEG400 acts as a catalyzer, accelerating the reaction rate, and protects the S-Ag nanocomposites from reacting to produce Ag2S. The antimicrobial experiments show that the S-Ag nanocomposites have greater antimicrobial activity on Staphylococcus aureus, Aspergillus niger and blue mold than Ag nanoparticles.
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http://dx.doi.org/10.1088/0957-4484/27/22/225602DOI Listing
June 2016

Estrogen enhances the bone regeneration potential of periodontal ligament stem cells derived from osteoporotic rats and seeded on nano-hydroxyapatite/collagen/poly(L-lactide).

Int J Mol Med 2016 Jun 12;37(6):1475-86. Epub 2016 Apr 12.

Department of Chemistry, Jinan University, Guangzhou, Guangdong 510632, P.R. China.

This study investigated the effects of estrogen on the bone regeneration potential of periodontal ligament stem cells (PDLSCs) derived from osteoporotic rats and seeded on a collagen-based composite scaffold [nano-hydroxyapatite/collagen/poly(L-lactide) (nHAC/PLA)]. For this purpose, 48 healthy 3‑month-old Sprague-Dawley female rats were divided into 2 groups as follows: the bilaterally ovariectomized (OVX) rats and sham‑operated rats. The PDLSCs were isolated at 3 months after surgery (by which time postmenopausal osteoporosis had developed). The effects of estrogen on the characteristics of these cells seeded in a culture plate and of the cells seeded on nHAC/PLA were then investigated. The PDLSC + nHAC/PLA constructs were implanted subcutaneously into the backs of severe combined immunodeficient (SCID) mice for 12 weeks in order to examine the role of estrogen in the bone formation ability of PDLSCs derived from osteoporotic rats. The results from methyl thiazolyl tetrazolium (MTT) assay revealed that the proliferation of the cells derived from the rats in the OVX group was significantly higher than that of the cells derived from the rats in the sham-operated group at the stage of logarithmic growth. The staining intensity of alkaline phosphatase (ALP) and the mineralization of the cells derived from the rats in the OVX group was significantly weaker than that of the cells from the rats in the sham-operated group. When the PDLSCs were seeded on nHAC/PLA, ALP activity, osteocalcin (OCN) secretion, mineral formation and the mRNA expression levels of ALP, OCN, estrogen receptor (ER)α and ERβ in the cells derived from the rats in the OVX group were markedly decreased. Treatment with 17β-estradiol (E2) significantly weakened the proliferative ability of the cells derived from the OVX group rats, and enhanced their osteogenic differentiation ability and the mRNA expression levels of ALP, OCN, ERα and ERβ. When the constructs were implanted into the backs of SCID mice for 12 weeks, the results of histological analysis indicated that the constructs derived from the OVX group rats had a few newly formed bones and osteoids; however, a great number of newly formed bones and osteoids were present in the ones from the sham-operated group and the OVX + E2 group rats. Our findings further indicate that estrogen deficiency impairs the osteogenic differentiation potential of PDLSCs, and that ER plays an important role in the bone regeneration ability of PDLSCs. Estrogen enhances the bone regeneration potential of PDLSCs derived from osteoporotic rats and seeded on nHAC/PLA. This study may provide insight into the clinical management of periodontal bone tissue repair in postmenopausal women with the use of estrogen-mediated PDLSCs seeded on nHAC/PLA.
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http://dx.doi.org/10.3892/ijmm.2016.2559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4866970PMC
June 2016

[Down-regulated clusterin expression enhances sensitivity of hepatoma cells to anti-cancer drugs].

Zhonghua Gan Zang Bing Za Zhi 2015 Nov;23(11):844-8

Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong 226001, China.

Objective: To investigate the relationship between and underlying mechanistic pathway of clusterin (CLU) and chemo-resistance ofhepatocellular carcinoma (HCC) cells.

Methods: CLU protein expression in HCC cell lines (Hep3B, SMMC7721, PLC, and HepG2) and HepG2/ADM cells was quantified by western blotting. Four short-hairpin (sh)RNAs designed to block CLU-mRNA were generated, screened by RT-PCR, and transfected into the cells to determine effects of CLU on cell viability and apoptosis. Effects of CLU blockade on drug efflux pump activity were measured by flow cytometry.

Results: CLU was found to be over-expressed in HCC cell lines and HepG2/ADM cells. The four shRNAs inhibited CLU-mRNA as follows (vs. levels in untransfected cells): shRNA-1: 73.68% (q =23.011, P < 0.01), shRNA-2: 39.26% (q =11.991, P < 0.01), shRNA-3: 62.36% (q =19.392, P < 0.01), and shRNA-4: 55.35% (q =17.149, P < 0.01). shRNA-mediated depletion of CLU led to increased sensitivity to anti-cancer drugs and increased doxorubicin-induced apoptosis in HepG2/ADM cells, as evidenced by the apoptosis ratio of the shRNA-1 group of 39.28% vs. the apoptosis ratio of the untransfected control group of 4.92%. Silencing of CLU also decreased drug etflux pump activity, and the level of MDR1/P-gp expression was significantly reduced (shRNA-1 group vs.untransfected control group: q =14.604, P < 0.01).

Conclusion: CLU repression may enhance sensitivity of HCC cells to anti-cancers drugs and represents a potential molecular-target for reversal of multidrug-resistant HCC.
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http://dx.doi.org/10.3760/cma.j.issn.1007-3418.2015.11.009DOI Listing
November 2015
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