119 results on '"Xin, Shan"'
Search Results
2. Diverging targets mediate the pathological roleof miR-199a-5p and miR-199a-3p by promoting cardiac hypertrophy and fibrosis
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Jia-Xin Feng, Yong-Heng Fu, Xi-Long Zheng, Yu-Min Yan, Zhi-Qin Hu, Yu-Qing Huang, Zhuo Zhang, Zhi-Xin Shan, Jie-Ning Zhu, Meng-Zhen Zhang, Ji-Shen Guo, Ni Zeng, Jin-Dong Xu, Jin-Zhu Duan, and Xi-Pei Wang
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Cardiac fibrosis ,microRNA-199a-5p ,cardiac fibrosis ,microRNA-199a-3p ,Alpha (ethology) ,RM1-950 ,Downregulation and upregulation ,Fibrosis ,Drug Discovery ,Serum response factor ,microRNA ,medicine ,biology ,Sirtuin 1 ,business.industry ,cardiac hypertrophy ,medicine.disease ,Cancer research ,biology.protein ,cardiovascular system ,Molecular Medicine ,Original Article ,PPARGC1A ,Therapeutics. Pharmacology ,business - Abstract
MicroRNA-199a-5p (miR-199a-5p) and -3p are enriched in the myocardium, but it is unknown whether miR-199a-5p and -3p are co-expressed in cardiac remodeling and what roles they have in cardiac hypertrophy and fibrosis. We show that miR-199a-5p and -3p are co-upregulated in the mouse and human myocardium with cardiac remodeling and in Ang-II-treated neonatal mouse ventricular cardiomyocytes (NMVCs) and cardiac fibroblasts (CFs). miR-199a-5p and -3p could aggravate cardiac hypertrophy and fibrosis in vivo and in vitro. PPAR gamma coactivator 1 alpha (Ppargc1a) and sirtuin 1 (Sirt1) were identified as target genes to mediate miR-199a-5p in promoting both cardiac hypertrophy and fibrosis. However, miR-199a-3p aggravated cardiac hypertrophy and fibrosis through targeting RB transcriptional corepressor 1 (Rb1) and Smad1, respectively. Serum response factor and nuclear factor κB p65 participated in the upregulation of miR-199a-5p and -3p in Ang-II-treated NMVCs and mouse CFs, and could be conversely elevated by miR-199a-5p and -3p. Together, Ppargc1a and Sirt1, Rb1 and Smad1 mediated the pathological effect of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively. This study suggests a possible new strategy for cardiac remodeling therapy by inhibiting miR-199a-5p and -3p., Graphical abstract, Transcription factor SRF and NF-κB p65 regulate the co-expression of miR-199a-5p and -3p by positive feedback in the pathological cardiac remodeling. Ppargc1a and Sirt1, Rb1 and Smad1 mediate the pathological role of miR-199a-5p and -3p by promoting cardiac hypertrophy and fibrosis, respectively.
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- 2021
3. Influenza Virus Precision Diagnosis and Continuous Purification Enabled by Neuraminidase-Resistant Glycopolymer-Coated Microbeads
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Gefei Li, Xin-Shan Ye, Boyang Cheng, Wenxiao Ma, Demin Zhou, Juan Mo, and Shin Ichiro Shoda
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Materials science ,viruses ,Glycopolymer ,Chromatography, Affinity ,Virus ,Madin Darby Canine Kidney Cells ,chemistry.chemical_compound ,Dogs ,Influenza A Virus, H1N1 Subtype ,Limit of Detection ,Polysaccharides ,Influenza, Human ,Animals ,Humans ,General Materials Science ,Surface plasmon resonance ,Infectivity ,biology ,Viral Vaccine ,Surface Plasmon Resonance ,Viral Load ,Virology ,Microspheres ,HEK293 Cells ,Carbohydrate Sequence ,chemistry ,Colloidal gold ,biology.protein ,Ultracentrifuge ,Neuraminidase - Abstract
Rapid diagnosis and vaccine development are critical to prevent the threat posed by viruses. However, rapid tests, such as colloidal gold assays, yield false-negative results due to the low quantities of viruses; moreover, conventional virus purification, including ultracentrifugation and nanofiltration, is multistep and time-consuming, which limits laboratory research and commercial development of viral vaccines. A rapid virus enrichment and purification technique will improve clinical diagnosis sensitivity and simplify vaccine production. Hence, we developed the surface-glycosylated microbeads (glycobeads) featuring chemically synthetic glycoclusters and reversible linkers to selectively capture the influenza virus. The surface plasmon resonance (SPR) evaluation indicated broad spectrum affinity of S-linked glycosides to various influenza viruses. The magnetic glycobeads were integrated into clinical rapid diagnosis, leading to a 30-fold lower limit of detection. Additionally, the captured viruses can be released under physiological conditions, delivering purified viruses with >50% recovery and without decreasing their native infectivity. Notably, this glycobead platform will facilitate the sensitive detection and continuous one-step purification of the target virus that contributes to future vaccine production.
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- 2021
4. Dickkopf 3: a Novel Target Gene of miR-25-3p in Promoting Fibrosis-Related Gene Expression in Myocardial Fibrosis
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Yu-Min Yan, Rong Pan, Yi-Hong Wen, Jing Yang, Xian-Hong Fang, Ni Zeng, An-Zhi Zhao, Zhi-Xin Shan, and Jie-Ning Zhu
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0301 basic medicine ,Cardiac fibrosis ,Pharmaceutical Science ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Fibrosis ,Gene expression ,microRNA ,Genetics ,Medicine ,Gene ,Genetics (clinical) ,biology ,business.industry ,medicine.disease ,030104 developmental biology ,cardiovascular system ,Cancer research ,biology.protein ,Molecular Medicine ,Myocardial fibrosis ,ACTA2 ,Cardiology and Cardiovascular Medicine ,business - Abstract
Increasing evidence has shown that microRNAs (miRNAs) participate in cardiac fibrosis. We aimed to elucidate the effect of miRNA miR-25-3p on cardiac fibrosis. MiRNA microarray was used to profile miRNAs in the myocardium of angiotensin-II (Ang-II)-infused mice. Effect of miR-25-3p on expression of fibrosis-related genes, including Col1a1, Col3a1, and Acta2, was investigated both in vitro and in vivo. MiR-25-3p was shown increased in the myocardium of Ang-II-infused mice and patients with heart failure. MiR-25-3p enhanced fibrosis-related gene expression in mouse cardiac fibroblasts (mCFs) and in the myocardium of Ang-II-infused mice. Dickkopf 3 (Dkk3) was identified as a target gene of miR-25-3p, and Dkk3 could ameliorate Smad3 activation and fibrosis-related gene expression via enhancing Smad7 expression in mCFs. Additionally, NF-κB signal was proven to mediate upregulation of miR-25-3p in cardiac fibrosis. Our findings suggest that miR-25-3p enhances cardiac fibrosis by suppressing Dkk3 to activate Smad3 and fibrosis-related gene expression.
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- 2021
5. Donor <scp>Preactivation‐Based</scp> Glycosylation: An Efficient Strategy for Glycan Synthesis
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Xianjin Qin and Xin-Shan Ye
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Glycan ,chemistry.chemical_compound ,Glycosylation ,biology ,chemistry ,Stereochemistry ,biology.protein ,General Chemistry ,Chemoselectivity ,Solvent effects ,Oligosaccharide synthesis - Published
- 2021
6. Synthesis and immunological evaluation of N-acyl modified Globo H derivatives as anticancer vaccine candidates
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Chengcheng Song, Xiu-Jing Zheng, Xin-Shan Ye, and Canjia Zhai
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Synthetic vaccine ,Glycosylation ,Glycoconjugate ,medicine.medical_treatment ,Pharmaceutical Science ,H antigen ,010402 general chemistry ,01 natural sciences ,Biochemistry ,chemistry.chemical_compound ,Immune system ,Drug Discovery ,medicine ,Pharmacology ,chemistry.chemical_classification ,biology ,010405 organic chemistry ,Immunogenicity ,Organic Chemistry ,0104 chemical sciences ,chemistry ,Cancer research ,biology.protein ,Molecular Medicine ,Antibody ,Adjuvant - Abstract
Globo H is a tumor-associated carbohydrate antigen (TACA), which serves as a valuable target for antitumor vaccine or cancer immunotherapies. However, most TACAs are T-cell-independent, and they cannot induce powerful immune response due to their poor immunogenicity. To address this problem, herein, several Globo H analogues with modification on the N-acyl group were prepared through a preactivation-based glycosylation strategy from the non-reducing end to the reducing end. These modified Globo H derivatives were then conjugated with carrier protein CRM197 to form glycoconjugates as anticancer vaccine candidates, which were used in combination with adjuvant glycolipid C34 for immunological studies. The immunological effects of these synthetic vaccine candidates were evaluated on Balb/c mice. The results showed that the fluorine-modified N-acyl Globo H conjugates can induce higher titers of IgG antibodies that can recognize the naturally occurring Globo H antigen on the surface of cancer cells and can eliminate cancer cells in the presence of a complement, indicating the potential of these synthetic glycoconjugates as anticancer vaccine candidates.
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- 2021
7. Recent advances in glycan synthesis
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Xin-Shan Ye and Bo-Han Li
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0301 basic medicine ,Glycan ,Glycosylation ,biology ,Chemistry ,Stereoisomerism ,Chemistry Techniques, Synthetic ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Chemical synthesis ,Enzymes ,0104 chemical sciences ,Analytical Chemistry ,carbohydrates (lipids) ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,Polysaccharides ,biology.protein - Abstract
Carbohydrates play important roles in life science, but their synthesis is always hampered by their complicated chemical structures. Scientists have never stopped trying to solve the problem of glycan synthesis from various aspects. Here a brief overview of recent progress in glycan synthesis, including chemical approaches, chemoenzymatic approaches, and automated synthesis, will be discussed, focusing on the efficiency of new glycosylation methods, the stereoselectivity of coupled products, and their applications in the assembly of complex glycan chains.
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- 2020
8. Design, synthesis and evaluation of carbamate-containing sialyltransferase inhibitors
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Wenming Li, Wanjun Yan, De-Cai Xiong, and Xin-Shan Ye
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Carbamate ,biology ,Biochemistry ,Design synthesis ,Chemistry ,Sialyltransferase ,medicine.medical_treatment ,medicine ,biology.protein ,Pharmaceutical Science - Published
- 2020
9. Engineering a bacterial sialyltransferase for di-sialylation of a therapeutic antibody
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Yue Wang, Xin-Shan Ye, Liangren Zhang, Mingqun Wang, Kaimeng Liu, Zhenming Liu, and Xiaodong Dou
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chemistry.chemical_classification ,Glycosylation ,biology ,Photobacterium ,Sialyltransferase ,Organic Chemistry ,Mutant ,Mutagenesis (molecular biology technique) ,Protein Engineering ,Biochemistry ,Antibodies ,Sialyltransferases ,carbohydrates (lipids) ,chemistry.chemical_compound ,Enzyme ,chemistry ,Sialic Acids ,biology.protein ,Physical and Theoretical Chemistry ,Antibody ,Bioorthogonal chemistry ,Glycoprotein ,beta-D-Galactoside alpha 2-6-Sialyltransferase - Abstract
Terminal α-2,6-sialylation of N-glycans is a humanized glycosylation that affects the properties and efficacy of therapeutic glycoproteins. Fc di-sialylation (a biantennary N-glycan with two α-2,6-linked sialic acids) of IgG antibodies imparts them with enhanced anti-inflammatory activity and other roles. However, the microheterogeneity of N-glycoforms presents a challenge for therapeutic development. Therefore, controlled sialylation has drawn considerable attention, but direct access to well-defined di-sialylated antibodies remains limited. Herein, a one-pot three-enzyme protocol was developed by engineering a bacterial sialyltransferase to facilitate the modification of therapeutic antibodies with N-acetylneuraminic acid or its derivatives towards optimized glycosylation. To overcome the low proficiency of bacterial sialyltransferase in antibody remodeling, the Photobacterium sp. JT-ISH-224 α-2,6-sialyltransferase (Psp2,6ST) was genetically engineered by terminal truncation and site-directed mutagenesis based on its protein crystal structure. With the optimized reaction conditions and using activity-based screening of various Psp2,6ST variants, a truncated mutant Psp2,6ST (111-511)-His6 A235M/A366G was shown to effectively improve the catalytic efficiency of antibody di-sialylation. Herceptin and the donor substrate promiscuity allow the introduction of bioorthogonal modifications of N-acetylneuraminic acid into antibodies for site-specific conjugation. 2-AB hydrophilic interaction chromatography analysis of the released N-glycans and intact mass characterization confirmed the high di-sialylation of Herceptin via the optimized one-pot three-enzyme reaction. This study established a versatile enzymatic approach for producing highly di-sialylated IgG antibodies. It provides new insights into engineering bacterial sialyltransferase for adaptation to the enzymatic glycoengineering of therapeutic antibodies and the glycosite-specific conjugation of antibodies.
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- 2020
10. Glycan Assembly Strategy: From Concept to Application
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Xianjin Qin, Mingli Liu, and Xin-Shan Ye
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Glycan ,Glycosylation ,biology ,Carbohydrate chemistry ,Chemistry ,General Chemical Engineering ,Carbohydrate synthesis ,General Chemistry ,Computational biology ,Biochemistry ,carbohydrates (lipids) ,chemistry.chemical_compound ,Hot topics ,Polysaccharides ,Materials Chemistry ,Natural source ,biology.protein - Abstract
Glycans have been hot topics in recent years due to their exhibition of numerous biological activities. However, the heterogeneity of their natural source and the complexity of their chemical synthesis impede the progress in their biological research. Thus, the development of glycan assembly strategies to acquire plenty of structurally well-defined glycans is an important issue in carbohydrate chemistry. In this review, the latest advances in glycan assembly strategies from concepts to their applications in carbohydrate synthesis, including chemical and enzymatic/chemo-enzymatic approaches, as well as solution-phase and solid-phase/tag-assisted synthesis, are summarized. Furthermore, the automated glycan assembly techniques are also outlined.
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- 2021
11. Synthesis and biological evaluation of bergenin derivatives as new immunosuppressants
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Youhong Niu, Qin Li, Meng Wang, Xin-Shan Ye, Yan-Fen Wu, Chengcheng Song, and Lihua Deng
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Pharmacology ,biology ,Organic Chemistry ,Pharmaceutical Science ,Bergenin ,Alkylation ,biology.organism_classification ,Biochemistry ,Combinatorial chemistry ,chemistry.chemical_compound ,Chemistry ,chemistry ,Drug Discovery ,Splenocyte ,Molecular Medicine ,Bergenia ,Inhibitory effect ,IC50 ,Biological evaluation - Abstract
Bergenin, which is isolated from Bergenia species, exhibits various pharmacological properties. In the search for new types of immunosuppressants, a series of bergenin derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by the CCK-8 assay. The experimental data demonstrated that compounds 7 and 13 showed the strongest inhibition effects on mouse splenocyte proliferation (IC(50) = 3.52 and 5.39 μM, respectively). Further studies revealed that the inhibitory effect may come from the suppression of both IFN-γ and IL-4 cytokines. Alkylated derivatives of bergenin with n-hexyl and n-heptyl on the two phenolic hydroxyl groups showed better inhibitory activities. The hydrophobicity of bergenin derivatives, the configuration of the 4-OH in bergenin, and the ability to form hydrogen bonds of the substituents on the C-4 position are important to the immunosuppressive activity. This work proved that the modifications of bergenin may represent a new route to the discovery of a new class of immunosuppressive agents.
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- 2021
12. Sensing of mycobacterial arabinogalactan by galectin‐9 exacerbates mycobacterial infection
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Shaorong Gao, Anca Dorhoi, Gang Pei, Haipeng Liu, Yong Wu, Jie Wang, Yang Wang, Zhonghua Liu, Bo Yan, Baoxue Ge, Feifei Li, Ruiliang Jin, Xiangyang Wu, Ruijuan Zheng, Lin Wang, Fen Tang, Peng Zhang, Chang Chen, Xin-Shan Ye, Stefan H. E. Kaufmann, Xiaochen Huang, Wei Sha, Lingming Chen, Lu Zhang, Hua Yang, Jiayu Chen, Detian Lai, Fei Wang, Peng Wang, Pedro Moura-Alves, Felix Randow, Mingtong Ma, Yajuan Cao, Lianhua Qin, Jianxia Chen, Jinyu Zhang, Liang-Dong Lyu, Gucheng Zeng, and Qin Sun
- Subjects
Galectins ,galectin‐9 ,virulence factor ,Galactans ,Biochemistry ,Article ,Virulence factor ,Microbiology ,Mycobacterium tuberculosis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Arabinogalactan ,Genetics ,Animals ,Molecular Biology ,Zebrafish ,030304 developmental biology ,Galectin ,0303 health sciences ,Mycobacterium bovis ,mycobacterial arabinogalactan ,biology ,Kinase ,Chemistry ,matrix metalloproteinases ,transforming growth factor β‐activated kinase 1 ,Articles ,biology.organism_classification ,Microbiology, Virology & Host Pathogen Interaction ,030217 neurology & neurosurgery ,Signal Transduction ,Transforming growth factor ,Mycobacterium - Abstract
Mycobacterial arabinogalactan (AG) is an essential cell wall component of mycobacteria and a frequent structural and bio‐synthetical target for anti‐tuberculosis (TB) drug development. Here, we report that mycobacterial AG is recognized by galectin‐9 and exacerbates mycobacterial infection. Administration of AG‐specific aptamers inhibits cellular infiltration caused by Mycobacterium tuberculosis (Mtb) or Mycobacterium bovis BCG, and moderately increases survival of Mtb‐infected mice or Mycobacterium marinum‐infected zebrafish. AG interacts with carbohydrate recognition domain (CRD) 2 of galectin‐9 with high affinity, and galectin‐9 associates with transforming growth factor β‐activated kinase 1 (TAK1) via CRD2 to trigger subsequent activation of extracellular signal‐regulated kinase (ERK) as well as induction of the expression of matrix metalloproteinases (MMPs). Moreover, deletion of galectin‐9 or inhibition of MMPs blocks AG‐induced pathological impairments in the lung, and the AG‐galectin‐9 axis aggravates the process of Mtb infection in mice. These results demonstrate that AG is an important virulence factor of mycobacteria and galectin‐9 is a novel receptor for Mtb and other mycobacteria, paving the way for the development of novel effective TB immune modulators., Arabinogalactan is a virulence factor of mycobacteria. Binding of galectin‐9 to mycobacterial arabinogalactan triggers matrix metalloproteinases via TAK1‐ERK signaling, which promotes mycobacterial infection and increases lung injury.
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- 2021
13. Novel role of the clustered miR‐23b‐3p and miR‐27b‐3p in enhanced expression of fibrosis‐associated genes by targeting TGFBR3 in atrial fibroblasts
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Zhen Xiao, Jingnan Liang, Jing Yang, Huiming Guo, Jie-Ning Zhu, Shulin Wu, Zhen-Zhen Yang, Xi-Long Zheng, Wenyan Dong, Zhi-Xin Shan, Shujing Yuan, Rong Pan, Xian-Hong Fang, and Hui Li
- Subjects
0301 basic medicine ,Atrial Appendage ,microRNA‐27b‐3p ,Transforming Growth Factor beta1 ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Atrial Fibrillation ,medicine ,Humans ,Heart Atria ,Smad3 Protein ,Receptor ,Cell Proliferation ,Sick Sinus Syndrome ,biology ,business.industry ,Cell growth ,human atrial fibroblast ,Angiotensin II ,Atrial fibrillation ,Cell Biology ,Transfection ,Original Articles ,Fibroblasts ,medicine.disease ,TGFBR3 ,microRNA‐23b‐3p ,MicroRNAs ,030104 developmental biology ,Collagen Type III ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,atrial fibrosis ,Cancer research ,biology.protein ,Molecular Medicine ,Original Article ,Proteoglycans ,ACTA2 ,business ,Receptors, Transforming Growth Factor beta ,Transforming growth factor ,Smad3 ,Signal Transduction - Abstract
Atrial fibrillation (AF) is the most common type of arrhythmia in cardiovascular diseases. Atrial fibrosis is an important pathophysiological contributor to AF. This study aimed to investigate the role of the clustered miR‐23b‐3p and miR‐27b‐3p in atrial fibrosis. Human atrial fibroblasts (HAFs) were isolated from atrial appendage tissue of patients with sinus rhythm. A cell model of atrial fibrosis was achieved in Ang‐II‐induced HAFs. Cell proliferation and migration were detected. We found that miR‐23b‐3p and miR‐27b‐3p were markedly increased in atrial appendage tissues of AF patients and in Ang‐II‐treated HAFs. Overexpression of miR‐23b‐3p and miR‐27b‐3p enhanced the expression of collagen, type I, alpha 1 (COL1A1), COL3A1 and ACTA2 in HAFs without significant effects on their proliferation and migration. Luciferase assay showed that miR‐23b‐3p and miR‐27b‐3p targeted two different sites in 3ʹ‐UTR of transforming growth factor (TGF)‐β1 receptor 3 (TGFBR3) respectively. Consistently, TGFBR3 siRNA could increase fibrosis‐related genes expression, along with the Smad1 inactivation and Smad3 activation in HAFs. Additionally, overexpression of TGFBR3 could alleviate the increase of COL1A1, COL3A1 and ACTA2 in HAFs after transfection with miR‐23b‐3p and miR‐27b‐3p respectively. Moreover, Smad3 was activated in HAFs in response to Ang‐II treatment and inactivation of Smad3 attenuated up‐regulation of miR‐23b‐3p and miR‐27b‐3p in Ang‐II‐treated HAFs. Taken together, these results suggest that the clustered miR‐23b‐3p and miR‐27b‐3p consistently promote atrial fibrosis by targeting TGFBR3 to activate Smad3 signalling in HAFs, suggesting that miR‐23b‐3p and miR‐27b‐3p are potential therapeutic targets for atrial fibrosis.
- Published
- 2019
14. Chemical synthesis of glycans and applications in carbohydrate-based vaccines
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Yongshi Wang and Xin-Shan Ye
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chemistry.chemical_classification ,Glycan ,Glycosylation ,Glycobiology ,Glycoconjugate ,General Chemical Engineering ,Immunogenicity ,General Chemistry ,Biology ,Carbohydrate ,Polysaccharide ,Biochemistry ,Chemical synthesis ,chemistry.chemical_compound ,chemistry ,Materials Chemistry ,biology.protein - Abstract
Carbohydrates play important roles in many biological processes. However, the lack of resources of structurally-defined carbohydrates and their weak immunogenicity have always restricted the development of chemical glycobiology especially carbohydrate-based vaccines. The progress in chemical synthesis of carbohydrates and glycoconjugates has greatly promoted the development of carbohydrate-based vaccines including antibacterial vaccines, anti-tumor vaccines and anti-HIV vaccines. The use of one-pot glycosylation strategy and solid-phase glycosylation strategy is able to synthesize oligosaccharides and even polysaccharides more effectively than before. Glycoconjugates produced by combining the carbohydrate antigens and proper protein carriers improve the immunogenicity of carbohydrates. This review covers the general methods and strategies of carbohydrate chemical synthesis, and the recent development of carbohydrate-based vaccines, and also summarizes related work of our group, hoping to offer readers better understanding of chemical glycobiology especially carbohydrate-based vaccines.
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- 2018
15. Novel carbohydrate-triazole derivatives as potential α-glucosidase inhibitors
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Zi-Pei Zhang, De-Cai Xiong, Jian-Xing Hu, Yan-Fen Wu, Wan-Ying Xue, and Xin-Shan Ye
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Stereochemistry ,Stacking ,Carbohydrates ,01 natural sciences ,03 medical and health sciences ,0302 clinical medicine ,Drug Discovery ,medicine ,Glycoside Hydrolase Inhibitors ,Acarbose ,biology ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Hydrogen bond ,α glucosidase ,General Medicine ,Carbohydrate ,Triazoles ,Enzyme assay ,In vitro ,0104 chemical sciences ,Molecular Docking Simulation ,Complementary and alternative medicine ,030220 oncology & carcinogenesis ,biology.protein ,Triazole derivatives ,medicine.drug - Abstract
A series of novel pyrano[2, 3-d]trizaole compounds were synthesized and their α-glucosidase inhibitory activities were evaluated by in vitro enzyme assay. The experimental data demonstrated that compound 10f showed up to 10-fold higher inhibition (IC5074.0 ± 1.3 μmol·L-1) than acarbose. The molecular docking revealed that compound 10f could bind to α-glucosidase via the hydrophobic, π-π stacking, and hydrogen bonding interactions. The results may benefit further structural modifications to find new and potent α-glucosidase inhibitors.
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- 2020
16. Proteomic analysis of healthy and atretic porcine follicular granulosa cells
- Author
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Ya Liu, Xiaoyu Guan, Fugui Fang, Yani Fan, Xin Shan, Yinghui Lin, Yunsheng Li, Yunhai Zhang, Xu Yan, Tong Yu, and Jianling Wu
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0301 basic medicine ,Proteomics ,endocrine system ,Swine ,Granulosa cell ,Follicular Atresia ,Biophysics ,Apoptosis ,Biology ,Biochemistry ,03 medical and health sciences ,Follicle ,Tandem Mass Spectrometry ,Follicular phase ,Animals ,Atretic Follicle ,Granulosa Cells ,030102 biochemistry & molecular biology ,Follicular atresia ,Antral follicle ,Cell biology ,030104 developmental biology ,Protein destabilization ,Female ,Signal transduction ,Chromatography, Liquid - Abstract
Follicular atresia is initiated with the apoptosis of granulosa cells (GCs) after birth in mammals. The molecular mechanisms underlying GC apoptosis during follicular selection are unclear at present. The objective of this study is to identify the proteins and pathways that may be involved in porcine follicular atresia. Proteins isolated from GCs collected from healthy and atretic follicles were detected by tandem mass tag (TMT) protein labeling and LC-MS/MS. A total of 4591 proteins in the healthy follicle granulosa cell (HFGC) and atretic follicle granulosa cell (AFGC) groups were identified, and 399 differentially abundant proteins were found between the HFGC and AFGC groups; of which 262 proteins were significantly up-regulated and 137 proteins were significantly down-regulated. Differential protein enrichment analysis showed that proteins involved in proteolysis, protein destabilization, phagocytosis, and engulfment were more abundant in the AFGC group. Also, these proteins were mainly involved in the lysosome, phagosome, autophagy, and apoptosis pathways. Specially, PTGFRN is potential important regulated protein in the development of the antral follicle, and down-regulation of PTGFRN in GCs may lead to follicular atresia. Our study shows that the identified proteins and their related signaling pathways may play crucial roles during health follicle develop to atretic follicle. SIGNIFICANCE: Follicular atresia during 'selection' reduces the reproductive potential of sows. In this study, we found 399 proteins differentially abundant. between the HFGC and AFGC groups. These results establish a foundation for elucidating the mechanism of follicular atresia in swine.
- Published
- 2020
17. Azo-PROTAC: Novel Light-Controlled Small-Molecule Tool for Protein Knockdown
- Author
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Zheng-Yu Jiang, Meng-Chen Lu, Wen-Xin Shan, Xuan-Yu Wang, Yu-Hui Jin, Qidong You, and Yan Wang
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Ultraviolet Rays ,Ubiquitin-Protein Ligases ,Dasatinib ,Fusion Proteins, bcr-abl ,Protein degradation ,Ligands ,01 natural sciences ,03 medical and health sciences ,Cell Line, Tumor ,Drug Discovery ,Humans ,Lenalidomide ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,0303 health sciences ,Gene knockdown ,ABL ,biology ,Chemistry ,Ubiquitination ,Signal transducing adaptor protein ,Stereoisomerism ,Fusion protein ,Small molecule ,0104 chemical sciences ,Ubiquitin ligase ,010404 medicinal & biomolecular chemistry ,Proteolysis ,Biophysics ,biology.protein ,Molecular Medicine ,Azo Compounds ,K562 cells - Abstract
Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells. The light-induced configuration change can switch the active state to induce protein degradation activity, which can be reversely controlled by light exposure in intact cells. We compared the protein degradation abilities of Azo-PROTACs with different configurations and linker lengths. Using the stable form with the best degradation ability against the BCR-ABL fusion and ABL proteins in myelogenous leukemia K562 cells, we showed that Azo-PROTAC combines the potent protein knockdown and facile cell uptake properties of the small-molecule PROTAC with a reversible photoswitchability, offering a promising chemical knockdown strategy based on the light-induced reversible on/off properties.
- Published
- 2020
18. Cyanidin-related antidepressant-like efficacy requires PI3K/AKT/FoxG1/FGF-2 pathway modulated enhancement of neuronal differentiation and dendritic maturation
- Author
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Jing Chen, Zhiyang Lv, Qian Wang, Zhiheng Huang, Shilin Dai, Qinan Wu, Xin Shan, and Jie Wang
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Pharmacology ,0303 health sciences ,biology ,medicine.diagnostic_test ,Chemistry ,Neurogenesis ,Antagonist ,Pharmaceutical Science ,Fibroblast growth factor ,Doublecortin ,03 medical and health sciences ,0302 clinical medicine ,Complementary and alternative medicine ,Western blot ,030220 oncology & carcinogenesis ,Drug Discovery ,biology.protein ,medicine ,Molecular Medicine ,Hippocampus (mythology) ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology - Abstract
Background Cyanidin (CY) is one of the most abundant anthocyanidins found in red-purple diet sources such as grapes, blueberries and purple corns. CY has been proven to exhibit a wide range of biological functions including antioxidant, antiviral, anticarcinogenic and anti-inflammatory properties. Purpose This study investigated the anti-depressive activity of CY and its related mechanism. Methods In the behavioral tests, CY-related effects on depressive symptoms were evaluated. Then the changes in PI3K/AKT/FOXG1/FGF-2 signaling and adult neurogenesis including doublecortin (DCX+) cell number, dendritic length, secondary and third dendrites number in the hippocampus were investigated by Immunofluorescence and Western blot analyses. PI3K antagonist LY 294,002 was used to verify the unique impact of PI3K/AKT/FoxG1/FGF-2 signaling on CY-related antidepressant efficacy. Results CY grossly reversed CUMS-induced behavioral defects, The DCX+ cell number and protein levels increased in CUMS mice receiving CY administration. LY 294,002 successfully blocked CY-induced improvements in depressive behaviors, neurogenesis, and protein levels in CUMS mice. Conclusion The findings demonstrated that CY was efficacious in alleviating depression-like symptoms, which was dependent on PI3K/AKT/FoxG1/FGF-2 signaling-modulated neurogenesis enhancement.
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- 2020
19. 131I-Evans blue: evaluation of necrosis targeting property and preliminary assessment of the mechanism in animal models
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Qiaomei Jin, Nan Yao, Zhiqi Yin, Dejian Huang, Dong Jian Zhang, Wei Liu, Fei Peng, Xin Shan, Jian Zhang, Qi Luo, and Yuan-Yu Zhao
- Subjects
0301 basic medicine ,Pathology ,Necrosis ,CT-DNA, calf-thymus DNA ,T2WI, T2-weighted imaging ,RPLI, reperfused liver infarction ,chemistry.chemical_compound ,0302 clinical medicine ,DWI, diffusion-weighted imaging ,T1WI, T1-weighted imaging ,General Pharmacology, Toxicology and Pharmaceutics ,Hyp, hypericin ,Evans Blue ,Neurodegeneration ,Necrosis imaging ,% ID/g, percentage of the injected dose per gram of tissue ,EB, evans blue ,Radioactivity ,030220 oncology & carcinogenesis ,Original Article ,H&E, haematoxylin-eosin ,medicine.symptom ,medicine.medical_specialty ,Programmed cell death ,Biodistribution ,DMSO, dimethylsulfoxide ,RCP, radiochemical purity ,CE-T1WI, contrast-enhanced T1WI ,Biology ,PI, propidium iodide ,Necrosis avidity ,03 medical and health sciences ,medicine ,Avidity ,DNA binding ,131I-Evans blue ,131I-EB, 131I-evans blue ,RFA, radiofrequency ablation ,MPS, mononuclear phagocyte system ,NAAs, necrosis-avid agents ,TLC, thin layer chromatography ,lcsh:RM1-950 ,medicine.disease ,In vitro ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,chemistry ,MRI, magnetic resonance imaging ,DNA ,SD rats, Sprague–Dawley rats - Abstract
Necrosis is a form of cell death, which is related to various serious diseases such as cardiovascular disease, cancer, and neurodegeneration. Necrosis-avid agents (NAAs) selectively accumulated in the necrotic tissues can be used for imaging and/or therapy of related diseases. The aim of this study was to preliminarily investigate necrosis avidity of 131I-evans blue (131I-EB) and its mechanism. The biodistribution of 131I-EB at 24 h after intravenous administration showed that the radioactivity ratio of necrotic to viable tissue was 3.41 in the liver and 11.82 in the muscle as determined by γ counting in model rats. Autoradiography and histological staining displayed preferential uptake of 131I-EB in necrotic tissues. In vitro nuclear extracts from necrotic cells exhibited 82.3% of the uptake in nuclei at 15 min, as well as 79.2% of the uptake at 2 h after 131I-EB incubation. The DNA binding study demonstrated that evans blue (EB) has strong binding affinity with calf-thymus DNA (CT-DNA) (Ksv=5.08×105 L/(mol/L)). Furthermore, the accumulation of 131I-EB in necrotic muscle was efficiently blocked by an excess amount of unlabeled EB. In conclusion, 131I-EB can not only detect necrosis by binding the DNA released from necrotic cells, but also image necrotic tissues generated from the disease clinically., Graphical abstract In the present study, we demonstrated that 131I-evens blue (EB) could specifically bind to necrotic tissues image necrosis in living animals. Furthermore, the necrosis targeting mechanism of EB might be attributed to its binding to exposed DNA in necrotic areas.fx1
- Published
- 2017
20. Design, synthesis and cytotoxic evaluation of a novel series of benzo[d]thiazole-2-carboxamide derivatives as potential EGFR inhibitors
- Author
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Chao Zhang, Xin-Shan Deng, Guang-Peng Meng, Wu Jiaofeng, Chun Hu, Qing-Chun Zhao, Lan Zhang, and Xue-Song Li
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biology ,010405 organic chemistry ,medicine.drug_class ,Organic Chemistry ,Carboxamide ,Pharmacology ,biology.organism_classification ,01 natural sciences ,Molecular biology ,0104 chemical sciences ,HeLa ,010404 medicinal & biomolecular chemistry ,chemistry.chemical_compound ,chemistry ,Cell culture ,biology.protein ,medicine ,Cytotoxic T cell ,Epidermal growth factor receptor ,General Pharmacology, Toxicology and Pharmaceutics ,Thiazole ,Cytotoxicity ,EGFR inhibitors - Abstract
A novel series of benzo[d]thiazole-2-carboxamide derivatives have been de novo designed based on virtual screening methods. The target compounds were synthesized and evaluated for the cytotoxicity against epidermal growth factor receptor high-expressed cancer cell lines (A549, HeLa, and SW480), epidermal growth factor receptor low-expressed cell line (HepG2) and human liver normal cell line (HL7702). Several target compounds have showed moderate to excellent potency against A549, HeLa, and SW480 and weak cytotoxic effects against HepG2, which implies they are probably epidermal growth factor receptor inhibitors. And scarcely did they exhibit any activities against HL7702, which signifies they are likely to overcome the nonspecific toxicity against normal cells. Especially, the compound 6-[2-(diethylamino)-2-oxoethoxy]-N-(furan-2-ylmethyl)benzo[d]thiazole-2-carboxamide (6i) was identified as a promising agent, exhibiting the most potent cytotoxic activities with IC50 values of 4.05, 12.17, 6.76 μM against the A549, HeLa, and SW480 cell lines, respectively.
- Published
- 2017
21. Transition State-Based Sialyltransferase Inhibitors: Mimicking Oxocarbenium Ion by Simple Amide
- Author
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Jian Guo, Wenming Li, Weiwei Xue, and Xin-Shan Ye
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0301 basic medicine ,Magnetic Resonance Spectroscopy ,Glycosylation ,Sialyltransferase ,Stereochemistry ,Oxocarbenium ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,Amide ,Drug Discovery ,Humans ,Moiety ,Enzyme Inhibitors ,Chromatography, High Pressure Liquid ,chemistry.chemical_classification ,biology ,010405 organic chemistry ,Nuclear magnetic resonance spectroscopy ,Amides ,Sialyltransferases ,0104 chemical sciences ,Sialic acid ,carbohydrates (lipids) ,030104 developmental biology ,Enzyme ,chemistry ,biology.protein ,Molecular Medicine ,Spectrophotometry, Ultraviolet - Abstract
In the new transition-state based sialyltransferase inhibitors, an amide group was placed at the corresponding C-2 position of CMP-sialic acid to mimic the geometry and charge distribution in the transition state, and simple aromatic or aliphatic rings were used instead of the sialic acid moiety. All synthetic compounds exhibited excellent α(2-6)-sialyltransferase inhibition, resulting in up to a 2600-fold higher affinity for the enzyme than CMP-Neu5Ac, suggesting that amide is a key element for simulating transition-state features.
- Published
- 2017
22. MicroRNA-92b-3p suppresses angiotensin II-induced cardiomyocyte hypertrophy via targeting HAND2
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Lei Huang, Xueju Yu, Zhi-Xin Shan, Geng Qingshan, Zhi-Qin Hu, Yu-Qing Huang, Jie-Ning Zhu, and Ying-Qing Feng
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0301 basic medicine ,Heart Defects, Congenital ,Heart Ventricles ,Cardiomegaly ,Biology ,030226 pharmacology & pharmacy ,General Biochemistry, Genetics and Molecular Biology ,Muscle hypertrophy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,microRNA ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Luciferase ,Myocytes, Cardiac ,General Pharmacology, Toxicology and Pharmaceutics ,RNA, Small Interfering ,3' Untranslated Regions ,Heart Failure ,Messenger RNA ,Angiotensin II ,Myocardium ,General Medicine ,Transfection ,Cardiomyopathy, Hypertrophic ,Cell biology ,Up-Regulation ,Mice, Inbred C57BL ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,HAND2 Gene ,biology.protein ,HAND2 ,Signal Transduction - Abstract
Aims The pathological cardiac hypertrophy will develop into heart failure, which has no effective treatment currently. Previous studies have proved that microRNAs (miRNAs) participate in the development of cardiac hypertrophy and regulate the pathological progress. In this study, we want to investigate the role of microRNA-92b-3p (miR-92b-3p) in cardiomyocyte hypertrophy and the mechanisms involved. Materials and methods Neonatal mouse ventricular cells (NMVCs) were isolated from the hearts of 1–3-d-old newborn C57BL6 mice. The isolated NMVCs were induced hypertrophic phenotype by Angiotensin-II (Ang-II) and the cell size was examined by FITC-phalloidin staining assay. The expression of miR-92b-3p was determined by quantitative real-time PCR (qRT-qPCR). MRNA and protein level of β-MHC, ACTA1 and HAND2 in NMVCs transfected with miR-92b-3p mimic and inhibition were assessed by RT-qPCR assay and western blot assay, respectively. Dual luciferase assay was used to verify the interaction between miR-92b-3p and the 3′-untranslated region (UTR) of HAND2 gene. Key findings MiR-92b-3p and HAND2 were significantly increased in Ang-II-induced NMVCs. Overexpression of miR-92b-3p can ameliorate Ang-II-induced cardiomyocyte hypertrophy. MiR-92b-3p negatively regulated HAND2 expression at the transcriptional level. Both miR-92b-3p mimic and HAND2 siRNA could efficiently inhibit Ang-II-induced hypertrophy in mouse cardiomyocytes. Significance MiR-92b-3p inhibits Ang-II-induced cardiomyocyte hypertrophy via targeting HAND2.
- Published
- 2019
23. Anti-depressant effects of oil from fructus gardeniae via PKA-CREB-BDNF signaling
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Qiang Fu, Jie Ruan, Xin Shan, Li Liu, and Baomei Xia
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0301 basic medicine ,Biophysics ,Gardenia jasminoides ,Pharmacology ,CREB ,Biochemistry ,Hippocampus ,Pathogenesis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Western blot ,medicine ,Hippocampus (mythology) ,Animals ,Plant Oils ,Ketamine ,Medicine, Chinese Traditional ,Protein kinase A ,Cyclic AMP Response Element-Binding Protein ,Molecular Biology ,Research Articles ,Brain-derived neurotrophic factor ,Sulfonamides ,Plants, Medicinal ,biology ,medicine.diagnostic_test ,Behavior, Animal ,Chemistry ,Depression ,Brain-Derived Neurotrophic Factor ,Cell Biology ,Gardenia jasminoides oil extract ,biology.organism_classification ,Gardenia ,Isoquinolines ,Cyclic AMP-Dependent Protein Kinases ,Disease Models, Animal ,030104 developmental biology ,Gene Expression Regulation ,Fruit ,biology.protein ,030217 neurology & neurosurgery ,PKA/CREB/BDNF ,medicine.drug ,Research Article - Abstract
The dried ripe fruit of Gardenia jasminoides Ellis was usually applied as an herb medicine in Traditional Chinese Medicine. It was suggested that the Gardenia jasminoides oil extract (oil from Fructus Gardeniae [OFG]) might serve as a potential treatment for depression, whereas its pathogenesis still remained not fully understood. The present research was conducted to evaluate the anti-depressive effect of OFG in mice and explore its potential mechanism. The OFG and ketamine (KET) were intragastrically and intraperitoneally treated, respectively. Thereafter, the animals were subjected to the behavior tests. The expressions of protein kinase A (PKA), brain derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB) in hippocampus were detected by Western blot. The selective PKA inhibitor H-89 was also applied to confirm the mechanism. As a result, OFG and KET treatment improved the behavior performance. Furthermore, the administrations of OFG effectively enhanced the expressions of PKA, p-CREB, and BDNF. With the application of selective PKA inhibitor H-89, the ameliorated effects caused by OFG were blocked, but not by KET. In conclusion, the presented work indicated that OFG-exerted protective effect on depression through PKA-CREB-BDNF signaling.
- Published
- 2019
24. Chelerythrine Attenuates the Inflammation of Lipopolysaccharide-Induced Acute Lung Inflammation Through NF-κB Signaling Pathway Mediated by Nrf2
- Author
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Lu Fan, Ye Fan, Li Liu, Weiwei Tao, Xin Shan, Yu Dong, Lin Li, Sen Zhang, and Hanqing Wang
- Subjects
0301 basic medicine ,LPS ,Lipopolysaccharide ,Inflammation ,Lung injury ,Pharmacology ,medicine.disease_cause ,NF-κB ,Nrf2 ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Pharmacology (medical) ,Interleukin 6 ,chelerythrine ,Original Research ,biology ,lcsh:RM1-950 ,ALI ,lcsh:Therapeutics. Pharmacology ,030104 developmental biology ,Chelerythrine ,chemistry ,inflammation ,biology.protein ,Tumor necrosis factor alpha ,medicine.symptom ,Oxidative stress - Abstract
Chelerythrine (CH), is a kind of benzo[c] phenanthridine alkaloid isolated from plants such as Chelidonium, with pharmacological activities as antitumor, antibiosis and anti-inflammation. However, few studies have demonstrated whether CH could protect against lipopolysaccharide (LPS)-induced acute lung injury (ALI), and the underlying mechanism is also uncertain. The purpose of the present study was to investigate the anti-inflammatory effects of CH on LPS-induced ALI in mice and in RAW264.7 cells. In this study, we demonstrated that treatment with CH significantly ameliorated LPS-induced pathological changes in the lung. CH also attenuated LPS-induced W/D ratio, inflammatory cell infiltration. Meanwhile, LPS-induced Tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β) production and oxidative stress were markedly suppressed by CH. Furthermore, western blot showed that CH suppressed LPS-stimulated inflammation of RAW264.7 cells through activation of nuclear factor kappa-B (NF-κB) pathway. Knocking down of nuclear factor erythroid 2-related factor 2 (Nrf2) led to the reduction of nuclear translocation of the NF-κB p65, which triggered inflammation. These experimental results provided evidence that CH could be a potential therapeutic candidate for the intervention of ALI caused by LPS.
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- 2018
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25. Ginkgolide B treatment regulated intestinal flora to improve high-fat diet induced atherosclerosis in ApoE−/− mice
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Xin Shan, Jie Wang, Jing Chen, Zhiyang Lv, Yuwei Yang, and Qingbo Tu
- Subjects
Male ,0301 basic medicine ,Mice, Knockout, ApoE ,TMA/TMAO ,Pharmacology ,Gut flora ,Lactones ,Mice ,0302 clinical medicine ,RNA, Ribosomal, 16S ,Bacteroides ,Helicobacter ,biology ,Ginkgo biloba ,High fat diet ,FMO3 ,digestive, oral, and skin physiology ,General Medicine ,Ginkgolide B ,Plaque, Atherosclerotic ,030220 oncology & carcinogenesis ,Oxygenases ,medicine.symptom ,Inflammation ,RM1-950 ,Diet, High-Fat ,Methylamines ,03 medical and health sciences ,Intestinal flora ,Fibrinolytic Agents ,medicine ,Animals ,Humans ,Gene ,Lipid metabolism ,Atherosclerosis ,Lipid Metabolism ,biology.organism_classification ,medicine.disease ,Hypoglycemia ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,Disease Models, Animal ,Ginkgolides ,030104 developmental biology ,Phthalic Anhydrides ,Therapeutics. Pharmacology ,Dyslipidemia - Abstract
Intestinal flora plays a major role in cardiovascular diseases, like atherosclerosis (AS). Ginkgolide B (GB), a natural substance extracted from Ginkgo biloba L., is recently acknowledged as a potential therapeutic drug of AS. However, the underlying mechanism of GB is not fully clear. Thus, we evaluated whether the antiatherosclerotic effect of GB was related to alterations in gut microbial structure and if so, whether specific bacterial taxa contributed to the beneficial effects of GB. We constructed a high fat diet (HFD)-induced ApoE−/− mice model to explore the antiatherosclerotic effects of GB. The effects of GB on lipid metabolism, hypoglycemia, inflammation and gut barrier integrity were also investigated. Then HFD inventories and high throughput sequencing of the V3-V4 region of the bacterial 16S ribosomal RNA gene were used to characterize how GB modulated gut microbiome composition. We found that HFD-induced dyslipidemia, inflammation, increased atherosclerotic plaque and gut barrier dysfunction were reduced by GB treatment. Moreover, GB treatment obviously inhibited the mRNA level and protein expression of FMO3, and then decreased the concentrations of TMA and TMAO, which was related to changes of gut microbiota in HFD-fed mice. Modulation of gut microbiota, specifically the increased abundance of Bacteroides and decreased abundance of Helicobacter, might contribute to the antiatherosclerotic effects of GB. Our findings first support the therapeutic value of GB on gut microbiota manipulation in treating AS, which still need to further study.
- Published
- 2021
26. Study on the attenuated effect of Ginkgolide B on ferroptosis in high fat diet induced nonalcoholic fatty liver disease
- Author
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Xin Shan, Yuwei Yang, Jie Wang, Qin Gao, Zhiyang Lv, and Jing Chen
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,NF-E2-Related Factor 2 ,Diet, High-Fat ,Toxicology ,GPX4 ,medicine.disease_cause ,Lipid peroxidation ,Palmitic acid ,Lactones ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Fibrinolytic Agents ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Ferroptosis ,Humans ,Mice, Knockout ,chemistry.chemical_classification ,biology ,Chemistry ,Lipid metabolism ,Hep G2 Cells ,medicine.disease ,Mice, Inbred C57BL ,Ferritin ,Oxidative Stress ,Ginkgolides ,030104 developmental biology ,Endocrinology ,Transferrin ,biology.protein ,Lipid Peroxidation ,030217 neurology & neurosurgery ,Oxidative stress - Abstract
Ginkgolide B (GB), a main constituent of Ginkgo biloba extracts, reduces hepatic lipid accumulation and ameliorates nonalcoholic fatty liver disease (NAFLD) in obese mice, but the potential mechanism is unclear. Here we investigated the attenuated effects of GB on the disorder of lipid metabolism, oxidative stress and iron deposition in NAFLD and its potential mechanism associated with ferroptosis. Our preliminary research focused on high fat diet (HFD)-induced ApoE-/-mice gavaged with GB (20 and 30 mg kg-1•d-1, approximately equal to the human dose of 2 and 3 mg kg-1•d-1, respectively) and palmitic acid and oleic acid (PA/OA)-induced HepG2 cells treated with GB (4, 8, 16 μg/mL), respectively. Hepatic injury was assessed via biochemical, histopathological and immunohistochemical evaluations. In order to examine the mechanism of GB on ferroptosis-regulated pathway, we analyzed the expression levels of ferroptosis-related proteins, including nuclear factor erythroid 2 (Nrf2), glutathione peroxidase 4 (GPX4), heme oxygenase-1 (HO-1), transferrin receptor-1 (TFR1) and ferritin heavy chain-1 (FTH1) in vivo and vitro experiments by Western blotting. In order to further verify the correlation pathway of ferroptosis, after Nrf2 short hairpin RNA interference, we analyzed the effects of GB on Nrf2 pathway. Both HFD-fed mice and PA/OA-induced HepG2 cells displayed ferroptosis-based panel of biomarkers such as iron overload with the up-regulation of TFR1 and the down-regulation of FTH1, lipid peroxidation and inhibition of Nrf2 activity, which further induced GPX4 and HO-1 levels. Remarkably, after Nrf2 interference, GB treatment significantly increased Nrf2 expression, indicating that GB exerted anti-ferroptosis effects by activation of Nrf2 pathway. Our results are preliminarily illustrated that GB treatment has a specific effect on lipid accumulation and oxidative stress caused ferroptosis in NAFLD, possibly through Nrf2 signaling pathway.
- Published
- 2020
27. Altering the Specificity of the Antibody Response to HIV gp120 with a Glycoconjugate Antigen
- Author
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Canjia Zhai, Xin-Shan Ye, Chang-Cheng Liu, and Xiu-Jing Zheng
- Subjects
0301 basic medicine ,Glycan ,Glycoconjugate ,Oligosaccharides ,HIV Antibodies ,HIV Envelope Protein gp120 ,01 natural sciences ,Biochemistry ,Epitope ,Mannans ,Affinity maturation ,Epitopes ,03 medical and health sciences ,Antigen ,Animals ,Antigens ,AIDS Vaccines ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Vaccines, Synthetic ,biology ,010405 organic chemistry ,Antibodies, Monoclonal ,Serum Albumin, Bovine ,General Medicine ,HIV envelope protein ,Antibodies, Neutralizing ,Virology ,0104 chemical sciences ,030104 developmental biology ,Immunization ,chemistry ,Antibody Formation ,Immunology ,biology.protein ,Molecular Medicine ,Cattle ,Female ,Antibody ,Glycoconjugates ,Broadly Neutralizing Antibodies - Abstract
Some conserved glycans on the HIV envelope protein are targets of broadly neutralizing antibodies (bnAbs) of HIV. BnAbs provide a precise definition of broadly neutralizing epitopes on the envelope protein of HIV. These epitopes are promising for vaccine design. Many glycan-related antigens with high affinity to bnAbs have been tested as immunogens in vivo. However, it was found that no bnAb-like antibodies were induced. Vaccination with different immunogens containing the same neutralizing epitope may enhance the affinity maturation of antibodies which focus on the shared epitope. This combined immunization strategy showed great potential in peptide epitope-based vaccine design. However, it has not yet been explored on glycan-related epitopes to date. Herein, we take 2G12 as a model to validate this strategy on glycan-related epitopes. A high-affinity antigen of 2G12 was constructed by conjugating the D1 arm tetramannoside to bovine serum albumin. Then, the glycoconjugate was coimmunized with a recombinant gp120, which was expected to selectively benefit the induction of antibodies recognizing the neutralizing epitope of 2G12 on gp120. Mice were inoculated with the two antigens simultaneously or alternately to determine the suitable regimen for this strategy. The serological assays demonstrated that the antibody titers and subtypes responded to the whole gp120 were not improved, and the proportion of antibodies competitively bound to the 2G12 epitope was not enhanced significantly either. However, the coimmunized glycoconjugate selectively raised the proportion of antibodies recognizing D1 arm tetramannoside-related structures on gp120. These results provide important experience for the design of glycan-dependent bnAb-based vaccines.
- Published
- 2016
28. Synthesis and immunological evaluation of MUC1 glycopeptide conjugates bearing N-acetyl modified STn derivatives as anticancer vaccines
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Chengcheng Song, Xiu-Jing Zheng, An Xiao, Xin-Shan Ye, Yue Gui, and Chang-Xin Huo
- Subjects
Synthetic vaccine ,010402 general chemistry ,Cancer Vaccines ,digestive system ,01 natural sciences ,Biochemistry ,Mice ,Antigen ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,Antigens, Tumor-Associated, Carbohydrate ,Physical and Theoretical Chemistry ,skin and connective tissue diseases ,neoplasms ,MUC1 ,chemistry.chemical_classification ,Mice, Inbred BALB C ,biology ,010405 organic chemistry ,Chemistry ,Immune Sera ,Immunogenicity ,Mucin-1 ,Organic Chemistry ,Glycopeptides ,digestive system diseases ,biological factors ,Glycopeptide ,0104 chemical sciences ,Hemocyanins ,biology.protein ,Female ,Immunization ,Antibody ,Glycoprotein ,Keyhole limpet hemocyanin - Abstract
Glycoprotein MUC1 is an attractive target for anti-tumor vaccine development. However, the weak immunogenicity of MUC1 remains a significant problem. To solve this problem, several STn derivatives with N-acetyl modifications were synthesized and incorporated into a 20-amino acid MUC1 tandem repeat sequence. The modified STn-MUC1 glycopeptides were further connected to a carrier protein keyhole limpet hemocyanin (KLH). The immunological effects of these synthetic vaccine conjugates were evaluated using the BALB/c mouse model. The results showed that vaccine V2 elicited higher titers of antibodies which cross-reacted with the native STn-MUC1 antigen. Moreover, the elicited antisera reacted with the STn-MUC1 antigen-positive tumor cells, indicating that the carbohydrate antigen modification strategy may hold potential to overcome the weak immunogenicity of natural MUC1 glycopeptides.
- Published
- 2016
29. Macrophage migration inhibitory factor promotes expression of GLUT4 glucose transporter through MEF2 and Zac1 in cardiomyocytes
- Author
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Zhi-Xin Shan, Xi-Yong Yu, Yong-Heng Fu, Shulin Wu, Weiwei Yuan, Xiao Zou, Yeyou Liang, Jie-Ning Zhu, Min Yang, Chun-Yu Deng, Xi-Long Zheng, Qiu-Xiong Lin, and Wensi Zhu
- Subjects
Male ,Mef2 ,medicine.medical_specialty ,Diabetic Cardiomyopathies ,Endocrinology, Diabetes and Metabolism ,Cell Cycle Proteins ,chemical and pharmacologic phenomena ,AMP-Activated Protein Kinases ,Biology ,Ventricular Function, Left ,Mice ,Endocrinology ,AMP-activated protein kinase ,Internal medicine ,otorhinolaryngologic diseases ,medicine ,Animals ,Genes, Tumor Suppressor ,Myocytes, Cardiac ,Macrophage Migration-Inhibitory Factors ,Protein kinase B ,Transcription factor ,Cells, Cultured ,Glucose Transporter Type 4 ,MEF2 Transcription Factors ,Histocompatibility Antigens Class II ,Glucose transporter ,AMPK ,musculoskeletal system ,Receptor, Insulin ,Antigens, Differentiation, B-Lymphocyte ,Intramolecular Oxidoreductases ,Mice, Inbred C57BL ,biology.protein ,Macrophage migration inhibitory factor ,hormones, hormone substitutes, and hormone antagonists ,GLUT4 ,Transcription Factors - Abstract
Objective Evidence shows that both macrophage migration inhibitory factor (MIF) and GLUT4 glucose transporter are involved in diabetic cardiomyopathy (DCM), but it remains largely unknown whether and how MIF regulates GLUT4 expression in cardiomyocytes. The present study aims to investigate the mechanism underlying the modulation of GLUT4 by MIF in cardiomyocytes. Material and methods Activations of AKT and AMPK signaling, and expressions of MIF, GLUT4 and the candidate GLUT4 regulation associated transcription factors in the diabetic mouse myocardium were determined. The screened transcription factors mediating MIF-promoted GLUT4 expression were verified by RNA interference (RNAi) and electrophoretic mobility shift assay (EMSA), respectively. Results MIF was increased, but GLUT4 was decreased in the diabetic mouse myocardium. MIF could enhance glucose uptake and up-regulate GLUT4 expression in NMVCs. Expressions of transcription factor MEF2A, -2C, -2D and Zac1 were significantly up-regulated in MIF-treated neonatal mouse ventricular cardiomyocytes (NMVCs), and markedly reduced in the diabetic myocardium. Knockdown of MEF2A, -2C, -2D and Zac1 could significantly inhibit glucose uptake and GLUT4 expression in cardiomyocytes. Moreover, EMSA results revealed that transcriptional activities of MEF2 and Zac1 were significantly increased in MIF-treated NMVCs. AMPK signaling was activated in MIF-stimulated NMVCs, and AMPK activator AICAR could enhance MEF2A, -2C, -2D, Zac1 and GLUT4 expression. Additionally, MIF effects were inhibited by an AMPK inhibitor compound C and siRNA targeting MIF receptor CD74, suggesting the involvement of CD74-dependent AMPK activation. Conclusions Transcription factor MEF2 and Zac1 mediate MIF-induced GLUT4 expression through CD74-dependent AMPK activation in cardiomyocytes.
- Published
- 2015
30. Frontispiece: Synthetic Glycans and Glycomimetics: A Promising Alternative to Natural Polysaccharides
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Gao-Lan Zhang and Xin-Shan Ye
- Subjects
chemistry.chemical_classification ,Glycan ,chemistry ,biology ,Biochemistry ,Glycomimetic ,Organic Chemistry ,biology.protein ,General Chemistry ,Oligosaccharide ,Polysaccharide ,Catalysis - Published
- 2018
31. Rational Design of Dimeric Lysine N-Alkylamides as Potent and Broad-Spectrum Antibacterial Agents
- Author
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Jianfeng Cai, Jianxing Hu, Yan-Fen Wu, Youhong Niu, Alekhya Nimmagadda, Cao Yafei, Xin-Shan Ye, and Minghui Wang
- Subjects
0301 basic medicine ,Staphylococcus aureus ,Gram-negative bacteria ,Cell Membrane Permeability ,Drug resistance ,Microbial Sensitivity Tests ,Gram-Positive Bacteria ,01 natural sciences ,Hemolysis ,Bacterial cell structure ,03 medical and health sciences ,chemistry.chemical_compound ,Antibiotic resistance ,Drug Resistance, Multiple, Bacterial ,Drug Discovery ,Gram-Negative Bacteria ,Escherichia coli ,Humans ,biology ,010405 organic chemistry ,Chemistry ,Lysine ,Rational design ,biology.organism_classification ,Small molecule ,Amides ,0104 chemical sciences ,Anti-Bacterial Agents ,030104 developmental biology ,Biochemistry ,Biofilms ,Drug Design ,Molecular Medicine ,Lead compound ,Bacteria - Abstract
Antibiotic resistance is one of the biggest threats to public health, and new antibacterial agents hence are in an urgent need to combat infectious diseases caused by multidrug-resistant (MDR) pathogens. Utilizing dimerization strategy, we rationally designed and efficiently synthesized a new series of small molecule dimeric lysine alkylamides as mimics of AMPs. Evaluation of these mimics against a panel of Gram-positive and Gram-negative bacteria including MDR strains was performed, and a broad-spectrum and potent compound 3d was identified. This compound displayed high specificity toward bacteria over mammalian cell. Time-kill kinetics and mechanistic studies suggest that compound 3d quickly eliminated bacteria in a bactericidal mode by disrupting bacterial cell membrane. In addition, lead compound 3d could inhibit biofilm formation and did not develop drug resistance in S. aureus and E. coli over 14 passages. These results suggested that dimeric lysine nonylamide has immense potential as a new type of novel small molecular agent to combat antibiotic resistance.
- Published
- 2018
32. Synthetic Glycans and Glycomimetics: A Promising Alternative to Natural Polysaccharides
- Author
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Xin-Shan Ye and Gao-Lan Zhang
- Subjects
Glycan ,Biocompatible Materials ,010402 general chemistry ,Polysaccharide ,01 natural sciences ,Catalysis ,Glycomimetic ,Polysaccharides ,medicine ,Carbohydrate Conformation ,Animals ,chemistry.chemical_classification ,Vaccines, Synthetic ,biology ,Bacteria ,010405 organic chemistry ,Heparin ,Organic Chemistry ,Polysaccharides, Bacterial ,Anticoagulants ,General Chemistry ,Oligosaccharide ,Carbohydrate ,0104 chemical sciences ,chemistry ,Biochemistry ,biology.protein ,Carbohydrate conformation ,Conjugate ,medicine.drug - Abstract
A large quantity of polysaccharide-derived conjugate vaccines have been developed to combat various pathogenic infections. Another prominent polysaccharide, heparin, is listed as an essential drug by the World Health Organization (WHO) to treat thrombus. One of their common problems is that they all derive from natural polysaccharides. Specifically, capsular polysaccharides are mainly obtained from bacterial fermentation and unfractionated heparin is extracted from animal tissues such as porcine mucosa. The quality of natural polysaccharides is inconsistent and traces of contamination would cause a disaster. By contrast, the use of chemical or chemoenzymatic methods could provide structurally homogeneous and quality-controlled glycans. To date, large numbers of polysaccharide fragments and their analogues have been synthesized and evaluated. Some of them even showed comparable activities to their corresponding natural polysaccharides. Here, the latest advances in these synthetic glycan analogues ranging from carbohydrate-based vaccines, heparin-related therapeutics and glycomimetics of polysaccharides are summarized.
- Published
- 2017
33. Activation of miR-34a-5p/Sirt1/p66shc pathway contributes to doxorubicin-induced cardiotoxicity
- Author
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Zhi-Xin Shan, Deming Gou, Chun-Mei Tang, Yong-Heng Fu, Jie-Ning Zhu, Shulin Wu, Qiu-Xiong Lin, Hong-Wen Fei, Zhi-Qin Hu, Wen-Yu Li, and Hui Yang
- Subjects
Male ,0301 basic medicine ,Src Homology 2 Domain-Containing, Transforming Protein 1 ,lcsh:Medicine ,Pharmacology ,Article ,Cell Line ,Rats, Sprague-Dawley ,03 medical and health sciences ,Sirtuin 1 ,microRNA ,medicine ,Animals ,Humans ,Doxorubicin ,lcsh:Science ,Cardiotoxicity ,Multidisciplinary ,biology ,business.industry ,Myocardium ,lcsh:R ,medicine.disease ,Rats ,Lymphoma ,MicroRNAs ,030104 developmental biology ,Cell culture ,Apoptosis ,biology.protein ,lcsh:Q ,Female ,Lymphoma, Large B-Cell, Diffuse ,Signal transduction ,business ,Signal Transduction ,medicine.drug - Abstract
The molecular mechanisms underlying anthracyclines-induced cardiotoxicity have not been well elucidated. MiRNAs were revealed dysregulated in the myocardium and plasma of rats received Dox treatment. MicroRNA-34a-5p (miR-34a-5p) was verified increased in the myocardium and plasma of Dox-treated rats, but was reversed in rats received Dox plus DEX treatments. Human miR-34a-5p was also observed increased in the plasma of patients with diffuse large B-cell lymphoma after 9- and 16-week epirubicin therapy. Up-regulation of miR-34a-5p was observed in Dox-induced rat cardiomyocyte H9c2 cells. MiR-34a-5p could augment Bax expression, but inhibited Bcl-2 expression, along with the increases of the activated caspase-3 and mitochondrial potentials in H9C2 cells. MiR-34a-5p was verified to modulate Sirt1 expression post-transcriptionally. In parallel to Sirt1 siRNA, miR-34a-5p could enhance p66shc expression, accompanied by increases of Bax and the activated caspase-3 and a decrease of Bcl-2 in H9c2 cells. Moreover, enforced expression of Sirt1 alleviated Dox-induced apoptosis of H9c2 cells, with suppressing levels of p66shc, Bax, the activated caspase-3 and miR-34a-5p, and enhancing Bcl-2 expression. Therefore, miR-34a-5p enhances cardiomyocyte apoptosis by targeting Sirt1, activation of miR-34a-5p/Sirt1/p66shc pathway contributes to Dox-induced cardiotoxicity, and blockage of this pathway represents a potential cardioprotective effect against anthracyclines.
- Published
- 2017
34. Attenuation of micro <scp>RNA</scp> ‐16 derepresses the cyclins D1, D2 and E1 to provoke cardiomyocyte hypertrophy
- Author
-
Su-juan Kuang, Jie-Ning Zhu, Xi-Long Zheng, Qiu-Xiong Lin, Yeyou Liang, Meng-Zhen Zhang, Yong-Heng Fu, Zhi-Xin Shan, Yulin Liao, Xiao Zou, Shuai Huang, Chun-Yu Deng, and Xi-Yong Yu
- Subjects
Male ,STAT3 Transcription Factor ,medicine.medical_specialty ,cardiomyocyte ,Cardiomegaly ,Endogeny ,retinoblastoma protein ,Cell Line ,Muscle hypertrophy ,Proto-Oncogene Proteins c-myc ,Rats, Sprague-Dawley ,Mice ,Phenylephrine ,cyclin ,microRNA-16 ,Cyclins ,Internal medicine ,microRNA ,medicine ,Animals ,Cyclin D2 ,Humans ,Cyclin D1 ,Myocytes, Cardiac ,Aorta, Abdominal ,Phosphorylation ,Cyclin ,biology ,business.industry ,Activator (genetics) ,cardiac hypertrophy ,Retinoblastoma protein ,Original Articles ,Cell Biology ,Rats ,Cell biology ,Enzyme Activation ,Mice, Inbred C57BL ,Disease Models, Animal ,MicroRNAs ,HEK293 Cells ,Endocrinology ,cardiovascular system ,biology.protein ,Molecular Medicine ,business ,medicine.drug - Abstract
Cyclins/retinoblastoma protein (pRb) pathway participates in cardiomyocyte hypertrophy. MicroRNAs (miRNAs), the endogenous small non-coding RNAs, were recognized to play significant roles in cardiac hypertrophy. But, it remains unknown whether cyclin/Rb pathway is modulated by miRNAs during cardiac hypertrophy. This study investigates the potential role of microRNA-16 (miR-16) in modulating cyclin/Rb pathway during cardiomyocyte hypertrophy. An animal model of hypertrophy was established in a rat with abdominal aortic constriction (AAC), and in a mouse with transverse aortic constriction (TAC) and in a mouse with subcutaneous injection of phenylephrine (PE) respectively. In addition, a cell model of hypertrophy was also achieved based on PE-promoted neonatal rat ventricular cardiomyocyte and based on Ang-II-induced neonatal mouse ventricular cardiomyocyte respectively. We demonstrated that miR-16 expression was markedly decreased in hypertrophic myocardium and hypertrophic cardiomyocytes in rats and mice. Overexpression of miR-16 suppressed rat cardiac hypertrophy and hypertrophic phenotype of cultured cardiomyocytes, and inhibition of miR-16 induced a hypertrophic phenotype in cardiomyocytes. Expressions of cyclins D1, D2 and E1, and the phosphorylated pRb were increased in hypertrophic myocardium and hypertrophic cardiomyocytes, but could be reversed by enforced expression of miR-16. Cyclins D1, D2 and E1, not pRb, were further validated to be modulated post-transcriptionally by miR-16. In addition, the signal transducer and activator of transcription-3 and c-Myc were activated during myocardial hypertrophy, and inhibitions of them prevented miR-16 attenuation. Therefore, attenuation of miR-16 provoke cardiomyocyte hypertrophy via derepressing the cyclins D1, D2 and E1, and activating cyclin/Rb pathway, revealing that miR-16 might be a target to manage cardiac hypertrophy.
- Published
- 2015
35. Synthetic and immunological studies of N-acyl modified S-linked STn derivatives as anticancer vaccine candidates
- Author
-
Chang-Cheng Liu, Xiu-Jing Zheng, Xin-Shan Ye, An Xiao, Chang-Xin Huo, Shuang Sun, and Zhuo Lv
- Subjects
Male ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Glycan ,biology ,Glycoconjugate ,Carbohydrate chemistry ,Immunogenicity ,Organic Chemistry ,Cancer Vaccines ,Biochemistry ,Antigen ,chemistry ,biology.protein ,Animals ,Antigens, Tumor-Associated, Carbohydrate ,Female ,Immunization ,Physical and Theoretical Chemistry ,Antibody ,Glycoconjugates ,Keyhole limpet hemocyanin ,Conjugate - Abstract
It is well known that tumor cells express some aberrant glycans, termed tumor-associated carbohydrate antigens (TACAs). TACAs are good targets for the development of carbohydrate-based anticancer vaccines. However, one of the major problems is that carbohydrate antigens possess a weak immunogenicity. To tackle this problem, a number of unnatural N-modified S-linked STn analogues were designed and prepared. Reaction of the modified STn disaccharides with bifunctional adipic acid p-nitrophenyl diester provided the corresponding activated esters, which was followed by the conjugation with keyhole limpet hemocyanin (KLH), affording the corresponding protein conjugates. The immunological properties of these glycoconjugates were evaluated in a mouse model. The results showed that the modified glycoconjugates stimulated the production of IgG antibodies that are capable of recognizing the naturally occurring STn antigen, helping the discovery of carbohydrate-based anticancer vaccine candidates.
- Published
- 2015
36. Rapid probing of sialylated glycoproteins in vitro and in vivo via metabolic oligosaccharide engineering of a minimal cyclopropene reporter
- Author
-
Yang Yu, Hui-Xin Luo, Xin-Shan Ye, Cong Wang, Jingjing Zhu, De-Cai Xiong, Guihua Tai, Yuqian Ye, and Ming-Jie Han
- Subjects
Cyclopropanes ,Glycan ,Oligosaccharides ,Biochemistry ,Metabolic engineering ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Labelling ,Animals ,Humans ,Physical and Theoretical Chemistry ,Glycoproteins ,chemistry.chemical_classification ,Staining and Labeling ,biology ,Organic Chemistry ,Oligosaccharide ,N-Acetylneuraminic Acid ,Sialic acid ,Metabolic Engineering ,chemistry ,Molecular Probes ,biology.protein ,Bioorthogonal chemistry ,Glycoprotein - Abstract
ManNAc analogues are important chemical tools for probing sialylation dynamically via metabolic oligosaccharide engineering (MOE). The size of N-acyl and the nature of the chemical handle are two determinants of metabolic incorporation efficiency. We demonstrated a minimal, stable, bioorthogonal, and reactive N-Cp (N-(cycloprop-2-ene-1-ylcarbonyl)) group and the imaging of sialylated glycans using Ac4ManNCp in vitro and in vivo. The results revealed that the Cp group can efficiently be incorporated into the cellular sialic acid and detected rapidly by the reaction with FITC-Tz in different cells. The metabolic incorporation efficiency of non-cytotoxic Ac4ManNCp is not only superior to Ac4ManNMCp, but also superior to the widely-used Ac4ManNAz in some cell lines. Moreover, when Ac4ManNCp was administered to mice, a rapid and intense labelling of splenocytes as well as glycoproteins of sera and organs was observed. This is the first reported metabolic labelling of cyclopropene-modified sugars in vivo. Therefore, Ac4ManNCp is a powerful probe for efficient and rapid MOE and it may find wide applications in the labelling of glycans.
- Published
- 2015
37. Pilose antler peptide attenuates LPS-induced inflammatory reaction
- Author
-
Juanjuan Tang, Weiwei Tao, Li Liu, Yanyan Chen, Xin Shan, Baomei Xia, Yu Dong, and Xiaolan Cheng
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Lipopolysaccharides ,Cell Survival ,Inflammation ,Pharmacology ,Biochemistry ,Superoxide dismutase ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Structural Biology ,Malondialdehyde ,medicine ,Animals ,Protein kinase A ,Molecular Biology ,biology ,Superoxide Dismutase ,NF-kappa B ,NF-κB ,General Medicine ,Rats ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,biology.protein ,Cytokines ,Tumor necrosis factor alpha ,medicine.symptom ,Inflammation Mediators ,Mitogen-Activated Protein Kinases ,Peptides ,Nucleus ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
The present study was designed to study the effects of pilose antler peptide (PAP) on primary culture of nucleus pulposus cells in intervertebral disc. We demonstrated that PAP significantly inhibited lipopolysaccharides (LPS) induced over-production of inflammatory factors including interleukin-1β (IL-1β), tumor necrosis Factor-α (TNF-α) and interleukin-6 (IL-6) in nucleus pulposus cells. PAP also attenuated increase of malondialdehyde (MDA) and decrease of superoxide dismutase (SOD) induced by LPS challenge in a concentration-dependent manner. Moreover, the expression of the protein levels of mitogen-activated protein kinase (MAPK)/nuclear transcription factor-κB(NF-κB) were increased accompanying with the LPS challenge, which were significantly reversed after PAP treatment. Our results demonstrated the ability of PAP to antagonize LPS-mediated inflammation in primary culture of nucleus pulposus in intervertebral disc, suggesting a beneficial potential for its clinical application.
- Published
- 2017
38. Upscale production of a recombinant cyclodextrin glycosyltransferase from Paenibacillus macerans in Escherichia coli
- Author
-
Pi-Wu Wang, Wen-Xin Shan, and Yi-Nan Yang
- Subjects
Paenibacillus macerans ,chemistry.chemical_classification ,Cyclodextrin ,Cyclodextrin glycosyltransferase ,Environmental Science (miscellaneous) ,Biology ,medicine.disease_cause ,Agricultural and Biological Sciences (miscellaneous) ,carbohydrates (lipids) ,chemistry.chemical_compound ,chemistry ,Biochemistry ,Tryptone ,medicine ,Glycerol ,Yeast extract ,Original Article ,Fermentation ,Escherichia coli ,Biotechnology - Abstract
Cyclodextrin glucanotransferase (CGTase) is an important enzyme with multiple functions in starch utilization. In the present study, a fermentation process for the production of CGTase from Escherichia coli harboring the recombinant plasmid pET28b(+)-CGTase was investigated and optimized. The optimal fermentation and expression conditions were 10.0 g/L glycerol, 20.0 g/L tryptone, and 10.0 g/L yeast extract with an initial pH of 7.0, an IPTG concentration of 0.1 mM and an induction temperature of 28 °C for 10 h. The resulting CGTase activity reached up to 36.4 U/L and was 2.1-fold higher than before optimization. Under these optimal fermentation conditions, the up-scaled fermentation was carried out in a 500-L fermentor, and a CGTase activity of 45.2 U/L was achieved. This study provides a foundation for the industrial production of CGTase.
- Published
- 2017
39. Redirecting Killer T Cells through Incorporation of Azido Sugars for Tethering Ligands
- Author
-
Demin Zhou, Chuanling Zhang, Weiling Wang, Qing Xia, Zhiying Zhao, Xin-Shan Ye, Ziwei Zhang, Sulong Xiao, and Lihe Zhang
- Subjects
0301 basic medicine ,Glycan ,Azides ,Time Factors ,Cell Survival ,Integrin ,010402 general chemistry ,Ligands ,01 natural sciences ,Biochemistry ,03 medical and health sciences ,Jurkat Cells ,Folic Acid ,Polysaccharides ,Cell Line, Tumor ,Cytotoxic T cell ,Humans ,IL-2 receptor ,Cytotoxicity ,Molecular Biology ,biology ,Dose-Response Relationship, Drug ,Organic Chemistry ,Rational design ,Natural killer T cell ,Chimeric antigen receptor ,0104 chemical sciences ,030104 developmental biology ,biology.protein ,Sialic Acids ,Molecular Medicine ,Immunotherapy ,Oligopeptides ,T-Lymphocytes, Cytotoxic - Abstract
The genetic expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. To broaden the versatility of T cells as tumor-specific killers, we developed a non-genetic approach by which azide-containing sialic acids were metabolically incorporated to modify cellular sialyl glycans. Given displaying such a chemical moiety on T cells, small molecular ligands such as RGD and folate, as proof-of-concept, instead of supersized antibodies were clicked orthogonally, leading to highly selective, time- and dose-dependent cytotoxicity to integrin αvβ3- and folate receptor-positive cells, respectively. This chemical approach provided a facile platform for rational design of cytotoxic T cells for targeted immunotherapy.
- Published
- 2017
40. Cell cycle arrest, apoptosis and autophagy induced by iminosugars on K562 cells
- Author
-
Yifa Zhou, Xin-Shan Ye, Jingjing Zhu, Guan-Nan Wang, and Guihua Tai
- Subjects
Membrane Potential, Mitochondrial ,Pharmacology ,Programmed cell death ,Cell cycle checkpoint ,Autophagy ,G1 Phase ,Antineoplastic Agents ,Apoptosis ,Cell Cycle Checkpoints ,Cell cycle ,Biology ,Resting Phase, Cell Cycle ,Imino Sugars ,Cell biology ,Gene Expression Regulation, Neoplastic ,Heat shock protein ,Humans ,Signal transduction ,K562 Cells ,Protein kinase A ,Protein kinase B - Abstract
Iminosugars have gained a remarkable importance as new therapeutic agents since 1966. In this study, compounds A and B, two iminosugar analogs synthesized previously, showed an inhibition of the growth of K562 cells. They allowed cell cycle arrested at the G0/G1 phase, promoted apoptotic activities and also lowered the mitochondrial membrane potential. Further exploration of the apoptosis mechanism revealed that compound B significantly suppressed the expression of Hsp70, which is a major anti-apoptotic molecular chaperone. Significant decrease was also found in the expression of Akt, a serine/threonine-specific protein kinase with anti-apoptosis activities also known as protein kinase B (PKB). At mitochondria level in comparison with compound A, compound B brought a better promotion in the expression of pro-apoptotic protein Bad in Bcl-2 family. As a result of the promotion, the expression of anti-apoptotic protein Bcl-xL was down-regulated. Cytochrome c was released, activating the intrinsic signaling pathways of caspase and resulting in the occurrence of cascade reaction. In addition, compound B stimulated autophagy effectively by up-regulating Beclin 1, thus causing the conversion of LC3-I to LC3-II through Akt/mTOR signaling pathway. In summary, these results indicated that compounds A and B induced cell death through multiple pathways. The disclosed results not only provide an evidence of antitumor activity of iminosugars as a foundation for further studies, but also may find potential applications in chronic myeloid leukemia therapy as new heat shock protein inhibitors and autophagy inducer.
- Published
- 2014
41. Fn14 Promotes Differentiation of Human Mesenchymal Stem Cells into Heart Valvular Interstitial Cells by Phenotypic Characterization
- Author
-
Xi-Yong Yu, Xiaoying Liu, Wei Huang, Zhi-Xin Shan, Qiu-Xiong Lin, Yigang Wang, Yangxin Li, Min Yang, Jian Zhuang, and Ding-Zhang Xiao
- Subjects
Physiology ,Cellular differentiation ,Clinical Biochemistry ,Mesenchymal stem cell ,Cell ,Cell Biology ,Transfection ,Biology ,Cell biology ,Extracellular matrix ,medicine.anatomical_structure ,Cell culture ,Immunology ,medicine ,Bone marrow ,PI3K/AKT/mTOR pathway - Abstract
Despite the fact that tissue engineered heart valves (TEHV) hold great promise for heart valve disease treatment, one of the challenges is to find suitable seeding cells. Bone marrow derived mesenchymal stem cells (MSCs) were considered to be one of the best seed cell sources. In this study we propose a novel approach to promote stem cell differentiation into the seed cells of TEHV, valvular interstitial cells (VICs). Newly induced MSCs (iMSCs) were created from a co-culture niche in which healthy human donor derived MSCs were co-cultured with cardiac fibroblasts (H9C2 cell line). Then iMSCs were transfected with either a mock vector (iMSCs(mock) ) as controls or with a vector that overexpresses thefibroblast inducible factor 14 (Fn14) gene (iMSCs(Fn14) ). Immunofluorescence staining was performed to assay VIC differentiation. Western blot analysis was performed to analyze the involved signaling pathway. The results demonstrate that the expression of α-smooth muscle actin (SMA) was significantly higher in iMSCs(Fn14) as compared with iMSC(mock) , and MSC, and also had higher co-alignment of α-actinin and stress fiber (F-actin) in bundles. Additionally, increased biosynthesis of extracellular matrix (ECM) proteins including collagen I, collagen III, and fibronection were observed in iMSCs(Fn14) in comparison with iMSCs(mock) . These data observed in iMSCs(Fn14) were in accordance with VIC phenotype from normal heart valves. In addition, the PI3K/Akt signaling pathway was activated in iMSCs(Fn14) which allowed higher Akt phosphorylation (p-Akt) levels and SMA levels, whereas, it was attenuated by LY294002 (PI3K/Akt inhibitor). These new findings of the effect of Fn14 on VIC-like cell differentiation may provide a novel therapeutic strategy for heart valve disease treatment.
- Published
- 2014
42. Human Umbilical Cord Mesenchymal Stem Cells Infected with Adenovirus ExpressingHGFPromote Regeneration of Damaged Neuron Cells in a Parkinson’s Disease Model
- Author
-
Bing Han, Yuzhen Zhang, Xin-Shan Liu, Jin-Feng Li, Yutong Wang, Yun-Liang Wang, Hui-Cui Gong, Shuang Geng, Shanshan Wang, and Hong-Lei Yin
- Subjects
Article Subject ,Cell Survival ,Intracellular Space ,lcsh:Medicine ,Enzyme-Linked Immunosorbent Assay ,Cell Separation ,Biology ,medicine.disease_cause ,Models, Biological ,Neuroprotection ,General Biochemistry, Genetics and Molecular Biology ,Calcium in biology ,Adenoviridae ,Cell Line ,Umbilical Cord ,Transduction, Genetic ,medicine ,Humans ,Neurons ,General Immunology and Microbiology ,Hepatocyte Growth Factor ,Regeneration (biology) ,lcsh:R ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Parkinson Disease ,General Medicine ,Molecular biology ,Nerve Regeneration ,Cell biology ,Calbindin 1 ,Cell culture ,Culture Media, Conditioned ,Calcium ,Hepatocyte growth factor ,Intracellular ,Research Article ,medicine.drug - Abstract
Parkinson’s disease (PD) is a neurodegenerative movement disorder that is characterized by the progressive degeneration of the dopaminergic (DA) pathway. Mesenchymal stem cells derived from human umbilical cord (hUC-MSCs) have great potential for developing a therapeutic agent as such. HGF is a multifunctional mediator originally identified in hepatocytes and has recently been reported to possess various neuroprotective properties. This study was designed to investigate the protective effect of hUC-MSCs infected by an adenovirus carrying theHGFgene on the PD cell model induced by MPP+ on human bone marrow neuroblastoma cells. Our results provide evidence that the cultural supernatant from hUC-MSCs expressing HGF could promote regeneration of damaged PD cells at higher efficacy than the supernatant from hUC-MSCs alone. And intracellular free Ca2+obviously decreased after treatment with cultural supernatant from hUC-MSCs expressing HGF, while the expression of CaBP-D28k, an intracellular calcium binding protein, increased. Therefore our study clearly demonstrated that cultural supernatant of MSC overexpressingHGFwas capable of eliciting regeneration of damaged PD model cells. This effect was probably achieved through the regulation of intracellular Ca2+levels by modulating of CaBP-D28k expression.
- Published
- 2014
43. Design and synthesis of new KRN7000 analogues
- Author
-
Man Sun, Yuhang Wang, and Xin-Shan Ye
- Subjects
biology ,Stereochemistry ,medicine.medical_treatment ,Organic Chemistry ,Carbohydrate ,Biochemistry ,chemistry.chemical_compound ,Cytokine ,Glycolipid ,chemistry ,CD1D ,Galactose ,Drug Discovery ,medicine ,biology.protein ,Moiety ,Peptide bond ,Linker - Abstract
Presented by CD1d protein, KRN7000, a potent synthetic α-galactosylceramide, is known to stimulate the iNKT cells to produce different bioactive cytokines. Six new KRN7000 analogues, in which the amide bond in KRN7000 is replaced with O, NH, or ester groups incorporating variation of the acyl chain, or possessing an additional four-atom linker between the galactose and phytosphingosine moiety, were designed and synthesized. The synthetic compounds were evaluated for their ability to stimulate cytokine release and the preliminary structure–activity relationships were discussed. The synthetic strategy will benefit the construction of more KRN7000 derivatives, which may contribute to cytokine profile bias.
- Published
- 2013
44. Drying-Rewetting Effects on Soil Nitrogen and Enzyme Activities Dynamics
- Author
-
Deng Hua Yan, Xin Shan Song, Ying Ying Zheng, and Yuan Wang
- Subjects
Denitrifying bacteria ,Soil test ,biology ,Chemistry ,Environmental chemistry ,Soil organic matter ,biology.protein ,General Medicine ,Soil fertility ,Soil type ,Water content ,Humus ,Enzyme assay - Abstract
With climate changes, soil may experience frequent drying-rewetting events. Water stress influences soil nitrogen transformation by affecting microbial growth and enzyme activities. The objective of this study was to determine effects of drying-rewetting cycles on soil N transformations and enzyme activities involved. The results show high correlations between soil inorganic N (NH4+-N & NO3--N) concentrations and soil moisture. Drying and rewetting events contributed to the accumulation of NO3--N. There was a significant correlation between NH4+-N/TDN and urease activities with a correlation coefficient of 0.88. Denitrifying enzyme activity showed a high positive correlation with soil moisture.
- Published
- 2013
45. Synthesis and evaluation of glucosamine-6-phosphate analogues as activators of glmS riboswitch
- Author
-
Pui Sai Lau, Guan-Nan Wang, Xin-Shan Ye, and Yingfu Li
- Subjects
Riboswitch ,biology ,medicine.drug_class ,Organic Chemistry ,Antibiotics ,Ribozyme ,Bacillus subtilis ,Phosphate ,biology.organism_classification ,Biochemistry ,chemistry.chemical_compound ,Cell wall biosynthesis ,chemistry ,Glucosamine ,Drug Discovery ,medicine ,biology.protein ,Bacteria - Abstract
The glmS riboswitch is a ribozyme found in numerous Gram-positive bacteria and responds to the cellular concentrations of glucosamine 6-phosphate (GlcN6P). Given the importance of GlcN6P for cell wall biosynthesis, the glmS riboswitch has become a new drug target for the development of antibiotics. Herein, we describe the efficient synthesis of three GlcN6P analogues and their evaluation on inducing self-cleavage of the glmS riboswitch from Bacillus subtilis. Our results provide valuable information for further elucidation of the structure–activity relationships and drug design for glmS riboswitch antibiotics.
- Published
- 2012
46. Hsp90aa1: a novel target gene of miR-1 in cardiac ischemia/reperfusion injury
- Author
-
Ning Tan, Wei Guo, Jie ning Zhu, Chun Mei Tang, Zhi-Xin Shan, Wen si Zhu, Yong Heng Fu, and Qiu xiong Lin
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Time Factors ,Ischemia ,Apoptosis ,Myocardial Reperfusion Injury ,030204 cardiovascular system & hematology ,Article ,Andrology ,Rats, Sprague-Dawley ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,microRNA ,medicine ,Myocyte ,Animals ,Myocytes, Cardiac ,HSP90 Heat-Shock Proteins ,Psychological repression ,Multidisciplinary ,biology ,business.industry ,Myocardium ,medicine.disease ,Hsp90 ,Cardiovascular physiology ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Cardiology ,biology.protein ,business ,Reperfusion injury - Abstract
The role of microRNA-1 (miR-1) in ischemia/reperfusion (I/R)-induced injury is not well illustrated. The present study aimed to investigate the expression and potential target of miR-1 in the myocardium of a rat model of I/R. The apoptosis of cardiomyocytes in the ischemic rat myocardium increased on day 1, then attenuated on day 3 and day 7 post-I/R. Heat shot protein 90 (Hsp90) aa1 mRNA expression was decreased post-I/R and Hsp90aa1 protein level was decreased on day1 post-I/R, but was reversed on day 3 and day 7 post-I/R. MiR-1 was downregulated post-I/R and repression of miR-1 in cultured neonatal rat ventricular cells (NRVCs) led to an increase of Bcl-2 and decreases of Bax and active caspase-3. Dual luciferase reporter assays revealed that miR-1 interacted with the 310–315 nt site at the 3′UTR of Hsp90aa1 and miR-1 was verified to inhibit Hsp90aa1 expression at the posttranscriptional level. Over-expression of Hsp90aa1 could attenuate oxygen-glucose deprivation (OGD)-induced apoptosis of NRVCs. Additionally, miR-1 mimic, in parallel to Hsp90aa1 siRNA, could enhance OGD-induced apoptosis of NRVCs. Taken together, our results reveal that Hsp90aa1 is a novel target of miR-1 and repression of miR-1 may contribute to the recovery of Hsp90aa1 during myocardial I/R.
- Published
- 2016
47. ChemInform Abstract: Broadly Neutralizing Antibody-Guided Carbohydrate-Based HIV Vaccine Design: Challenges and Opportunities
- Author
-
Chang-Cheng Liu, Xiu-Jing Zheng, and Xin-Shan Ye
- Subjects
Affinity maturation ,Antigenicity ,Chronic infection ,Immune system ,Immunization ,biology ,Antigen ,Chemistry ,biology.protein ,General Medicine ,HIV vaccine ,Antibody ,Virology - Abstract
The HIV envelope (Env) is heavily glycosylated, facilitating the spread and survival of HIV in many ways. Some potent broadly neutralizing antibodies (bnAbs) such as 2G12, PG9, PG16, and PGTs can recognize the conserved glycan residues on Env. The bnAbs, which often emerge after many years of chronic infection, provide insight into the vulnerability of HIV and can therefore guide the design of vaccines. Many carbohydrate-conjugated vaccines have been designed to induce bnAb-like antibodies, but none have yet been successful. The low antigenicity of these vaccines is one possible explanation. New strategies have been applied to obtain high-affinity antigens of glycan-dependent and other bnAbs. However, when used as immunogens in vivo, high-affinity antigens are still insufficient in eliciting bnAb-like antibodies. bnAbs generally possess some unusual features and may therefore be suppressed by the host immune system. In view of this situation, some immunization regimens based on the affinity maturation of antibodies have been tested. Herein we summarize recent studies into the design of carbohydrate-based HIV vaccines and some valuable experiences gained in work with other bnAb-based HIV vaccines.
- Published
- 2016
48. Synthesis and Evaluation of Glycoconjugates Comprising N-Acyl-Modified Thomsen-Friedenreich Antigens as Anticancer Vaccines
- Author
-
Chengcheng Song, Xin-Shan Ye, Shuang Sun, Xiu-Jing Zheng, Chang-Xin Huo, and Qin Li
- Subjects
Cellular immunity ,Glycoconjugate ,Cell Survival ,Lymphocyte ,Biology ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Cancer Vaccines ,Cell Line ,Mice ,Antigen ,Bacterial Proteins ,Drug Discovery ,medicine ,Animals ,Antigens, Tumor-Associated, Carbohydrate ,Lymphocytes ,General Pharmacology, Toxicology and Pharmaceutics ,Pharmacology ,chemistry.chemical_classification ,Antiserum ,Diphtheria toxin ,Mice, Inbred BALB C ,010405 organic chemistry ,Immunogenicity ,Organic Chemistry ,Molecular biology ,0104 chemical sciences ,medicine.anatomical_structure ,chemistry ,Immunoglobulin G ,biology.protein ,Molecular Medicine ,Female ,Antibody ,Glycoconjugates - Abstract
Thomsen-Friedenreich (TF) antigen is an important tumor-associated carbohydrate antigen. Its low immunogenicity, however, limits its application in the development of anticancer vaccines. To solve this problem, several N-acyl-modified TF derivatives were synthesized and conjugated with carrier protein CRM197 (a mutated diphtheria toxoid cross-reactive material). The immunological results in BALB/c mice demonstrated that these modified TF antigen conjugates could stimulate the production of higher titers of IgG antibodies that cross-reacted with native TF antigen. These glycoconjugates showed strong lymphocyte proliferative response, suggesting that they can induce cellular immunity. Furthermore, the elicited antisera reacted strongly with TF-positive tumor cells (4T1). In particular, the N-monofluoroacetyl-modified TF conjugate 4-CRM197 showed the strongest complement-dependent cytotoxicity effect against 4T1 cells, implying the potential of this glycoconjugate as an anticancer vaccine.
- Published
- 2016
49. Crocetin ester improves myocardial ischemia via Rho/ROCK/NF-κB pathway
- Author
-
Zhiheng Huang, Wang Hanqing, Weiwei Tao, Wenda Xue, Gang Chen, Xin Shan, Jin-Ao Duan, Qiang Su, Yanyan Chen, and Chen Nan
- Subjects
0301 basic medicine ,Immunology ,Crocetin ,SOD1 ,Myocardial Ischemia ,Pharmacology ,Gardenia jasminoides ,Superoxide dismutase ,Rats, Sprague-Dawley ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Superoxide Dismutase-1 ,Lactate dehydrogenase ,Immunology and Allergy ,Animals ,Vitamin A ,Creatine Kinase ,rho-Associated Kinases ,biology ,Chemistry ,Myocardium ,NF-kappa B ,Heart ,Malondialdehyde ,biology.organism_classification ,Crocus ,Carotenoids ,Rats ,030104 developmental biology ,Biochemistry ,030220 oncology & carcinogenesis ,biology.protein ,Cytokines ,Creatine kinase ,Dismutase ,Inflammation Mediators ,Signal Transduction - Abstract
Crocetin ester (CE) is the active ingredient of Crocus sativus L. stigmas and Gardenia jasminoides Ellis fruit. The main purpose of the present study was to investigate the protective effect of CE on isoproterenol (ISO)-induced acute myocardial ischemia (AMI) through Rho/ROCK/NF-κB pathway and explore its underlying mechanism. Administration of CE (25 and 50 mg/kg) could significantly reduce the serum contents of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6). In addition, pretreatment with CE attenuated the contents of creatine kinase (CK), malondialdehyde (MDA) and the activities of lactate dehydrogenase (LDH), superoxide dismutase (SOD) in serum. Treatment with CE also improved the histopathological alteration and decreased the ST elevation. Furthermore, CE could ameliorate the cardiac expressions of Cu, Zn-superoxide dismutase (SOD1), MDA5, Rho, ROCK, p-IκB and p-NF-κBp65 in ISO-induced rats. It was assumed that CE might be a new therapeutic candidate for the treatment of AMI possibly through the inhibition of Rho/ROCK/NF-κB pathway.
- Published
- 2016
50. High levels of glucose induce 'metabolic memory' in cardiomyocyte via epigenetic histone H3 lysine 9 methylation
- Author
-
Xi Yong Yu, Zhi-Xin Shan, Shu Guang Lin, Saidan Zhang, Yong-Jian Geng, Jia Liang Liang, Yangxin Li, Qiu Xiong Lin, He Ping Lei, and Shi Long Zhong
- Subjects
medicine.medical_specialty ,Methyltransferase ,Epigenetics in learning and memory ,Biology ,Methylation ,Chromatin remodeling ,Cell Line ,Epigenesis, Genetic ,Histones ,Histone H3 ,Internal medicine ,Histone methylation ,Genetics ,medicine ,Humans ,Myocytes, Cardiac ,Epigenetics ,Promoter Regions, Genetic ,Molecular Biology ,Cells, Cultured ,Inflammation ,Interleukin-6 ,Lysine ,General Medicine ,Molecular biology ,Chromatin ,Glucose ,Endocrinology ,Gene Expression Regulation ,Cytokines ,Inflammation Mediators ,Chromatin immunoprecipitation - Abstract
Diabetic patients continue to develop inflammation and cardiovascular complication even after achieving glycemic control, suggesting a "metabolic memory". Metabolic memory is a major challenge in the treatment of diabetic complication, and the mechanisms underlying metabolic memory are not clear. Recent studies suggest a link between chromatin histone methylation and metabolic memory. In this study, we tested whether histone 3 lysine-9 tri-methylation (H3K9me3), a key epigenetic chromatin marker, was involved in high glucose (HG)-induced inflammation and metabolic memory. Incubating cardiomyocyte cells in HG resulted in increased levels of inflammatory cytokine IL-6 mRNA when compared with myocytes incubated in normal culture media, whereas mannitol (osmotic control) has no effect. Chromatin immunoprecipitation (ChIP) assays showed that H3K9me3 levels were significantly decreased at the promoters of IL-6. Immunoblotting demonstrated that protein levels of the H3K9me3 methyltransferase, Suv39h1, were also reduced after HG treatment. HG-induced apoptosis, mitochondrial dysfunction and cytochrome-c release were reversible. However, the effects of HG on the expression of IL-6 and the levels of H3K9me3 were irreversible after the removal of HG from the culture. These results suggest that HG-induced sustained inflammatory phenotype and epigenetic histone modification, rather than HG-induced mitochondrial dysfunction and apoptosis, are main mechanisms responsible for metabolic memory. In conclusion, our data demonstrate that HG increases expression of inflammatory cytokine and decreases the levels of histone-3 methylation at the cytokine promoter, and suggest that modulating histone 3 methylation and inflammatory cytokine expression may be a useful strategy to prevent metabolic memory and cardiomyopathy in diabetic patients.
- Published
- 2012
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