39 results on '"Genshen Zhong"'
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2. RNA-seq data of WT and ATPIF1 knockout neutrophil after LPS stimulation
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钟根深(Genshen Zhong)
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Multiisolate ,Raw sequence reads ,Medical - Abstract
the neutrophils were isolated from the mice bone marrow which was wild type mice or ATPIF1 knockout mice (C57BL/6 background), and then stimulated with LPS. The neutrophils were collected for RNA-seq after 2 hours.
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- 2023
- Full Text
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3. The anti-aging mechanism of Berberine associated with metabolic control
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Xiaofang Guo, Xiwen Xiong, Lijun Zhao, Genshen Zhong, and Xiaofei Zhu
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- 2023
4. Contributors
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Idris Adewale Ahmed, Sandro Argüelles, David Arráez-Román, Antonio Ayala, Hanna Barlit, Andrzej Bartke, George W. Booz, Nady Braidy, Savannah Brannan, Viktoriia Buheruk, Jared M. Campbell, Mercedes Cano, María de la Luz Cádiz-Gurrea, Ali E. Eid, Angélica Guerrero-Castilla, Xiaofang Guo, Alexander Koliada, Vitaly K. Koltover, Nataliia Kuzub, Vyacheslav M. Labunskyy, Dudley W. Lamming, Oleh V. Lushchak, Francesco Marotta, Gaelle P. Massoud, Maryam Abimbola Mikail, Mario F. Muñoz, Nataliia Naumova, Praveen K. Patnaik, Veronika Piskovatska, Layale Rached, Perminder S. Sachdev, Antonio Segura-Carretero, Sara Shoushtari, Tatjana A. Skipa, Olha Strilbytska, Alexander M. Vaiserman, María del Carmen Villegas-Aguilar, Xiwen Xiong, Andriy Yabluchanskiy, Yiu To Yeung, Alina Zayachkivska, Lijun Zhao, Genshen Zhong, Xiaofei Zhu, and Fouad A. Zouein
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- 2023
5. Interplay between the Gut Microbiome and Metabolism in Ulcerative Colitis Mice Treated with the Dietary Ingredient Phloretin
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Dong Yan, Puze Li, Genshen Zhong, Jinsong Qi, Min Li, Jie Ren, Minna Wu, and Mingyong Wang
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Male ,Phloretin ,Metabolite ,Flavonoid ,Gut flora ,Pharmacology ,Applied Microbiology and Biotechnology ,Feces ,Mice ,chemistry.chemical_compound ,Mesalazine ,RNA, Ribosomal, 16S ,medicine ,Animals ,chemistry.chemical_classification ,biology ,digestive, oral, and skin physiology ,General Medicine ,Metabolism ,biology.organism_classification ,Gastrointestinal Microbiome ,Mice, Inbred C57BL ,Metabolic pathway ,chemistry ,Colitis, Ulcerative ,Netilmicin ,Metabolic Networks and Pathways ,Biotechnology ,medicine.drug - Abstract
A growing number of healthy dietary ingredients in fruits and vegetables have been shown to exhibit diverse biological activities. Phloretin, a dihydrochalcone flavonoid that is abundant in apples and pears, has anti-inflammatory effects on ulcerative colitis (UC) mice. The gut microbiota and metabolism are closely related to each other due to the existence of the food-gut axis in the human colon. To investigate the interplay of faecal metabolites and the microbiota in UC mice after phloretin treatment, phloretin (60 mg/kg) was administered by gavage to ameliorate dextran sulfate sodium (DSS)-induced UC in mice. Gut microbes and faecal metabolite profiles were detected by high-throughput sequencing and liquid chromatography mass spectrometry (LC-MS) analysis, respectively. The correlations between gut microbes and their metabolites were evaluated by Spearman correlation coefficients. The results indicated that phloretin reshaped the disturbed faecal metabolite profile in UC mice and improved the metabolic pathways by balancing the composition of faecal metabolites such as norepinephrine, mesalazine, tyrosine, 5-acetyl-2,4-dimethyloxazole, and 6-acetyl-2,3-dihydro-2-(hydroxymethyl)-4(1H)-pyridinone. Correlation analysis identified the relations between the gut microbes and their metabolites. Proteus was negatively related to many faecal metabolites, such as norepinephrine, L-tyrosine, laccarin, dopamine glucuronide, and 5-acetyl-2,4-dimethyloxazole. The abundance of unidentified Bacteriodales_S24-7_group was positively related to ecgonine, 15-KETE and 6-acetyl-2,3-dihydro-2-(hydroxymethyl)-4(1H)-pyridinone. The abundance of Christensenellaceae_R-7_group was negatively related to the levels of 15-KETE and netilmicin. Stenotrophomonas and 15-KETE were negatively related, while Intestinimonas and alanyl-serine were positively related. In conclusion, phloretin treatment had positive impacts on faecal metabolites in UC mice, and the changes in faecal metabolites were closely related to the gut microbiota.
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- 2021
6. scRNA-seq reveals ATPIF1 activity in control of T cell antitumor activity
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Genshen Zhong, Qi Wang, Ying Wang, Ying Guo, Meiqi Xu, Yaya Guan, Xiaoying Zhang, Minna Wu, Zhishan Xu, Weidong Zhao, Hongkai Lian, Hui Wang, and Jianping Ye
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Mice ,Adenosine Triphosphate ,Oncology ,Immunology ,Melanoma, Experimental ,Animals ,Immunology and Allergy ,Immunotherapy ,CD8-Positive T-Lymphocytes ,Single-Cell Analysis - Abstract
ATP synthase inhibitory factor 1 (ATPIF1) is a mitochondrial protein with an activity in inhibition of F
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- 2022
7. Mitochondrial protein IF1 is a potential regulator of glucagon-like peptide (GLP-1) secretion function of the mouse intestine
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Yaya Guan, Xiwen Xiong, Yanhong Xu, Ying Wang, Jiaojiao Zhang, Jianping Ye, Shuang Shen, Hui Wang, Genshen Zhong, Xiaoying Zhang, and Xinyu Cao
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medicine.medical_specialty ,medicine.medical_treatment ,RM1-950 ,Mitochondrion ,Glucagon ,03 medical and health sciences ,0302 clinical medicine ,Insulin resistance ,Internal medicine ,Mitophagy ,medicine ,Secretion ,General Pharmacology, Toxicology and Pharmaceutics ,Gene knockout ,030304 developmental biology ,0303 health sciences ,ANT2 ,Chemistry ,Microbiota ,Insulin ,ATPIF1 ,Glucose tolerance ,medicine.disease ,Endocrinology ,030220 oncology & carcinogenesis ,Original Article ,Therapeutics. Pharmacology ,Signal transduction ,GLP-1 ,L-cells - Abstract
IF1 (ATPIF1) is a nuclear DNA-encoded mitochondrial protein whose activity is inhibition of the F1Fo-ATP synthase to control ATP production. IF1 activity remains unknown in the regulation of GLP-1 activity. In this study, IF1 was examined in the diet-induced obese mice using the gene knockout (If1-KO) mice. The mice gained more body weight on a high fat diet without a change in food intake. Insulin tolerance was impaired, but the oral glucose tolerance was improved through an increase in GLP-1 secretion. The KO mice exhibited an improved intestine structure, mitochondrial superstructure, enhanced mitophagy, reduced apoptosis and decreased adenine nucleotide translocase 2 (ANT2) protein in the intestinal epithelial cells together with preserved gut microbiota. The data suggest that GLP-1 secretion was enhanced in the obese If1-KO mice to preserve glucose tolerance through a signaling pathway of ANT2/mitochondria/L-cells/GLP-1/insulin. IF1 is a potential mitochondrial target for induction of GLP-1 secretion in L-cells., Graphical abstract IF1 is a new target in the induction of GLP-1 secretion in the intestinal L-cells, which exhibit decreased apoptosis and increased mitophagy from ANT2 reduction in the If1-KO mice.Image 1
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- 2021
8. The Differences between Luminal Microbiota and Mucosal Microbiota in Mice
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Genshen Zhong, Yunying An, Minna Wu, Puze Li, Mingyong Wang, and Jianmin Li
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Colon ,Duodenum ,Firmicutes ,digestive system ,Applied Microbiology and Biotechnology ,Mice ,Lactobacillus ,medicine ,Animals ,Intestinal Mucosa ,Alistipes ,Bifidobacterium ,Mucous Membrane ,Bacteria ,biology ,Chemistry ,Microbiota ,Lachnospiraceae ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Bacteroidetes ,Biodiversity ,General Medicine ,biology.organism_classification ,Molecular biology ,medicine.anatomical_structure ,Organ Specificity ,Metagenome ,Metagenomics ,Biotechnology - Abstract
The differences between luminal microbiota (LM) and mucosal microbiota (MAM) were little known, especially in duodenum. In this study, LM and MAM in colon and duodenum of mice were investigated through 16S rRNA high-throughput sequencing. The lowest bacterial diversity and evenness were observed in duodenal LM (D_LM), followed by duodenal MAM (D_MAM). Meanwhile, the bacterial diversity and evenness were obviously increased in D_MAM than these in D_LM, while no significant difference was observed between colonic MAM (C_MAM) and colonic LM (C_LM). PCoA analysis also showed that bacterial communities of LM and MAM in duodenum were completely separated, while these in colon overlapped partly. The ratio of Firmicutes to Bacteroidetes (F/B) in D_MAM was significantly higher than that in D_LM. Lactobacillus was largely enriched and was the characteristic bacteria in D_LM. The characteristic bacteria in D_MAM were Turicibacter, Parasutterella, Marvinbryantia and Bifidobacterium, while in C_LM they were Ruminiclostridium_6, Ruminiclostridium_9, Ruminococcaceae_UCG_007 and Lachnospiraceae_UCG_010, and in C_MAM they were Lachnospiraceae_NK4A136, Mucispirillum, Alistipes, Ruminiclostridium and Odoribacter. The networks showed that more interactions existed in colonic microbiota (24 nodes and 74 edges) than in duodenal microbiota (17 nodes and 29 edges). The 16S rDNA function prediction results indicated that bigger differences of function exist between LM and MAM in duodenum than these in colon. In conclusion, microbiota from intestinal luminal content and mucosa were different both in colon and in duodenum, and bacteria in colon interacted with each other much more closely than those in duodenum.
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- 2020
9. Novel cyclometalated iridium(<scp>iii</scp>) phosphine-imine (P^N) complexes: highly efficient anticancer and anti-lung metastasis agents in vivo
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Zhe Liu, Xianglei Jia, Zhishan Xu, Lihua Guo, Shujiao Chen, Genshen Zhong, Yuliang Yang, and Xingxing Ge
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0303 health sciences ,Cell cycle checkpoint ,DNA damage ,Chemistry ,010402 general chemistry ,01 natural sciences ,In vitro ,0104 chemical sciences ,Inorganic Chemistry ,03 medical and health sciences ,In vivo ,Apoptosis ,Histone methyltransferase ,Cancer cell ,Cancer research ,Cytotoxicity ,030304 developmental biology - Abstract
Herein, a new class of iridium(III)-based metal complexes with phosphine-imine (P^N) ligands are synthesized and authenticated. These complexes show high cytotoxicities against seven cancer cells in vitro. Simultaneously, antitumor mechanism studies show that complex Ir3 induces apoptosis by depolarization of mitochondrial membrane potential, ROS overproduction and ROS-mediated DNA damage. Importantly, BIX01294, a G9a histone methyltransferase inhibitor, could markedly sensitize Ir3-induced cytotoxicity, cell cycle arrest, apoptosis and inhibition of migration in HCT116 cancer cells in vitro. Finally, we show that combined treatment with Ir3 and BIX01294 potently inhibits tumour growth and lung metastasis in vivo. Taken together, we demonstrate that BIX01294 could potently sensitize iridium(III)-based metal complex-induced inhibition of tumour progression and provide the basis for developing new metal-based anticancer agents and therapeutic strategies in vivo for effective cancer therapy.
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- 2020
10. Inhibitor of Differentiation-2 Protein Ameliorates DSS-Induced Ulcerative Colitis by Inhibiting NF-κB Activation in Neutrophils
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Xiwen Xiong, Minna Wu, Weidong Zhao, Yichun Wang, Dong Yan, Puze Li, Wancheng Xiong, Jie Ren, Jiaojiao Zhang, Jing Xueqian, Min Li, and Genshen Zhong
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Male ,nuclear factor kappa B (NF-κB) ,Colon ,Immunology ,medicine.disease_cause ,law.invention ,Proinflammatory cytokine ,Feces ,neutrophils ,law ,medicine ,Animals ,Humans ,Immunology and Allergy ,Colitis ,Escherichia coli ,Inhibitor of Differentiation Protein 2 ,Original Research ,biology ,Chemistry ,Dextran Sulfate ,NF-kappa B ,RC581-607 ,medicine.disease ,Ulcerative colitis ,Molecular biology ,Recombinant Proteins ,Hedgehog signaling pathway ,ulcerative colitis (UC) ,Mice, Inbred C57BL ,intestinal barrier ,Inhibitor of differentiation-2 (ID2) ,biology.protein ,Recombinant DNA ,Cytokines ,Colitis, Ulcerative ,Caco-2 Cells ,Antibody ,Immunologic diseases. Allergy ,Infiltration (medical) ,recombinant protein - Abstract
The loss of inhibitor of differentiation-2 (ID2) could lead to the development of colitis in mice, supplementation with exogenous ID2 protein might be a potential strategy to ameliorate colitis. In this study, the effects of ID2 protein supplementation on Dextran sodium sulfate (DSS)-induced colitis were investigated. Firstly, we confirmed that the expression of ID2 was reduced in the colon tissues of DSS-induced colitis mice and patients with ulcerative colitis (UC). Then, we constructed a recombinant plasmid containing the human Id2 gene and expressed it in Escherichia coli (E. coli) successfully. After purification and identification, purified hID2 could ameliorate DSS-induced colitis efficiently in mice by improving disease symptoms, decreasing the levels of proinflammatory cytokines in colon tissues, maintaining the integrity of intestinal barrier and reducing the infiltration of neutrophils and macrophages in the colon. Further study showed that hID2 could be endocytosed efficiently by neutrophils and macrophages, and hID2 lost its protection function against colitis when neutrophils were depleted with an anti-Gr-1 antibody. hID2 decreased the mRNA levels of IL-6, IL-1β and TNF-α in lipopolysaccharides (LPS)-stimulated neutrophils and efficiently inhibited the activation of NF-κB signalling pathway in neutrophils. Interestingly, hID2 showed a synergistic role in inhibition of NF-κB activation with pyrrolidine dithiocarbamic acid (PDTC), an inhibitor of NF-κB activation. Therefore, this study demonstrated the potential use of hID2 to treat UC, and hID2 protein might be a promising anti-inflammatory agent that targets the NF-κB signalling pathway in neutrophils.
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- 2021
11. Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity
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Xiwen Xiong, Chenyan Yang, Wei-Qi He, Jiahui Yu, Yue Xin, Xinge Zhang, Rong Huang, Honghui Ma, Shaofang Xu, Zun Li, Jie Ma, Lin Xu, Qunyi Wang, Kaiqun Ren, Xiaoli S. Wu, Christopher R. Vakoc, Jiateng Zhong, Genshen Zhong, Xiaofei Zhu, Yu Song, Hai-Bin Ruan, and Qingzhi Wang
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Multidisciplinary ,Helminthiasis ,General Physics and Astronomy ,Epithelial Cells ,Mice, Transgenic ,General Chemistry ,General Biochemistry, Genetics and Molecular Biology ,Intestines ,Mice, Inbred C57BL ,Mice ,Animals ,Sirtuins ,Goblet Cells ,Intestinal Mucosa ,STAT6 Transcription Factor ,Immunity, Mucosal - Abstract
Dynamic regulation of intestinal epithelial cell (IEC) differentiation is crucial for both homeostasis and the response to helminth infection. SIRT6 belongs to the NAD+-dependent deacetylases and has established diverse roles in aging, metabolism and disease. Here, we report that IEC Sirt6 deletion leads to impaired tuft cell development and type 2 immunity in response to helminth infection, thereby resulting in compromised worm expulsion. Conversely, after helminth infection, IEC SIRT6 transgenic mice exhibit enhanced epithelial remodeling process and more efficient worm clearance. Mechanistically, Sirt6 ablation causes elevated Socs3 expression, and subsequently attenuated tyrosine 641 phosphorylation of STAT6 in IECs. Notably, intestinal epithelial overexpression of constitutively activated STAT6 (STAT6vt) in mice is sufficient to induce the expansion of tuft and goblet cell linage. Furthermore, epithelial STAT6vt overexpression remarkedly reverses the defects in intestinal epithelial remodeling caused by Sirt6 ablation. Our results reveal a novel function of SIRT6 in regulating intestinal epithelial remodeling and mucosal type 2 immunity in response to helminth infection.
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- 2021
12. Discovery of novel ID2 antagonists from pharmacophore-based virtual screening as potential therapeutics for glioma
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Peiyuan Dou, Shitao Sun, Zhenli Li, Genshen Zhong, Jinle Hao, Yichun Wang, Qi Wang, Yichuang Liu, Minna Wu, and Bin Lin
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Models, Molecular ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,Antineoplastic Agents ,Biochemistry ,Small Molecule Libraries ,Neovascularization ,Structure-Activity Relationship ,In vivo ,Glioma ,Drug Discovery ,Tumor Cells, Cultured ,medicine ,Humans ,Potency ,Binding site ,Cytotoxicity ,Molecular Biology ,Cell Proliferation ,Inhibitor of Differentiation Protein 2 ,Virtual screening ,Dose-Response Relationship, Drug ,Molecular Structure ,Brain Neoplasms ,Chemistry ,Organic Chemistry ,Antagonist ,medicine.disease ,In vitro ,Cancer research ,Molecular Medicine ,Drug Screening Assays, Antitumor ,medicine.symptom ,Pharmacophore - Abstract
Glioma, especially the most aggressive type glioblastoma multiforme, is one of the central nervous system malignant cancer with a poor prognosis. Traditional treatments are mainly surgery combined with radiotherapy and chemotherapy, which is still not satisfactory. Therefore, it is of great clinical significance to find new therapeutic agents. Served as an inhibitor of differentiation, protein ID2 (inhibitor of DNA binding 2) plays an important role in neurogenesis, neovascularization and malignant development of gliomas. It has been shown that ID2 affects the malignant progression of gliomas through different mechanisms. In this study, a pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations on their ID2 inhibitory activities. Based on the cytotoxicity of these small-molecule compounds, two compounds were shown to effectively inhibit the viability of glioma cells in the low micromolar range. Among them, AK-778-XXMU was chosen for further study due to its better solubility in water. A SPR assay proved the high affinity between AK-778-XXMU and ID2 protein with the KD value as 129 nM. The plausible binding mode in the biding site of ID2 was studied by molecular docking. Subsequently, the cancer-suppressing potency of the compound was characterized both in vitro and in vivo. The data demonstrated that compound AK-778-XXMU is a potent ID2 antagonist which has the potential to be developed as a therapeutic agent against glioma.HighlightsTwo pharmacophores were built from the first-in-class pan-ID antagonists AGX51A pharmacophore-based virtual screening was carried out and 16 hit compounds were purchased for pharmacological evaluations in glioma inhibitionCompound AK-778-XXMU was identified to be a potent ID2 antagonist in the low submicromolar range (KD: 159 nM)
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- 2021
13. LncRNA NKILA regulates endothelium inflammation by controlling a NF-κB/KLF4 positive feedback loop
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Fen Yang, Xinxing Zhu, Yanyan Feng, Fangfang Cheng, Genshen Zhong, Liang Qiao, Jinjin Yu, Maoping Chu, Rui Guo, Zhihao Xu, Fulong Liu, Juntang Lin, and Jiang Du
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0301 basic medicine ,Transcription, Genetic ,Endothelium ,Kruppel-Like Transcription Factors ,Regulator ,Repressor ,Inflammation ,030204 cardiovascular system & hematology ,Biology ,Models, Biological ,DNA Methyltransferase 3A ,Endothelial activation ,Kruppel-Like Factor 4 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Human Umbilical Vein Endothelial Cells ,medicine ,Humans ,DNA (Cytosine-5-)-Methyltransferases ,Promoter Regions, Genetic ,Molecular Biology ,Feedback, Physiological ,fungi ,NF-kappa B ,NF-κB ,DNA Methylation ,Cell biology ,HEK293 Cells ,030104 developmental biology ,medicine.anatomical_structure ,Gene Expression Regulation ,chemistry ,KLF4 ,DNA methylation ,RNA, Long Noncoding ,Endothelium, Vascular ,medicine.symptom ,Cardiology and Cardiovascular Medicine - Abstract
Endothelium inflammation, a key event in vascular pathological process, can lead to endothelial activation and subsequent vascular disorders. Long non-coding RNA NKILA plays an important regulatory role in pro-inflammatory response. However, the underlying molecular basis by which NKILA regulates endothelial inflammation is poorly understood. In this study, we identify NKILA as a critical repressor to protect the endothelium from inflammation. Mechanistically, we show that NKILA is able to positively mediate the expression of KLF4, an anti-inflammatory atheroprotective regulator in endothelial cells (ECs), by a NF-κB-mediated DNA methylation mechanism. Moreover, NF-κB is found to help recruit DNMT3A to the CpG island of KLF4 promoter, facilitating KLF4 promoter DNA methylation and transcriptional repression. More importantly, we find KLF4 can inversely attenuate NF-κB transcriptional activity via establishing a NF-κB/KLF4 positive feedback loop, which is under the control of NKILA. Hence, sustained endothelium inflammation will occur, once the NKILA becomes dysfunctional. These studies revealed that NKILA can function as a vital regulator to protect the endothelium from inflammatory lesions and related vascular diseases.
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- 2019
14. LncRNA HOXA‐AS2 positively regulates osteogenesis of mesenchymal stem cells through inactivating NF‐κB signalling
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Liang Qiao, Jinjin Yu, Xinxing Zhu, Genshen Zhong, Juntang Lin, and Jiang Du
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0301 basic medicine ,Epithelial-Mesenchymal Transition ,Regulator ,HOXA‐AS2 ,Osteocytes ,osteogenesis ,03 medical and health sciences ,0302 clinical medicine ,lncRNA ,Cell Movement ,Humans ,Transcription factor ,Cells, Cultured ,Cell Proliferation ,Gene knockdown ,Histone deacetylase 2 ,Chemistry ,Regeneration (biology) ,Mesenchymal stem cell ,NF‐κB signalling ,NF-kappa B ,RNA ,Cell Differentiation ,Mesenchymal Stem Cells ,Cell Biology ,Original Articles ,Cell biology ,HDAC2 ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Molecular Medicine ,Alkaline phosphatase ,Original Article ,Female ,RNA, Long Noncoding - Abstract
As is previously reported, mesenchymal stem cells have potential ability to differentiate into osteocytes. However, the underlying mechanism during this biological process is poorly understood. In the present study, we identify a novel long non‐coding RNA named HOXA‐AS2 as a critical regulator during the formation of osteogenesis. Attenuation of HOXA‐AS2 can reduce the calcium deposition and repress the alkaline phosphatase activity. Moreover, the expressions of osteogenic marker genes are markedly downregulated after HOXA‐AS2 depletion. Mechanistically, we found HOXA‐AS2 can regulate the transcriptional activity of NF‐κB, a critical inhibitor of osteogenesis. More importantly, HOXA‐AS2 knockdown could result in the transcriptional repression of the osteogenic master transcription factor SP7 by a NF‐κB/HDAC2‐coordinated H3K27 deacetylation mechanism. Based on these studies, we conclude that HOXA‐AS2 may serve as a promising therapeutic target for bone tissue repair and regeneration in the near future.
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- 2018
15. IF1 connects obesity and insulin resistance through mitochondrial reprogramming in association with ANT2
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Xiaoying Zhang, Xinyu Cao, Xiwen Xong, Yanhong Xu, Ying Wang, Shuang Shen, Hui Wang, Yaya Guan, Genshen Zhong, Jianping Ye, and Jiaojiao Zhang
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medicine.medical_specialty ,ATP synthase ,biology ,Chemistry ,ATPase ,Respiratory chain ,Skeletal muscle ,Mitochondrion ,medicine.disease ,Insulin resistance ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,Mitophagy ,biology.protein ,medicine ,ATP–ADP translocase - Abstract
IF1 (ATPIF1) is a nuclear DNA-encoded protein with an activity in the inhibition of catalytic activity of F1Fo-ATP synthase (ATPase), an enzyme for ATP synthesis in mitochondria. A role of IF1 remains unknown in the metabolic disorder in obesity. In this study, IF1 was examined in the diet-induced obese (DIO) mice and a decrease in IF1 protein was observed in several tissues including the skeletal muscle, liver and intestine in the absence of mRNA alteration. Significance of the reduction was investigated in the IF1-KO mice, in which insulin sensitivity was improved in the absence of body weight alteration on Chow diet. On a high fat diet (HFD), the IF1-KO mice gain more body weight as a result of enhanced fat tissue growth. The energy expenditure and locomotion activity were decreased in the KO mice without an alteration in food intake. The increase in insulin sensitivity remained in the obese KO mice. The colon tissue exhibited a resistance to the HFD-induced atrophy with less cell apoptosis and more secretion of GLP-1. Mitochondria exhibited an enhanced ATP production and maximal oxygen consumption without an alteration in the respiratory chain proteins. However, the ATP level was reduced in the fasting condition in the muscle as well as the liver. Mitophagy was enhanced with elevated accumulation of PINK1 and Parkin proteins in the mitochondria. The protein abundance of ADP/ATP translocase 2 (ANT2) was decreased in the inner membrane of mitochondria to account for the reduced apoptosis and enhanced mitophagy. The data suggest that the IF1 reduction in obesity leads to reprogramming of mitochondrial metabolism in a compensatory response to maintain the insulin sensitivity through down-regulation of ANT2 protein.
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- 2020
16. ATPIF1 inactivation promotes antitumor immunity through metabolic reprogramming of CD8+ T cells
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Shuang Shen, Yichun Wang, Ming Shi, Yaya Guan, Hui Wang, Genshen Zhong, Minna Wu, Yunwei Lou, Ying Wang, Jianping Ye, Yuan Li, Xiaoying Zhang, Xinyu Cao, Jiaojiao Zhang, Zhongxin Zhang, and Yinming Liang
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Tumor microenvironment ,Immune system ,medicine.anatomical_structure ,Cancer immunotherapy ,Chemistry ,Tumor-infiltrating lymphocytes ,medicine.medical_treatment ,T cell ,Cell ,Cancer research ,medicine ,Cytotoxic T cell ,CD8 - Abstract
Induction of CD8+ T cell activity is a promising strategy in the cancer immunotherapy. In this study, we identified ATP synthase inhibitory factor 1 (ATPIF1) as a potential target in the induction of CD8+ T cell immunity against tumor. Inactivation of ATPIF1 gene in mice promoted the antitumor activity of CD8+ T cells leading to suppression of tumor growth of B16 melanoma and Lewis lung cancer. The phenotype was abolished by deletion of CD8+ T cells in the ATPIF1-KO mice. The tumor infiltrating CD8+ T cells exhibited strong activities in the proliferation, effector and memory as revealed by the single cell RNA sequencing results of CD45+ tumor infiltrating lymphocytes (TILs) isolated from the tumors. The CD8+ T cells expressed more antitumor makers in the tumor microenvironment and in coculture with the tumor cells. The cells had a higher level of glycolysis after the T cell receptor-mediated activation as revealed by the targeted metabolomics assay. The cells exhibited an extra activity of oxidative phosphorylation before the activation as indicated by the oxygen consumption rate. The cells gained capacities in the proliferation, apoptosis resistance and mitophagy in the glucose-limiting environment. These data suggest that inhibition of ATPIF1 activity by gene inactivation rewired the energy metabolism of CD8+ T cells to enhance their immune activities to the tumors. ATPIF1 is a potential molecular target in the induction of antitumor immunity through metabolic reprogramming of CD8+ T cells for the cancer immunotherapy.
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- 2020
17. An arginine-rich cell penetrating peptide contained anti-gelatinase scFv-LDM fusion protein shows potent antitumor efficacy in pancreatic cancer
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Zhishan Xu, Minna Wu, Genshen Zhong, Hongtao Liu, Liang Li, Shenghua Zhang, Ru Yang, and Yong-Su Zhen
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0301 basic medicine ,lidamycin ,medicine.diagnostic_test ,Chemistry ,Pancreatic cancer ,medicine.disease ,Fusion protein ,arginine-rich cell penetrating peptide ,03 medical and health sciences ,optical imaging ,030104 developmental biology ,0302 clinical medicine ,Cell killing ,Cyclin D1 ,Oncology ,Western blot ,In vivo ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,gelatianse ,Cytotoxicity ,Research Paper - Abstract
Pancreatic cancer (PC) is one of the most dangerous cancers with less than 5% survival rate in 5 years. This study was to evaluate the antitumor activities of dFv-LDP-AE and dFv-R-LDP-AE, two energized fusion protein targeting gelatinases, on pancreatic cancer. The fusion protein dFv-LDP-AE consists of two tandem anti-gelatianses scFv and an enediyne antibiotic lidamycin (LDM) for receptor binding and cell killing. To improve the penetration capability, the fusion protein dFv-LDP-AE was integrated with an arginine-rich cell penetrating peptide (Arg)9 and then generated the fusion protein dFv-R-LDP-AE. The current study demonstrated that dFv-LDP and dFv-R-LDP had high affinity with the antigen gelatinases and PC cells, the integration of (Arg)9 could increase the penetration rate of fusion protein in SW-1990 and PANC-1 cells. After enediyne-energized with chromophore of lidamycin, the energized fusion protein dFv-LDP-AE and dFv-R-LDP-AE showed potent cytotoxicity to PC cells and could induced the robust cell apoptosis and necrosis in vitro. Western blot showed that dFv-R-LDP-AE could increase PARP cleavage, and inhibited the expression of VEGF, Cyclin D1, Cox-2 and Bcl-2 in SW-1990 and PANC-1 cells. In vivo, at a tolerated dosage, dFv-LDP, dFv-LDP-AE and dFv-R-LDP-AE inhibited tumor growth by 20.42%, 56.31% (P < 0.01, compared to that of control) and 74.2% (P < 0.05, compared to that of dFv-LDP-AE) in pancreatic cancer SW-1990 xenografted mice, respectively. Moreover, the results of in vivo optical imaging showed that fusion protein dFv-R-LDP displayed prominent accumulation in the tumor in SW-1990 xenografted mice and Capan-2 orthotopic transplanted mice. These results showed that dFv-R-LDP-AE possessed potent antitumor efficacy on PC, which indicating it could be a promising candidate for targeting therapy of PC.
- Published
- 2018
18. Dual-functional cyclometalated iridium imine NHC complexes: highly potent anticancer and antimetastatic agents
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Zhenzhen Tian, Genshen Zhong, Yuliang Yang, Lihua Guo, Zhe Liu, and JuanJuan Li
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A549 cell ,Cisplatin ,chemistry.chemical_classification ,Reactive oxygen species ,biology ,010405 organic chemistry ,Chemistry ,Stereochemistry ,Cell migration ,010402 general chemistry ,biology.organism_classification ,01 natural sciences ,0104 chemical sciences ,Inorganic Chemistry ,HeLa ,Apoptosis ,Cell culture ,Cancer cell ,medicine ,medicine.drug - Abstract
A new class of cyclometalated iridium(III) complexes with imine-N-heterocyclic carbenes (NHC) as ligands were synthesized and fully characterized. One crystal structure is reported. All the six complexes exhibited highly potent anticancer activity against A549 cells, HeLa cells, HepG2 cells, GL261 cells and A549R cells. In particular, they were up to 9 and 37 times more potent than clinically used anticancer drug cisplatin towards A549 and A549R cell lines, respectively. Remarkably, mechanism studies showed that the complexes pass into cancer cells through an energy-dependent pathway and cause apoptosis via reactive oxygen species (ROS) generation, mitochondrial membrane potential dysfunction, and lysosomal damage. In addition, complex Ir6 effectively impeded cell migration and colony formation.
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- 2018
19. IF1 inactivation attenuates experimental colitis through downregulation of neutrophil infiltration in colon mucosa
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Jiaojiao Zhang, Ying Guo, Xiaoying Zhang, Beiyan Zhou, Hui Wang, Yichun Wang, Weidong Zhao, Genshen Zhong, Minna Wu, Jianping Ye, Jie Ren, Yuan Li, and Yunwei Lou
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Male ,Colon ,Neutrophils ,Immunology ,Down-Regulation ,Apoptosis ,Proinflammatory cytokine ,Mitochondrial Proteins ,Mice ,Immune system ,Downregulation and upregulation ,Lysosome ,Weight Loss ,Autophagy ,medicine ,Animals ,Immunology and Allergy ,Intestinal Mucosa ,Colitis ,Mice, Knockout ,Pharmacology ,Chemistry ,Dextran Sulfate ,Wild type ,Chloroquine ,medicine.disease ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Neutrophil Infiltration ,Cancer research ,Cytokines ,Female ,Lysosomes - Abstract
IF1 is a mitochondrial protein involved in the regulation of ATP synthase activity. The role of IF1 remains to be established in inflammatory bowel diseases (IBD). In this study, we report that IF1 gene inactivation generated protection against IBD in the dextran sodium sulfate (DSS) model. IF1 gene knockout (IF1-KO) mice developed less severe colitis than the wild type (WT) mice as judged by parameters including disease activity index (DAI), body weight loss, inflammatory cytokines, leukocyte infiltration and bacterial invasion in the colon tissue. The intestinal barrier integrity was protected in the colon tissue of IF1-KO mice through a reduction in apoptosis and inflammasomal activity. The protection was abolished in the KO mice after substitution of the immune cells with the wild type cells following bone marrow transplantation. Depletion of neutrophils with anti-Gr-1 antibody abolished the protection from colitis in IF1-KO mice. Neutrophil number was decreased in the peripheral blood of IF1-KO mice, which was associated with a reduction in LC3A/B proteins in the KO neutrophils in Rapamycin-induced autophagy response. Inhibition of autophagy with the lysosome inhibitor Chloroquine (CQ) decreased the absolute number of neutrophils in WT mice and protected the mice from colitis. Taken together, these findings suggest that IF1 may contribute to the pathogenesis of IBD through acceleration of neutrophil autophagy. The activity is attenuated in the IF1-KO mice through reduction of autophagy in neutrophils leading to resistance to IBD.
- Published
- 2021
20. Jarid2 is essential for the maintenance of tumor initiating cells in bladder cancer
- Author
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Chun-Zhi Ai, Shan Jiang, Xiang-Zhen Wang, Min Niu, Shanshan Xu, Xinxing Zhu, Shaoqi Tian, Yi-Zhou Jiang, Guangyao Li, Ya-Wei Yan, Xifeng Lu, Genshen Zhong, Shaojun Tang, and Yu Xue
- Subjects
0301 basic medicine ,Oncology ,Gerontology ,medicine.medical_specialty ,Population ,p16 ,urologic and male genital diseases ,tumor-initiating cells ,Jarid2 ,Tumor Initiating Cells ,03 medical and health sciences ,Cell Line, Tumor ,Internal medicine ,Humans ,Medicine ,histone modification ,University medical ,education ,education.field_of_study ,Bladder cancer ,business.industry ,Polycomb Repressive Complex 2 ,medicine.disease ,Urologic malignancy ,bladder tumors ,030104 developmental biology ,Urinary Bladder Neoplasms ,Cancer cell ,Neoplastic Stem Cells ,Christian ministry ,Stem cell ,business ,Signal Transduction ,Research Paper - Abstract
// Xin-Xing Zhu 1, 2, * , Ya-Wei Yan 1, 2, * , Chun-Zhi Ai 1 , Shan Jiang 1 , Shan-Shan Xu 1 , Min Niu 3 , Xiang-Zhen Wang 4 , Gen-Shen Zhong 5 , Xi-Feng Lu 6 , Yu Xue 7 , Shaoqi Tian 8 , Guangyao Li 9 , Shaojun Tang 10 , Yi-Zhou Jiang 1 1 Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China 2 Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong, College of Optoelectronic Engineering, Shenzhen University, Shenzhen, Guangdong, China 3 Department of Statics, University of Wisconsin-Madison, Madison, WI, USA 4 Maternal and Child Health Hospital of Nanshan District, Shenzhen, Guangdong, China 5 The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan, China 6 Department of Physiology, Center for Diabetes, Obesity and Metabolism, Shenzhen University, Shenzhen, Guangdong, China 7 Minnan Normal University, Zhangzhou, Fujian, China 8 The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China 9 Department of Health Outcomes and Policy, College of Medicine, University of Florida, Gainesville, FL, USA 10 Innovation Center for Biomedical Informatics, Georgetown University Medical Center, Washington, DC, USA * These authors contributed equally to this work Correspondence to: Yi-Zhou Jiang, email: jiangyz@szu.edu.cn Keywords: Jarid2, bladder tumors, tumor-initiating cells, p16, histone modification Received: November 24, 2016 Accepted: February 07, 2017 Published: February 20, 2017 ABSTRACT Bladder cancer is the most common urologic malignancy in China, with an increase of the incidence and mortality rates over past decades. Recent studies suggest that bladder tumors are maintained by a rare fraction of cells with stem cell proprieties. Targeting these bladder tumor initiating cell (TICs) population can overcome the drug-resistance of bladder cancer. However, the molecular and genetic mechanisms regulating TICs in bladder cancer remain poorly defined. Jarid2 is implicated in signaling pathways regulating cancer cell epithelial-mesenchymal transition, and stem cell maintenance. The goal of our study was to examine whether Jarid2 plays a role in the regulation of TICs in bladder cancer. We found that knockdown of Jarid2 was able to inhibit the invasive ability and sphere-forming capacity in bladder cancer cells. Moreover, knockdown of Jarid2 reduced the proportion of TICs and impaired the tumorigenicity of bladder cancer TICs in vivo . Conversely, ectopic overexpression of Jarid2 promoted the invasive ability and sphere-forming capacity in bladder cancer cells. Mechanistically, reduced Jarid2 expression led to the upregulation of p16 and H3K27me3 level at p16 promoter region. Collectively, we provided evidence that Jarid2 via modulation of p16 is a putative novel therapeutic target for treating malignant bladder cancer.
- Published
- 2017
21. Isoliquiritigenin decreases the incidence of colitis-associated colorectal cancer by modulating the intestinal microbiota
- Author
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Baoguo Deng, Minna Wu, Xinlai Qian, Yan Qu, Hai-ying Cao, Jinsong Li, Yaqi Wu, and Genshen Zhong
- Subjects
0301 basic medicine ,Male ,Rikenellaceae ,Gut flora ,Gastroenterology ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Chalcones ,RNA, Ribosomal, 16S ,Medicine ,colitis-associated colorectal cancer ,Medicine, Chinese Traditional ,Mice, Inbred BALB C ,biology ,High-Throughput Nucleotide Sequencing ,Colitis ,isoliquiritigenin ,Oncology ,030220 oncology & carcinogenesis ,gut ,Colorectal Neoplasms ,Isoliquiritigenin ,Research Paper ,medicine.medical_specialty ,Firmicutes ,Helicobacteraceae ,digestive system ,03 medical and health sciences ,Internal medicine ,microbiota ,Glycyrrhiza ,Animals ,Humans ,AOM/DSS ,business.industry ,Bacteroidetes ,Ruminococcus ,Probiotics ,Lachnospiraceae ,biology.organism_classification ,medicine.disease ,Gastrointestinal Microbiome ,Disease Models, Animal ,030104 developmental biology ,chemistry ,Immunology ,business - Abstract
// Minna Wu 2, 3, * , Yaqi Wu 2, * , Baoguo Deng 2 , Jinsong Li 4 , Haiying Cao 2 , Yan Qu 2 , Xinlai Qian 5 , Genshen Zhong 1, 3 1 Laboratory of Cancer Biotherapy, Institute of Neurology, the First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China 2 College of Basic Medicine, Xinxiang Medical University, Xinxiang, Henan, China 3 Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang Medical University, Xinxiang, Henan, China 4 Department of Pathology, the First Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China 5 Department of Pathology, the Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China * These authors have contributed equally to this work Correspondence to: Genshen Zhong, email: zhonggs@xxmu.edu.cn Keywords: isoliquiritigenin, gut, microbiota, AOM/DSS, colitis-associated colorectal cancer Received: February 12, 2016 Accepted: October 26, 2016 Published: November 15, 2016 ABSTRACT Imbalances in intestinal bacteria correlate with colitis-associated colorectal cancer (CAC). Traditional Chinese medicines have been used to adjust the gut microbiota, and isoliquiritigenin (ISL), a flavonoid extracted from licorice, has shown antitumor efficacy. In this study, the effects of ISL on CAC development and the gut microbiota were evaluated using an azoxymethane and dextran sulphate sodium (AOM/DSS)-induced mouse model of CAC (CACM). Histopathological analysis suggested that ISL reduced tumor incidence in vivo . Moreover, high-throughput sequencing and terminal restriction fragment length polymorphism (T-RFLP) studies of the bacterial 16S rRNA gene revealed that the structure of the gut microbial community shifted significantly following AOM/DSS treatment, and that effect was alleviated by treatment with high-dose ISL (150 mg/kg). Compared to the microbiota in the control mice (CK), the levels of Bacteroidetes decreased and the levels of Firmicutes increased during CAC development. ISL reversed the imbalance at the phylum level and altered the familial constituents of the gut microbiota. Specifically, the abundance of Helicobacteraceae increased after treatment with high-dose ISL, while the abundance of Lachnospiraceae and Rikenellaceae decreased. At the genus level, ISL reduced the abundance of opportunistic pathogens ( Escherichia and Enterococcus ), and increased the levels of probiotics, particularly butyrate-producing bacteria ( Butyricicoccus , Clostridium, and Ruminococcus ). Thus, ISL protects mice from AOM/DSS-induced CAC, and ISL and the gut microbiota may have synergistic anti-cancer effects.
- Published
- 2016
22. Chitooligosaccharides Prevents the Development of Colitis-Associated Colorectal Cancer by Modulating the Intestinal Microbiota and Mycobiota
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Minna Wu, Jianmin Li, Yunying An, Puze Li, Wancheng Xiong, Jinsong Li, Dong Yan, Mingyong Wang, and Genshen Zhong
- Subjects
Microbiology (medical) ,Mycobiota ,chitooligosaccharides ,lcsh:QR1-502 ,Microbiology ,lcsh:Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,Lactobacillus ,medicine ,microbiota ,colitis-associated colorectal cancer ,Colitis ,030304 developmental biology ,Original Research ,0303 health sciences ,biology ,030306 microbiology ,Azoxymethane ,high-throughput sequencing ,Akkermansia ,medicine.disease ,biology.organism_classification ,Enterococcus ,chemistry ,mycobiota ,Fusobacterium nucleatum ,Bacteria - Abstract
Gut microbes play a crucial role in the development of colorectal cancer. Chitooligosaccharides (COS), are oligomer that are depolymerized from chitosan and possess a wide range of biological activities. In this study, the effects of COS on colorectal cancer (CRC) development were evaluated using azoxymethane and dextran sulfate sodium (AOM/DSS) induced mouse model of CRC (CACM). In the COS-treated CRC group (CMCOS), COS protected mice from CRC by decreasing the disease activity index, tumor incidences and multiplicity, and the mRNA levels of COX-2, IL-6, TNF-α, IL-1β, IL-10, and IKK-β mRNA in colonic epithelial cells. The results of a cage-exchanged experiment, in which mice from the CACMe and CMCOSe treatments exchanged cages every day to interact with microbes, showed that gut microbes play an important role in preventing CAC by COS. The abundances of fecal bacteria (total bacteria, Lactobacillus, Enterococcus, Fusobacterium nucleatum and butyrate-producing bacteria) were detected by qPCR on the 0th, 1st, 3rd, 6th, 9th, and 10th weekends. Furthermore, microbiota and mycobiota were analyzed by high-throughput sequencing on an Illumina MiSeq PE300 system. COS protected mice from CRC by reversing the imbalance of bacteria and fungi, especially by reducing the abundance of Escherichia–Shigella, Enterococcus, and Turicibacter, and increasing the levels of Akkermansia, butyrate-producing bacteria and Cladosporium.
- Published
- 2019
23. Long Noncoding RNA HOXA-AS3 Integrates NF-κB Signaling To Regulate Endothelium Inflammation
- Author
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Yanli Liu, Yi-Zhou Jiang, Yi-Ze Wang, Jieqi Wen, Xifeng Lu, Genshen Zhong, Xin-Qi Zhong, Jinjin Yu, Du-Chu Chen, Demeng Chen, Shuibin Lin, Liang Qiao, and Xinxing Zhu
- Subjects
Genetic Markers ,Male ,Endothelium ,Regulator ,Inflammation ,Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,NF-KappaB Inhibitor alpha ,medicine ,Human Umbilical Vein Endothelial Cells ,Humans ,Promoter Regions, Genetic ,Molecular Biology ,030304 developmental biology ,Aged ,0303 health sciences ,Activator (genetics) ,NF-kappa B ,Promoter ,NF-κB ,Acetylation ,Cell Biology ,Middle Aged ,Atherosclerosis ,Long non-coding RNA ,Up-Regulation ,IκBα ,medicine.anatomical_structure ,Early Diagnosis ,HEK293 Cells ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Female ,RNA, Long Noncoding ,medicine.symptom ,Signal Transduction ,Research Article - Abstract
The long noncoding RNA HOXA-AS3 has recently been reported to act as a critical regulator in inflammation-linked lung adenocarcinoma. However, the roles of HOXA-AS3 in endothelium inflammation and related vascular disorders remain poorly defined. In the current study, we identified HOXA-AS3 to be a critical activator to promote NF-κB-mediated endothelium inflammation. HOXA-AS3, a chromatin-associated regulator which colocalizes with NF-κB at specific gene promoters, was found to interact with NF-κB and positively regulate its activity through control of the expression of the NF-κB inhibitor protein IκBα and the acetylation status at the K310 site of p65. More importantly, clinicopathological analysis showed that HOXA-AS3 expression has a significant positive correlation with atherosclerosis. Thus, we conclude that HOXA-AS3 may serve as a crucial biomarker for the clinical diagnosis of atherosclerosis, as well as a promising therapeutic target for the treatment of multiple inflammatory vascular diseases. In addition, this study suggests the functional importance of HOXA-AS3 in the regulation of inflammatory disorders.
- Published
- 2019
24. Saikosaponin-d ameliorates dextran sulfate sodium-induced colitis by suppressing NF-κB activation and modulating the gut microbiota in mice
- Author
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Jie Ren, Jinsong Li, Dong Yan, Yunying An, Hongfei Xue, Genshen Zhong, Wancheng Xiong, Min Li, Minna Wu, Yingguang Xie, and Puze Li
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Male ,0301 basic medicine ,medicine.medical_treatment ,Immunology ,Gut flora ,Pharmacology ,Feces ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Bupleurum falcatum ,Animals ,Humans ,Immunology and Allergy ,Oleanolic Acid ,Colitis ,MUC1 ,Mice, Inbred BALB C ,biology ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Dextran Sulfate ,Mucin ,Mucins ,NF-kappa B ,NF-κB ,Saponins ,medicine.disease ,biology.organism_classification ,Ulcerative colitis ,Gastrointestinal Microbiome ,Disease Models, Animal ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,Cytokines ,Colitis, Ulcerative ,Inflammation Mediators ,Signal Transduction - Abstract
Saikosaponin-d (SSd), extracts from Bupleurum falcatum L, exhibits anti-inflammatory and anti-infectious activities. However, the effect of SSd on intestinal inflammation has not been investigated. The aim of this study was to evaluate the effect of SSd on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice, and to elucidate the underlying mechanisms. UC was induced in mice by administrating 3% DSS in drinking water for 7 days. SSd (4 mg/kg and 8 mg/kg) was administered by gavage every day during the experimental process. The results showed that SSd treatment (8 mg/kg) significantly ameliorated UC mice by decreasing disease activity index (DAI), increasing colon length and improving pathological characteristics. SSd treatment (8 mg/kg) significantly suppressed the mRNA levels of pro-inflammatory cytokines including TNF-α, IL-6 and IL-1β, increased that of anti-inflammatory cytokine IL-10. Furthermore, SSd (8 mg/kg) suppressed the activation of NF-κB by decreasing the degradation and phosphorylation of IκB. SSd (8 mg/kg) also protected the intestinal barrier by increasing the mRNA levels of mucin (Muc1 and Muc2) and the protein levels of zonula occludens-1 (ZO-1) and Claudin-1. The 16S rDNA gene high-throughput sequencing revealed that SSd treatment (8 mg/kg) increased the alpha diversity and regulated the structure of gut microbiota in UC mice. Taken together, our findings demonstrated that SSd (8 mg/kg) improved DSS-induced intestinal inflammation by inhibiting NF-κB activation and regulated the gut microbiota.
- Published
- 2020
25. Novel half-sandwich iridium OˆC (carbene)-Complexes: In vitro and in vivo tumor growth suppression and pro-apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes
- Author
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Genshen Zhong, Yujiao Zhang, Yuliang Yang, Xianglei Jia, Zhishan Xu, Shumiao Zhang, Qing Du, Zhe Liu, and JuanJuan Li
- Subjects
0301 basic medicine ,Cancer Research ,Antineoplastic Agents ,Apoptosis ,Mitochondrion ,Iridium ,Ligands ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,Coordination Complexes ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Cell Proliferation ,A549 cell ,Mice, Inbred BALB C ,Chemistry ,Hep G2 Cells ,HCT116 Cells ,In vitro ,Cell biology ,Mitochondria ,030104 developmental biology ,Oncology ,Mechanism of action ,Cell culture ,A549 Cells ,030220 oncology & carcinogenesis ,Cancer cell ,Female ,medicine.symptom ,Lysosomes ,Reactive Oxygen Species ,HT29 Cells ,Methane ,HeLa Cells - Abstract
Herein we present half-sandwich IrIII complexes [(η5-Cpxbiph)Ir(OˆC)Cl] containing OˆC(NHC)-chelating ligand as anticancer and antimetastasis agents. All the complexes displayed high potency in vitro against a wide range of cancer cells. In addition, Ir2 significantly curb tumor growth in a colon cancer mouse xenograft model in vivo. Further mechanism of action studies indicate that Ir2-initiated apoptosis occurs through ROS-mediated cross-talk between mitochondria and lysosomes.
- Published
- 2018
26. Phloretin ameliorates dextran sulfate sodium-induced ulcerative colitis in mice by regulating the gut microbiota
- Author
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Min Li, Jie Ren, Mingyong Wang, Yunying An, Genshen Zhong, Jiazeng Cui, Duan Li, Dong Yan, Minna Wu, and Puze Li
- Subjects
CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Colon ,Phloretin ,CD8-Positive T-Lymphocytes ,Pharmacology ,Gut flora ,Proinflammatory cytokine ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Immune system ,Lactobacillus ,NLR Family, Pyrin Domain-Containing 3 Protein ,medicine ,Animals ,Alistipes ,Mice, Inbred BALB C ,biology ,Dextran Sulfate ,NF-kappa B ,technology, industry, and agriculture ,biology.organism_classification ,medicine.disease ,Ulcerative colitis ,Gastrointestinal Microbiome ,Transplantation ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Colitis, Ulcerative ,Spleen - Abstract
Phloretin, extracted from the pericarp and velamen of apples or pears, is a dihydrochalcone flavonoid with anti-bacterial and anti-inflammatory activities. It has been reported that phloretin has anti-inflammatory effects in ulcerative colitis (UC) mice. However, the role of the gut microbiota in the phloretin anti-UC process remains unclear. In this study, we observed that the anti-UC effect of phloretin was affected by co-housing, probably because of the transmissible nature of the gut micobiota. Through fecal micobiota transplantation (FMT), the effects of the gut microbiota on the anti-UC of phloretin were further confirmed. UC was induced in mice by administrating 3% dextran sulfate sodium (DSS) in drinking water for 7 days. Phloretin (60 mg/kg) was administered by gavage every day during the experiment. Fecal microbes (109 CFU/mL) from phloretin-treated UC mice were administered by gavage to non-phloretin-treated UC mice for 7 days. The results showed that FMT, like phloretin, ameliorated UC by improving disease symptoms and colon inflammation, balancing inflammatory cytokines, maintaining intestinal barrier integrity, restoring systemic immune function, inhibiting NF-κB and NLRP3 inflammasome activation and ameliorating the oxidant stress. Both FMT and phloretin treatment increased the levels of Bacteroidetes, Alistipes and Lactobacillus and decreased those of Firmicutes, Oscillibacter and Ruminiclostridium_6. Correlation analysis between gut microbes and micro-environmental factors revealed that Alistipes abundance was negatively correlated with DAI, pathological score, and TNF-α, IL-6 and IL-1β levels, and Alistipes was more abundant in phloretin or FMT treated UC mice. Oscillibacter abundance was significantly positively correlated with IL-6 and IL-1β levels and pathological score, and Oscillibacter was increased in UC mice. Furthermore, network analysis of the dominant genera revealed that Alistipes abundance was negatively related to Oscillibacter abundance. In conclusion, this study suggests that the anti-UC effects of phloretin are achieved through regulation of the gut microbiota and phloretin has the potential to be developed as a promising agent for the treatment of UC.
- Published
- 2019
27. Effects of Agricultural Land Use Change on Fungal Community Composition
- Author
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Genshen Zhong, Wenxue Wei, Minna Wu, and Delong Meng
- Subjects
Ecology ,Land use ,Biology ,complex mixtures ,Tillage ,Terminal restriction fragment length polymorphism ,Community composition ,Agronomy ,Agricultural land ,Abundance (ecology) ,Soil water ,Paddy field ,Ecology, Evolution, Behavior and Systematics - Abstract
Anthropogenic disturbances, such as tillage, management practices, and fertilization, can influence soil microbial communities, but little is known about the effects of land use type on soil fungal communities. In this study, fungal abundance, diversity and community composition in soils were analyzed, to determine the impacts of different agricultural land use types, including old rice paddies (ORP), the long-term and (LTV), short-term (STV) cultivation of vegetables and Magnolia nursery plantations (MNP). Compared to the soils in ORP, the fungal abundance, determined by real-time quantitative polymerase chain reaction, was significantly higher in soils from LTV fields and lower in those from MNP; the copy numbers of the fungal ITS genes in the LTV soils were 30 times greater than in the MNP soils. The terminal restriction fragment length polymorphism (T-RFLP) results showed that the fungal community composition was obviously different in the different soils, based on land use type. Only three T...
- Published
- 2015
28. Small antibody fusion proteins with complementarity-determining regions and lidamycin for tumor targeting therapy
- Author
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Shenghua Zhang, Genshen Zhong, Yong-Su Zhen, Zhi‑Shan Xu, Minna Wu, and Xiao-Fang Guo
- Subjects
Cancer Research ,Gelatinases ,lidamycin ,biology ,business.industry ,hemic and immune systems ,chemical and pharmacologic phenomena ,Articles ,complementarity-determining region-3 ,Molecular biology ,Fusion protein ,In vitro ,Oncology ,Antigen ,In vivo ,Immunology ,biology.protein ,Enediyne ,Medicine ,Antibody ,tumor therapy ,Cytotoxicity ,business ,gelatinases - Abstract
Gelatinases are overexpressed in several types of maligancies and tumor stromal cells. Lidamycin is an enediyne antitumor antibiotic, which is composed of an apoprotein (LDP) and an active chromophore (AE). It is known that the heavy-chain complementarity-determining region-3 (CDR3) domain of scFv is important in antibody affinity. The aim of this study was to prepare the enediyne-energized fusion proteins with a heavy-chain CDR3 domain of anti-gelatinases scFv and lidamycin, and to evaluate their antitumor efficiency. Fusion proteins comprising the CDR3 domain and the lidamycin apoprotein were generated, and ELISA, immunofluorescence and FACS were used to analyze the binding of the fusion protein with antigen gelatinases. The purified fusion proteins were assembled with the lidamycin chromophore, and the antitumor effects were evaluated in vitro and in vivo. It was found that the CDR3-LDP and CDR3-LDP-CDR3 fusion proteins demonstrated high affinity towards antigen gelatinases. Following stimulation of CDR3-LDP with enediyne, the results of MTT showed potent cytotoxicity towards tumor cells; the IC50 values of CDR3-LDP-AE to HepG2 and Bel-7402 tumor cells were 1.05×10-11 and 6.6×10-14 M, respectively. In addition, CDR3-LDP-AE displayed a potent antitumor effect in H22 cell xenografts in mice; the combination of CDR3-LDP (10 mg/kg) and CDR3-LDP-AE (0.25 and 0.5 mg/kg) revealed that the tumor inhibitory rates were 85.2 and 92.7%, respectively (P
- Published
- 2013
29. A bispecific enediyne-energized fusion protein targeting both epidermal growth factor receptor and insulin-like growth factor 1 receptor showing enhanced antitumor efficacy against non-small cell lung cancer
- Author
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Ping Chen, Wang Peizhen, Liang Li, Xiaofei Zhu, Xiao-Fang Guo, Bao-guo Deng, Qingfang Miao, Hai-ying Cao, Yong-Su Zhen, and Genshen Zhong
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Lung Neoplasms ,Cell Survival ,medicine.medical_treatment ,Recombinant Fusion Proteins ,EGFR ,Apoptosis ,NSCLC ,03 medical and health sciences ,Insulin-like growth factor ,Mice ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Insulin-Like Growth Factor I ,Protein kinase B ,lidamycin ,biology ,business.industry ,Growth factor ,Cell Cycle ,Cancer ,medicine.disease ,Fusion protein ,Xenograft Model Antitumor Assays ,ErbB Receptors ,Disease Models, Animal ,bispecific fusion protein ,030104 developmental biology ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,biology.protein ,Female ,Enediynes ,business ,IGF-1R ,Protein Binding ,Signal Transduction ,Research Paper - Abstract
// Xiao-Fang Guo 1 , Xiao-Fei Zhu 2, 3 , Hai-Ying Cao 1 , Gen-Shen Zhong 4 , Liang Li 5 , Bao-Guo Deng 1 , Ping Chen 1 , Pei-Zhen Wang 1 , Qing-Fang Miao 5 , Yong-Su Zhen 5 1 Department of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China 2 Department of Clinical Immunology, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China 3 Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, Xinxiang, China 4 Laboratory of Cancer Biotherapy, Institute of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, China 5 Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Perking Union Medical College, Beijing, China Correspondence to: Xiao-Fang Guo, email: guoxiaofang_1981@126.com Yong-Su Zhen, email: zhenysm@126.com Keywords: EGFR, IGF-1R, lidamycin, bispecific fusion protein, NSCLC Received: July 04, 2016 Accepted: February 20, 2017 Published: March 06, 2017 ABSTRACT Epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) both overexpressed on non-small cell lung cancer (NSCLC) and are known cooperatively to promote tumor progression and drug resistance. This study was to construct a novel bispecific fusion protein EGF-IGF-LDP-AE consisting of EGFR and IGF-IR specific ligands (EGF and IGF-1) and lidamycin, an enediyne antibiotic with potent antitumor activity, and investigate its antitumor efficacy against NSCLC. Binding and internalization assays showed that EGF-IGF-LDP protein could bind to NSCLC cells with high affinity and then internalized into cells with higher efficiency than that of monospecific proteins. In vitro , the enediyne-energized analogue of bispecific fusion protein (EGF-IGF-LDP-AE) displayed extremely potent cytotoxicity to NSCLC cell lines with IC 50
- Published
- 2016
30. Long non-coding RNA HoxA-AS3 interacts with EZH2 to regulate lineage commitment of mesenchymal stem cells
- Author
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Shan Jiang, Xifeng Lu, Xinxing Zhu, Yi-Zhou Jiang, Genshen Zhong, Dong-bao Chen, Shanshan Xu, Chun-Zhi Ai, Demeng Chen, and Ya-Wei Yan
- Subjects
0301 basic medicine ,Mice, Nude ,Biology ,Epigenesis, Genetic ,03 medical and health sciences ,Mice ,Osteogenesis ,Gene expression ,Gene silencing ,Animals ,Humans ,Cell Lineage ,Enhancer of Zeste Homolog 2 Protein ,Gene Silencing ,Cells, Cultured ,Cell Proliferation ,Regulation of gene expression ,Genetics ,Gene knockdown ,Mice, Inbred BALB C ,Adipogenesis ,Osteoblasts ,Mesenchymal stem cell ,Correction ,Cell Differentiation ,Mesenchymal Stem Cells ,Long non-coding RNA ,Cell biology ,RUNX2 ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,030104 developmental biology ,Oncology ,RNA, Long Noncoding ,Reprogramming - Abstract
Long non-coding RNAs (lncRNAs) play an important role in gene regulation and are involving in diverse cellular processes. However, their roles in reprogramming of gene expression profiles during lineage commitment and maturation of mesenchymal stem cells (MSCs) remain poorly understood. In the current study, we characterize the expression of a lncRNA, HoxA-AS3, during the differentiation of MSCs. We showed that HoxA-AS3 is increased upon adipogenic induction of MSCs, while HoxA-AS3 remains unaltered during osteogenic induction. Silencing of HoxA-AS3 in MSCs resulted in decreased adipogenesis and expression of adipogenic markers, PPARG, CEBPA, FABP4 and ADIPOQ. Conversely, knockdown of HoxA-AS3 expression in MSCs exhibited an enhanced osteogenesis and osteogenic markers expression, including RUNX2, SP7, COL1A1, IBSP, BGLAP and SPP1. Mechanistically, HoxA-AS3 interacts with Enhancer Of Zeste 2 (EZH2) and is required for H3 lysine-27 trimethylation (H3K27me3) of key osteogenic transcription factor Runx2. Our data reveal that HoxA-AS3 acts as an epigenetic switch that determines the lineage specification of MSC.
- Published
- 2016
31. Lapatinib, a dual inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, potentiates the antitumor effects of cisplatin on esophageal carcinoma
- Author
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Xiao-Fang Guo, Xiaofei Zhu, Genshen Zhong, and Bao-guo Deng
- Subjects
MAPK/ERK pathway ,Cisplatin ,biology ,Cell growth ,medicine.drug_class ,business.industry ,Gastroenterology ,General Medicine ,Pharmacology ,Lapatinib ,Tyrosine-kinase inhibitor ,medicine ,biology.protein ,Epidermal growth factor receptor ,Signal transduction ,skin and connective tissue diseases ,business ,Protein kinase B ,medicine.drug - Abstract
Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) overexpression occurs in over 30% of esophageal carcinomas. Combination therapies of EGFR- and HER2-targeting agents with cytotoxic agents are considered a potential therapeutic strategy for esophageal cancer. The antitumor effects of lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2, cisplatin alone, and the combination of the two drugs on esophageal cancer cells were evaluated. The growth inhibition activity of lapatinib, cisplatin, and lapatinib plus cisplatin was measured by 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assays, and the combination index values were calculated. Additionally, cell cycle distribution and cell apoptosis treated with lapatinib or cisplatin alone and the combination of the two drugs were detected by flow cytometry analysis. The activation of EGFR and HER2 signaling pathways was monitored by Western blot analysis. These experimental data showed that the combination of lapatinib and cisplatin synergistically inhibited cell proliferation and exhibited an enhanced pro-apoptotic effect on esophageal cancer cells. The underlying mechanisms of potentiated effects of combined treatment were associated with reduced phosphorylation of EGFR and HER2, and the downstream signaling molecules AKT and extracellular regulated protein kinases (ERK). Our findings indicated that the combination of lapatinib and cisplatin is one of the promising treatment strategies for esophageal carcinomas with EGFR and HER2 overexpression.
- Published
- 2012
32. Pilot-scale production and purification of a staphylokinase-based fusion protein over-expressed in Escherichia coli
- Author
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Yang Liu, Chu-Tse Wu, Aiping Yu, Genshen Zhong, and Bingxing Shi
- Subjects
chemistry.chemical_classification ,Lysis ,Chromatography ,Ecology ,Expanded bed adsorption ,Staphylokinase ,Peptide ,Biology ,medicine.disease_cause ,Molecular biology ,Fusion protein ,law.invention ,chemistry ,law ,Genetics ,medicine ,Bioreactor ,Recombinant DNA ,Escherichia coli ,Ecology, Evolution, Behavior and Systematics ,Biotechnology - Abstract
SFH, a recombinant staphylokinase-based fusion protein linked by the factor Xa recognition peptide at the N-terminus of hirudin, is a promising therapeutic candidate for thromboembolic diseases. To develop SFH into a new thrombolytic agent, scaled-up production was carried out to provide sufficient preparation for animal safety and clinical studies. Here, we describe a pilot-scale cultivation and purification process for the production of SFH. A high-cell-density fed-batch cultivation for the production of SFH in E. coli was developed in a 40-L bioreactor, which produced about 1.1 g/L of recombinant protein. SFH was purified to homogeneity from the E. coli lysate by expanded bed adsorption chromatography and anion-exchange chromatography, with over 99% purity and 54% recovery. Moreover, the residual endotoxin content was less than 0.5 EU/mL. The molecular weight and in vitro bioactivity of SFH were also determined by electrospray ionization-mass spectrometry (ESI-MS) and fibrinolytic activity assay, respectively.
- Published
- 2008
33. Isolation and functional identification of a novel human hepatic growth factor: Hepatopoietin Cn
- Author
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Chun-Ping Cui, Genshen Zhong, Ping Wei, Chu-Tse Wu, Yang Liu, Shaojun Du, Bingxing Shi, Da-Jin Zhang, Zi-Kuan Guo, Dan-Li Wu, and Li-Sheng Wang
- Subjects
DNA Replication ,medicine.medical_treatment ,Molecular Sequence Data ,Biology ,Carboxyfluorescein diacetate succinimidyl ester ,Mice ,chemistry.chemical_compound ,In vivo ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Nuclear protein ,Cell Proliferation ,Liver injury ,Hepatology ,Hepatocyte Growth Factor ,Growth factor ,Cell Differentiation ,medicine.disease ,Recombinant Proteins ,Liver regeneration ,Liver Regeneration ,medicine.anatomical_structure ,Liver ,Biochemistry ,chemistry ,Hepatocyte ,Cattle ,Bromodeoxyuridine - Abstract
Hepatic stimulating substance (HSS) was first isolated from weanling rat liver in 1975 and found to stimulate hepatic DNA synthesis both in vitro and in vivo. Since then, mammalian and human HSS have been investigated for their potential to treat hepatic diseases. However, the essential nature in composition and structure of HSS remain puzzling because HSS has not been completely purified. Heating, ethanol precipitation, and ion-exchange chromatographies had been carried out to isolate the protein with specific stimulating activity from newborn calf liver, and [3H]thymidine deoxyribose (TdR)/bromodeoxyuridine (BrdU) incorporation and carboxyfluorescein diacetate succinimidyl ester (CFSE)-based proliferation assay to determine the bioactivity in vitro and in vivo. We report the purification of a novel 30-kDa protein from a crude extract of calf liver HSS. This protein is a member of the leucine-rich acidic nuclear protein family (LANP) and has been named hepatopoietin Cn (HPPCn). Studies of partially hepatectomized (PH) mice show that levels of HPPCn messenger RNA (mRNA) increase after liver injury. Furthermore, the recombinant human protein (rhHPPCn) was shown to stimulate hepatic DNA synthesis and activate signaling pathways involved in hepatocyte proliferation in vitro and in vivo. Conclusion: HPPCn is a novel hepatic growth factor that plays a role in liver regeneration. (HEPATOLOGY 2008;47:986–995.)
- Published
- 2008
34. Transarterial oily chemoembolization with lidamycin shows potent therapeutic efficacy in VX2 rabbit liver tumor
- Author
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Shuhua Huo, Huichao Xue, Genshen Zhong, Jinsong Li, Zhishan Xu, Jinsong Qi, Minna Wu, Yanjun Zhou, and Liang Li
- Subjects
Liver tumor ,Pharmacology ,OncoTargets and Therapy ,chemistry.chemical_compound ,Adriamycin ,In vivo ,medicine ,Pharmacology (medical) ,Cytotoxicity ,Original Research ,TOCE ,lidamycin ,biology ,VX2 ,business.industry ,hepatocellular carcinoma ,medicine.disease ,digestive system diseases ,Proliferating cell nuclear antigen ,Vascular endothelial growth factor ,Oncology ,chemistry ,Hepatocellular carcinoma ,Toxicity ,Lipiodol ,biology.protein ,business ,medicine.drug - Abstract
Genshen Zhong,1,* Jinsong Qi,2,* Shuhua Huo,1 Huichao Xue,3 Zhishan Xu,1 Jinsong Li,4 Yanjun Zhou,5 Minna Wu,1 Liang Li6 1Laboratory of Cancer Biotherapy, Institute of Neurology, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People’s Republic of China; 2Department of Intervention, 3Department of General Surgery, 4Department of Pathology, 5Department of Clinical Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan Province, People’s Republic of China; 6Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China *These authors contributed equally to this work Abstract: Transarterial oily chemoembolization (TOCE) is one of the most effective approaches for the treatment of patients with hepatocellular carcinoma (HCC), who are not suitable for surgical therapy. Lidamycin (LDM), a potent antitumor antibiotic, demonstrates good antitumor efficacy in various tumor types, both in vitro and in vivo. In this study, the antitumor efficacy of LDM combined with TOCE against the rabbit VX2 tumor was assessed. A toxicity assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) demonstrated that a combination of LDM with lipiodol did not impair the cytotoxicity of LDM against HepG2 cells in vitro. Using TOCE in rabbit VX2 tumor models, LDM showed a more powerful inhibitory effect against the tumor and lowered the expression levels of proliferating cell nuclear antigen (PCNA), cluster of differentiation 31 (CD31), and vascular endothelial growth factor (VEGF) compared to Adriamycin (ADM); moreover, this improvement was not accompanied by an increase of hepatotoxicity as shown by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. These results suggested that LDM combined with TOCE may be a feasible strategy in HCC therapy in the future. Keywords: lidamycin, TOCE, hepatocellular carcinoma, VX2, Adriamycin
- Published
- 2015
35. PTEN Plays an Important Role in Thrombin-Mediated Lung Cancer Cell Functions
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Lingyun Zhu, Qiaoyan Dong, Zhishan Xu, Aiping Yu, Min Yao, and Genshen Zhong
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Lung Neoplasms ,Article Subject ,Down-Regulation ,lcsh:Medicine ,Apoptosis ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Phosphatidylinositol 3-Kinases ,Cell Movement ,Cell Line, Tumor ,Proliferating Cell Nuclear Antigen ,SKP2 ,Tensin ,PTEN ,Humans ,Protein kinase B ,S-Phase Kinase-Associated Proteins ,PI3K/AKT/mTOR pathway ,General Immunology and Microbiology ,Akt/PKB signaling pathway ,Cell Cycle ,lcsh:R ,PTEN Phosphohydrolase ,Thrombin ,Cell migration ,General Medicine ,Cell biology ,Cancer research ,biology.protein ,MCF-7 Cells ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction ,Research Article - Abstract
Thrombin and its membrane receptor, protease-activated receptor 1 (PAR1), have been reported to promote the development of lung cancerin vitroandin vivo. However, the intracellular molecular mechanism or signaling pathway that mediates the cytological effects after the thrombin-receptor interaction is poorly understood. Our previous study observed that the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was downregulated in thrombin-stimulated lung cancer. In this study, the role of PTEN in thrombin-mediated cell function and the corresponding cell signaling pathway were studied in lung cancer cell Glc-82. The results indicated that thrombin downregulates the PTEN expression level and that PTEN plays an important role in thrombin-mediated Glc-82 functions, including cell cycle progression, cell apoptosis, and cell migration. The PI3K/AKT signaling pathway and its related proteins, including p27 and S phase kinase associated protein 2 (Skp2), are involved in the effects induced by PTEN downregulation. PAR1 plays a role in thrombin-mediated reduction of PTEN expression. This study suggested that the PTEN/PI3K/AKT signaling pathway plays an important role in thrombin/PAR1-mediated lung cancer cell growth and migration.
- Published
- 2015
36. Antitumor activities of dFv-LDP-AE: An enediyne-energized fusion protein targeting tumor-associated antigen gelatinases
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Minna Wu, Shenghua Zhang, Qingfang Miao, Yong-Su Zhen, Genshen Zhong, and Xiao-Fang Guo
- Subjects
Male ,Cancer Research ,Gelatinases ,Carcinoma, Hepatocellular ,Recombinant Fusion Proteins ,Cell ,Mice, Nude ,Apoptosis ,Biology ,Mice ,Cell Line, Tumor ,medicine ,Cytotoxic T cell ,Animals ,Humans ,Cytotoxicity ,Antibiotics, Antineoplastic ,Oncogene ,Liver Neoplasms ,General Medicine ,Cell Cycle Checkpoints ,Cell cycle ,Molecular biology ,Fusion protein ,Xenograft Model Antitumor Assays ,medicine.anatomical_structure ,Aminoglycosides ,Oncology ,Cancer research ,Enediynes ,Single-Chain Antibodies - Abstract
Gelatinases play an important role in tumor growth and metastasis, and overexpression of these molecules is strongly correlated with poor prognosis in a variety of malignant tumors. Lidamycin is an enediyne antitumor antibiotic with potent cytotoxicity. We previously reported that a tandem scFv format (dFv-LDP-AE) showed enhanced binding ability with gelatinases compared with the scFv-lidamycin conjugate (Fv-LDP-AE). In this study, the antitumor activities of dFv-LDP-AE on hepatocellular carcinoma (HCC) were evaluated in vitro and in vivo. By SDS-PAGE analysis, it was found that partial fusion protein dFv-LDP existed as dimer; the results of ELISA and immunofluorescence demonstrated that the fusion protein dFv-LDP could efficiently bind to hepatoma cells in vitro. The apparent arrest of cell cycle at G2/M phase and induction of apoptosis at nanomole levels indicated that the dFv-LDP-AE was very potent against HCC. In in vivo experiments, dFv-LDP-AE shown enhanced cytotoxic effects compared to those of LDM. Administration at mouse tolerable dosage level, the inhibition rate of tumor growth was 89.5% of dFv-LDP-AE vs. 73.6% of LDM on transplantable H22 in mice (P
- Published
- 2012
37. Lapatinib, a dual inhibitor of EGFR and HER2, has synergistic effects with 5-fluorouracil on esophageal carcinoma
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Bao-guo Deng, Genshen Zhong, Xiaofei Zhu, Zhitao Gao, Xiao-Fang Guo, and Hui Wang
- Subjects
Cancer Research ,Esophageal Neoplasms ,medicine.drug_class ,Receptor, ErbB-2 ,Apoptosis ,Pharmacology ,Lapatinib ,Tyrosine-kinase inhibitor ,chemistry.chemical_compound ,Cell Line, Tumor ,Medicine ,Humans ,MTT assay ,Propidium iodide ,Epidermal growth factor receptor ,skin and connective tissue diseases ,Protein kinase B ,Protein Kinase Inhibitors ,Cell Proliferation ,biology ,business.industry ,Cell growth ,Gene Amplification ,Drug Synergism ,General Medicine ,Cell cycle ,G1 Phase Cell Cycle Checkpoints ,ErbB Receptors ,Oncology ,chemistry ,biology.protein ,Quinazolines ,Fluorouracil ,business ,medicine.drug - Abstract
Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) amplification occurs in over 30% of esophageal carcinomas. Combination therapies with EGFR and HER2-targeting agents and cytotoxic agents are considered a potential therapeutic option for esophageal cancer. We evaluated the antitumor effects of lapatinib, a dual tyrosine kinase inhibitor which simultaneously inhibits EGFR and HER2, 5-fluorouracil (5-Fu) alone and in combination on esophageal cancer cells. The antiproliferative activity of lapatinib, 5-Fu and lapatinib plus 5-Fu was measured by MTT assay and the combination index (CI) values were calculated. Additionally, cell cycle distribution of lapatinib alone and the combination with 5-Fu were detected by flow cytometry analysis. Annexin V-FITC and propidium iodide stain were used for analyzing the apoptotic cells after cells were treated with either agent alone or in combination. The EGFR and HER2 activated signaling pathways were monitored by western blotting. The combination of lapatinib and 5-Fu synergistically inhibited cell proliferation and exhibited an enhanced proapoptotic effect on esophageal cancer cells. The potentiation effect of combined treatment was associated with downregulation of EGFR and HER2 signaling pathways because data from western blot analysis showed that lapatinib in combination with 5-Fu markedly reduced the phosphorylation of EGFR and HER2, and inhibited the activation of downstream signaling molecules, such as AKT and ERK. A significant G1 arrest was also observed in cell cycle analysis after exposing cells to lapatinib, however, combination with 5-Fu did not enhance G1 arrest. These results indicate that the combination of the lapatinib and 5-Fu is a promising treatment option for esophageal carcinoma with HER2 amplification.
- Published
- 2011
38. A tandem scFv-based fusion protein and its enediyne-energized analogue show intensified therapeutic efficacy against lung carcinoma xenograft in athymic mice
- Author
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Yi Li, Rui-Juan Gao, Xiujun Liu, Shenghua Zhang, Genshen Zhong, Qingfang Miao, and Yong-Su Zhen
- Subjects
Cancer Research ,Gelatinases ,Pathology ,medicine.medical_specialty ,Lung Neoplasms ,Proliferation index ,Recombinant Fusion Proteins ,Mice, Nude ,Angiogenesis Inhibitors ,Antineoplastic Agents ,Mice ,Carcinoma ,medicine ,Enediyne ,Animals ,Humans ,Cell Proliferation ,biology ,Cancer ,medicine.disease ,Fusion protein ,Xenograft Model Antitumor Assays ,Aminoglycosides ,Oncology ,Tumor progression ,Microvessels ,biology.protein ,Cancer research ,Antibody ,Enediynes ,Apoproteins ,Single-Chain Antibodies - Abstract
Gelatinases play important roles in tumor progression and are abundantly expressed in a variety of malignant tumors. Antibody targeting gelatinases is a possible avenue to fight against cancer. However, antibody alone can not achieve curative efficacy. Herein, we demonstrated the intensified targeting therapy of a tandem scFv-based fusion protein and its enediyne-energized analogue against gelatinases-overexpressed tumor. A fusion protein dFv-LDP, comprising a tandem scFv of anti-gelatinases linked to the apoprotein (LDP) of lidamycin, was generated and showed strong tumor targeting capability in three different tumor xenografts. In PG-BE1 lung carcinoma xenograft, the tumor inhibition rate was 77.5% by dFv-LDP versus 94.2% by dFv-LDP-AE, the product of dFv-LDP assembled with the active enediyne chromophore (AE) of lidamycin. Moreover, the combination of dFv-LDP with dFv-LDP-AE further augmented the therapeutic efficacy, producing initial tumor shrinkage in five of six mice. The microvessel density (P
- Published
- 2009
39. Two characteristics of a recombinant fusion protein composed of staphylokinase and hirudin: high thrombus affinity and thrombus-targeting release ofanticoagulant activity
- Author
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Aiping, Yu, Chuanling, Zhang, Chunna, Dong, Hongyang, Yu, Genshen, Zhong, Lisheng, Wang, and Chutse, Wu
- Subjects
Mice ,Recombinant Fusion Proteins ,Factor X ,Animals ,Anticoagulants ,Metalloendopeptidases ,Thrombolytic Therapy ,Thrombosis ,Vena Cava, Inferior ,Hirudins ,Rats - Abstract
To improve thrombolytic effect, a fusion protein SFH composed of staphylokinase (SAK) and hirudin (HV) with blood coagulation factor Xa (FXa) recognition peptide as a linker, was designed. SFH showed improved thrombolytic effect and low bleeding in vivo. Two thrombus-targeting mechanisms might account for the above features of SFH. This study was designed to study the two thrombus-targeting mechanisms of SFH. ELISA and immunohistochemistry assay were used to study the improved thrombus selectivity of SFH and the results showed that SFH, compared with SAK, displayed higher affinity for thrombin and thrombin-rich thrombus. To verify the thrombus-targeting release of anticoagulant activity of SFH, FH-a derivative of HV with only FXa recognition sequence at N terminus of HV was designed and used in animal tests. In inferior vena cava thrombosis model, FH showed equal antithrombotic effect as HV, indicating that HV could be successfully released from FH by FXa cleavage in vivo. More importantly, no prolongation of plasma TT, APTT and PT were found in FH group, but significant prolongations were discovered in HV group. This revealed that the anticoagulant activity of FH was released in thrombus-targeting way and limited in the vicinity of the thrombus, and this could be extrapolated to SFH. In conclusion, the high thrombus affinity and thrombus-targeting release of anticoagulant activity of SFH assigned low bleeding risk to SFH.
- Published
- 2009
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