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1. Oncogenic β-catenin stimulation of AKT2–CAD-mediated pyrimidine synthesis is targetable vulnerability in liver cancer

Author

Liu, Fangming, Gai, Xiaochen, Wu, Yuting, Zhang, Baohui, Wu, Xiaoyu, Cheng, Rongrong, Tang, Bufu, Shang, Kezhuo, Zhao, Na, Deng, Weiwei, Chen, Jie, Zhang, Zhengyi, Gu, Song, Zheng, Liang, and Zhang, Hongbing

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Biological Sciences, Liver Cancer, Genetics, Rare Diseases, Chronic Liver Disease and Cirrhosis, Cancer, Liver Disease, Digestive Diseases, Aetiology, 2.1 Biological and endogenous factors, Good Health and Well Being, Animals, Aspartic Acid, Carcinogenesis, Dihydroorotase, Drug Delivery Systems, Ligases, Liver Neoplasms, Mice, Nucleotides, Phosphates, Proto-Oncogene Proteins c-akt, Pyrimidines, beta Catenin, beta-catenin, CAD, AKT2, pyrimidine synthesis, liver cancer, β-catenin
Abstract

CTNNB1, encoding β-catenin protein, is the most frequently altered proto-oncogene in hepatic neoplasms. In this study, we studied the significance and pathological mechanism of CTNNB1 gain-of-function mutations in hepatocarcinogenesis. Activated β-catenin not only triggered hepatic tumorigenesis but also exacerbated Tp53 deletion or hepatitis B virus infection-mediated liver cancer development in mouse models. Using untargeted metabolomic profiling, we identified boosted de novo pyrimidine synthesis as the major metabolic aberration in β-catenin mutant cell lines and livers. Oncogenic β-catenin transcriptionally stimulated AKT2, which then phosphorylated the rate-limiting de novo pyrimidine synthesis enzyme CAD (carbamoyl-phosphate synthetase 2, aspartate transcarbamoylase, dihydroorotase) on S1406 and S1859 to potentiate nucleotide synthesis. Moreover, inhibition of β-catenin/AKT2-stimulated pyrimidine synthesis axis preferentially repressed β-catenin mutant cell proliferation and tumor formation. Therefore, β-catenin active mutations are oncogenic in various preclinical liver cancer models. Stimulation of β-catenin/AKT2/CAD signaling cascade on pyrimidine synthesis is an essential and druggable vulnerability for β-catenin mutant liver cancer.

Published
2022

2. Comprehensive multiomics analysis of the effect of ginsenoside Rb1 on hyperlipidemia

Author

Zhan Kaixuan, Ma Yixin, Yang Guan-lin, Lv Xiaoming, Song Nan, Chen Si, Yu Ning, Zhao Na, Ju Xing, Cao Yuan, Sui Guoyuan, Wu Yao, and Jia Lianqun

Subjects
Proteomics, Aging, Ginsenosides, Linoleic acid, Metabolite, microbiome, Glyoxylate and dicarboxylate metabolism, Hyperlipidemias, Mice, chemistry.chemical_compound, Phosphatidylcholine, ginsenoside Rb1, Lipidomics, Animals, hyperlipidemia, Diacylglycerol kinase, Body Weight, Cell Biology, Metabolism, Lipid Metabolism, eye diseases, Disease Models, Animal, Liver, chemistry, Biochemistry, Glycerophospholipid, lipidomics, transcriptome, Research Paper
Abstract

We analyzed the effects of ginsenoside Rb1 on hyperlipidemic in model mice. Using stool, plasma and hepatic tissue samples, we observed that the genera Blautia and Allobaculum were increased and Turicibacter was decrease in Rb1-treated mice as compared to untreated model mice. Ether lipid metabolism, glycerolipid metabolism, and glyoxylate and dicarboxylate metabolism were differentially enriched between the Rb1 and model groups. Lipidomics revealed 169 metabolites differentially expressed between the model and Rb1 groups in a positive ion model and 58 in a negative ion model. These metabolites mainly participate in glycerophospholipid, linoleic acid, and alpha-linolenic acid metabolism. The main metabolites enriched in these three pathways were phosphatidylcholine, diacylglycerol and ceramide, respectively. In a transcriptome analysis, 766 transcripts were differentially expressed between the Rb1 and model groups. KEGG analysis revealed lysine degradation, inositol phosphate metabolism, and glycerophospholipid metabolism to be the main enriched pathways. Multiomics analysis revealed glycerophospholipid metabolism to be a common pathway and phosphatidylcholine the main metabolite differentially enriched between the Rb1 and model groups. Results from fecal transplanted germ-free mice suggest that to suppress hyperlipidemia, Rb1 regulates gut microbiota by regulating the synthesis and decomposition of phosphatidylcholine in glycerophospholipid metabolism, which in turn decreases serum total cholesterol.

Published
2021

3. TRIB3 promotes MYC-associated lymphoma development through suppression of UBE3B-mediated MYC degradation

Author

Fang Hua, Bing Cui, Yu-fen Yuan, Yang Xiao, Zaiwuli Yeerjiang, Chen-xi Zhao, Xiaowei Zhang, Ting-ting Zhang, Xiaoxi Lv, Jiao-jiao Yu, Zhao-na Yang, Shan-Shan Liu, Feng Wang, Zhuo-Wei Hu, Ke Li, Shuang Shang, and Jin-mei Yu

Subjects
Male, 0301 basic medicine, Ubiquitylation, General Physics and Astronomy, Cell Cycle Proteins, Mice, 0302 clinical medicine, Ubiquitin, Transcription (biology), hemic and lymphatic diseases, Gene Knock-In Techniques, RNA-Seq, Cell Self Renewal, Aged, 80 and over, Mice, Knockout, Regulation of gene expression, Non-hodgkin lymphoma, Multidisciplinary, biology, Lymphoma, Non-Hodgkin, Middle Aged, Ubiquitin ligase, Gene Expression Regulation, Neoplastic, TRIB3, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Disease Progression, Chromatin Immunoprecipitation Sequencing, Female, Proteasome Inhibitors, Adult, Proteasome Endopeptidase Complex, Adolescent, Ubiquitin-Protein Ligases, Science, Primary Cell Culture, Antineoplastic Agents, Protein Serine-Threonine Kinases, Article, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins c-myc, Young Adult, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Transcription factor, Aged, HEK 293 cells, Ubiquitination, General Chemistry, medicine.disease, Xenograft Model Antitumor Assays, Lymphoma, Repressor Proteins, HEK293 Cells, 030104 developmental biology, Proteolysis, biology.protein, Cancer research
Abstract

The transcription factor MYC is deregulated in almost all human cancers, especially in aggressive lymphomas, through chromosomal translocation, amplification, and transcription hyperactivation. Here, we report that high expression of tribbles homologue 3 (TRIB3) positively correlates with elevated MYC expression in lymphoma specimens; TRIB3 deletion attenuates the initiation and progression of MYC-driven lymphoma by reducing MYC expression. Mechanistically, TRIB3 interacts with MYC to suppress E3 ubiquitin ligase UBE3B-mediated MYC ubiquitination and degradation, which enhances MYC transcriptional activity, causing high proliferation and self-renewal of lymphoma cells. Use of a peptide to disturb the TRIB3-MYC interaction together with doxorubicin reduces the tumor burden in MycEμ mice and patient-derived xenografts. The pathophysiological relevance of UBE3B, TRIB3 and MYC is further demonstrated in human lymphoma. Our study highlights a key mechanism for controlling MYC expression and a potential therapeutic option for treating lymphomas with high TRIB3-MYC expression., c-MYC is often deregulated in human cancers including lymphomas. Here, the authors show that a member of the pseudokinase family, tribbles homologue 3 (TRIB3), interacts with c-MYC to suppress c-MYC ubiquitination and degradation, leading to increased proliferation and self-renewal of lymphoma cells.

Published
2020

4. PML-RARα interaction with TRIB3 impedes PPARγ/RXR function and triggers dyslipidemia in acute promyelocytic leukemia

Author

Zhuo Wei Hu, Hong-Hu Zhu, Bing Cui, Pingping Li, Ke Li, Feng Wang, Zhen Yu Li, and Zhao Na Yang

Subjects
Male, 0301 basic medicine, Oncogene Proteins, Fusion, Medicine (miscellaneous), Peroxisome proliferator-activated receptor, Cell Cycle Proteins, Mice, 0302 clinical medicine, AML, Leukemia, Promyelocytic, Acute, immune system diseases, lipid metabolism, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Cancer, Mice, Knockout, chemistry.chemical_classification, leukemia, Middle Aged, Leukemia, TRIB3, 030220 oncology & carcinogenesis, Female, Research Paper, Adult, Acute promyelocytic leukemia, Adolescent, Mice, Transgenic, Protein Serine-Threonine Kinases, Retinoid X receptor, Young Adult, 03 medical and health sciences, medicine, Animals, Humans, neoplasms, Aged, Dyslipidemias, Retrospective Studies, business.industry, tribbles, Lipid metabolism, medicine.disease, PPAR gamma, Repressor Proteins, Retinoid X Receptors, 030104 developmental biology, chemistry, Cancer research, business, Dyslipidemia, Lipoprotein
Abstract

Although dyslipidemia commonly occurs in patients with acute promyelocytic leukemia (APL) in response to anti-APL therapy, the underlying mechanism and the lipid statuses of patients with newly diagnosed APL remain to be addressed. Methods: We conducted a retrospective study to investigate the lipid profiles of APL patients. PML-RARα transgenic mice and APL cells-transplanted mice were used to assess the effects of APL cells on the blood/liver lipid levels. Subsequently, gene set enrichment analysis, western blot and dual luciferase reporter assay were performed to examine the role and mechanism of PML-RARα and TRIB3 in lipid metabolism regulation in APL patients at pretreatment and after induction therapy. Results: APL patients exhibited a higher prevalence of dyslipidemia before anti-APL therapy based on a retrospective study. Furthermore, APL cells caused secretion of triglycerides, cholesterol, and PCSK9 from hepatocytes and degradation of low-density lipoprotein receptors in hepatocytes, which elevated the lipid levels in APL cell-transplanted mice and Pml-Rarα transgenic mice. Mechanistically, pseudokinase TRIB3 interacted with PML-RARα to inhibit PPARγ activity by interfering with the interaction of PPARγ and RXR and promoting PPARγ degradation. Thus, reduced PPARγ activity in APL cells decreased leptin but increased resistin expression, causing lipid metabolism disorder in hepatocytes and subsequent dyslipidemia in mice. Although arsenic/ATRA therapy degraded PML-RARα and restored PPARγ expression, it exacerbated dyslipidemia in APL patients. The elevated TRIB3 expression in response to arsenic/ATRA therapy suppressed PPARγ activity by disrupting the PPARγ/RXR dimer, which resulted in dyslipidemia in APL patients undergoing therapy. Indeed, the PPAR activator not only enhanced the anti-APL effects of arsenic/ATRA by suppressing TRIB3 expression but also reduced therapy-induced dyslipidemia in APL patients. Conclusion: Our work reveals the critical role of the PML-RARα/PPARγ/TRIB3 axis in the development of dyslipidemia in APL patients, potentially conferring a rationale for combining ATRA/arsenic with the PPAR activator for APL treatment.

Published
2020

5. TRIB3 supports breast cancer stemness by suppressing FOXO1 degradation and enhancing SOX2 transcription

Author

Bing Cui, Fang Hua, Jiao-jiao Yu, Zhen-he Wang, Xiao Liang, Shuang Shang, Ke Li, Zhuo-Wei Hu, Xiaoxi Lv, Wei Sun, Pingping Li, Chen-xi Zhao, Xiaowei Zhang, Yuying Liu, Jin-mei Yu, Bo Huang, Feng Wang, Zhao-na Yang, Xue-ying Hou, and Shan-Shan Liu

Subjects
0301 basic medicine, Transcription, Genetic, medicine.medical_treatment, General Physics and Astronomy, Cell Cycle Proteins, FOXO1, Mice, Breast cancer, 0302 clinical medicine, Breast, skin and connective tissue diseases, Regulation of gene expression, Multidisciplinary, Cancer stem cells, Forkhead Box Protein O1, Middle Aged, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, Disease Progression, Neoplastic Stem Cells, Female, Stem cell, Protein Binding, Science, Breast Neoplasms, Protein Serine-Threonine Kinases, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, SOX2, Target identification, Cell Line, Tumor, medicine, SKP2, Animals, Humans, Protein kinase B, business.industry, SOXB1 Transcription Factors, General Chemistry, medicine.disease, Xenograft Model Antitumor Assays, Repressor Proteins, Radiation therapy, 030104 developmental biology, Tissue Array Analysis, Proteolysis, Cancer research, business, Proto-Oncogene Proteins c-akt
Abstract

The existence of breast cancer stem cells (BCSCs) is a major reason underlying cancer metastasis and recurrence after chemotherapy and radiotherapy. Targeting BCSCs may ameliorate breast cancer relapse and therapy resistance. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) positively associates with breast cancer stemness and progression. Elevated TRIB3 expression supports BCSCs by interacting with AKT to interfere with the FOXO1-AKT interaction and suppress FOXO1 phosphorylation, ubiquitination, and degradation by E3 ligases SKP2 and NEDD4L. The accumulated FOXO1 promotes transcriptional expression of SOX2, a transcriptional factor for cancer stemness, which in turn, activates FOXO1 transcription and forms a positive regulatory loop. Disturbing the TRIB3-AKT interaction suppresses BCSCs by accelerating FOXO1 degradation and reducing SOX2 expression in mouse models of breast cancer. Our study provides insights into breast cancer development and confers a potential therapeutic strategy against TRIB3-overexpressed breast cancer., Cancer stem cells contribute to breast cancer metastasis and recurrence. Here the authors show that TRIB3 enhances breast cancer stemness through interaction with AKT to promote FOXO1 stability, which then increases SOX2 activity.

Published
2019

6. Faciogenital Dysplasia 5 supports cancer stem cell traits in basal-like breast cancer by enhancing EGFR stability

Author

Shan-Shan Liu, Fang Hua, Bo Huang, Bing Cui, Zhen-he Wang, Jin-mei Yu, Jiao-jiao Yu, Yu-fen Yuan, Feng Wang, Zaiwuli Yeerjiang, Chen-xi Zhao, Xiaoxi Lv, Zhao-na Yang, Shuang Shang, Ting-ting Zhang, Xiaowei Zhang, Zhuo-Wei Hu, and Ke Li

Subjects
Tissue microarray, biology, Cell growth, Triple Negative Breast Neoplasms, General Medicine, medicine.disease, ErbB Receptors, Mice, Basal (phylogenetics), Breast cancer, Dysplasia, Cancer stem cell, Neoplastic Stem Cells, medicine, Cancer research, biology.protein, Animals, Guanine Nucleotide Exchange Factors, Humans, Immunohistochemistry, Female, Epidermal growth factor receptor
Abstract

Most basal-like breast cancers (BLBCs) are triple-negative breast cancers (TNBCs), which have the worst prognosis and distant metastasis-free survival among breast cancer subtypes. Now, no targeted therapies are available for patients with BLBC due to the lack of reliable and effective molecular targets. Here, we performed the BLBC tissue microarray-based immunohistochemical analysis and showed that Faciogenital Dysplasia 5 (FGD5) abundance is associated with poor prognosis in BLBCs. FGD5 deletion decreased the proliferation, invasion, and tumorsphere formation capacity of BLBC cells. Furthermore, genetic inhibition of Fgd5 in mouse mammary epithelial cells attenuated BLBC initiation and progression by reducing the self-renewal ability of tumor-initiating cells. In addition, FGD5 abundance was positively correlated with the abundance of epidermal growth factor receptor (EGFR) in BLBCs. FGD5 ablation decreased EGFR abundance by reducing EGFR stability in TNBC cells in 2D and 3D culture conditions. Mechanistically, FGD5 binds to EGFR and interferes with basal EGFR ubiquitination and degradation induced by the E3 ligase ITCH. Impaired EGFR degradation caused BLBC cell proliferation and promoted invasive properties and self-renewal. To verify the role of the FGD5-EGFR interaction in the regulation of EGFR stability, we screened a cell-penetrating α-helical peptide PER3 binding with FGD5 to disrupt the interaction. Treatment of BLBC patient-derived xenograft-bearing mice with the peptide PER3 disrupting the FGD5-EGFR interaction either with or without chemotherapy reduced BLBC progression. Our study identified FGD5 as a positive modulator of tumor-initiating cells and suggests a potential therapeutic option for the BLBC subtype of breast cancer.

Published
2021

7. Effects of aerobic exercise on hippocampal SUMOylation in APP/PS1 transgenic mice

Author

Yu Haizhen, Zhao Na, Zhang Chenfei, Xu Bo, and Xia Jie

Subjects
Genetically modified mouse, Male, medicine.medical_specialty, Amyloid beta, SUMO-1 Protein, SUMO protein, Mice, Transgenic, Hippocampal formation, Hippocampus, Pathogenesis, Mice, Alzheimer Disease, Internal medicine, Physical Conditioning, Animal, mental disorders, medicine, Presenilin-1, Aerobic exercise, Animals, Senile plaques, Messenger RNA, Amyloid beta-Peptides, biology, business.industry, General Neuroscience, Sumoylation, Mice, Inbred C57BL, Cysteine Endopeptidases, Endocrinology, biology.protein, business
Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease. SUMOylation, a post-translational modification, has been found to be dysregulated in the AD brain and to exacerbate learning and memory disabilities and increase amyloid beta (Aβ) expression further. To investigate whether exercise-induced alleviation of AD was associated with SUMOylation, which still remains unknown, 3-month-old C57BL/6 mice and APP/PS1 transgenic mice were randomly divided into the wild-type control (WC), wild-type exercise (WE), APP/PS1 control (AC), and APP/PS1 exercise (AE) groups. Mice in the exercise groups underwent a 3-month treadmill exercise regimen. We observed impaired learning and memory abilities in APP/PS1 mice, but the 3-month treadmill exercise regimen improved spatial learning and memory abilities in wild-type and APP/PS1 mice. In addition, senile plaques, SUMO1 mRNA, and SENP1 mRNA levels increased in the hippocampi of APP/PS1 mice. However, 3-month treadmill exercise decreased the levels of senile plaques, SUMO1 mRNA and SENP1 mRNA as well as may reduce SUMO1 modification in 6-month-old APP/PS1 mice, but SUMO2 mRNA expression, SUMO2/3 modification, and overall SUMOylation levels did not significantly change. Our results suggest that the impaired learning and memory abilities and aggregations of Aβ may relate to increased hippocampal SUMO1 transcription levels; the beneficial effects of treadmill exercise on learning and memory performances and AD pathogenesis may associated with the abatement of SUMO1 modification, but may not with SUMO2/3 modification.

Published
2020

8. Metformin suppresses melanoma progression by inhibiting KAT5-mediated SMAD3 acetylation, transcriptional activity and TRIB3 expression

Author

Bing Cui, Chen-xi Zhao, Bo Huang, Jiao-jiao Yu, Xiaoxi Lv, Xiaowei Zhang, Ke Li, Xia Li, Zhuo-Wei Hu, Tingting Zhang, Fang Hua, Zhao-na Yang, and Feng Wang

Subjects
0301 basic medicine, Cancer Research, Down-Regulation, Cell Cycle Proteins, Protein Serine-Threonine Kinases, Biology, Lysine Acetyltransferase 5, Metastasis, Mice, 03 medical and health sciences, Downregulation and upregulation, Cell Movement, Cell Line, Tumor, Genetics, medicine, Animals, Humans, Smad3 Protein, KAT5, Melanoma, Molecular Biology, Cell Proliferation, Regulation of gene expression, Autophagy, Acetylation, medicine.disease, Xenograft Model Antitumor Assays, Metformin, Gene Expression Regulation, Neoplastic, Mice, Inbred C57BL, Repressor Proteins, 030104 developmental biology, TRIB3, Disease Progression, Cancer research, medicine.drug
Abstract

Metformin has beneficial effects of preventing and treating cancers on type 2 diabetic patients. However, the role of metformin in non-diabetic cancer patients and the precise molecular mechanisms against cancer have not yet been sufficiently elucidated. We recently reported that the pseudokinase protein TRIB3 acts as a stress sensor linking metabolic stressors to cancer promotion by inhibiting autophagy and ubiquitin-proteasomal degradation systems; genetically abrogating of TRIB3 expression reduces tumourigenesis and cancer progression. Thus, TRIB3 is a potential therapeutic target for diverse cancers. In this study, we found that metformin attenuates melanoma growth and metastasis by reducing TRIB3 expression in non-diabetic C57BL/6 mice and diabetic KK-Ay mice; overexpression of TRIB3 protects metformin from the activation of autophagic flux, the clearance of accumulated tumour-promoting factors and the attenuation of tumour progression. We further elucidated that TRIB3 acts as an adaptor to recruit lysine acetyltransferase 5 (KAT5) to SMAD3 and induce a phosphorylation-dependent K333 acetylation of SMAD3, which sustains transcriptional activity of SMAD3 and subsequently enhances TRIB3 transcription. Metformin suppresses SMAD3 phosphorylation and decreases the KAT5/SMAD3 interaction, to attenuate the KAT5-mediated K333 acetylation of SMAD3, reduce the SMAD3 transcriptional activity and subsequent TRIB3 expression, thereby antagonizes melanoma progression. Together, our study not only defines a molecular mechanism by which metformin protects against melanoma progression by disturbing the KAT5/TRIB3/SMAD3 positive feedback loop in diabetes and non-diabetes mice, but also suggests a candidate diverse utility of metformin in tumour prevention and therapy because of suppressing stress protein TRIB3 expression.

Published
2018

9. Improved Tumor Targeting and Longer Retention Time of NIR Fluorescent Probes Using Bioorthogonal Chemistry

Author

Xianghan Zhang, Yongzhan Nie, Xiaoyuan Chen, Bo Wang, Zhongliang Wang, Zuhong Tian, Yunpeng Dai, Zhao Na, and Jie Tian

Subjects
Male, Fluorophore, Medicine (miscellaneous), Mice, Nude, 02 engineering and technology, NIR fluorescence probes, 010402 general chemistry, 01 natural sciences, Fluorescence, chemistry.chemical_compound, Mice, In vivo, Animals, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Fluorescent Dyes, Chemistry, 021001 nanoscience & nanotechnology, Small molecule, Combinatorial chemistry, gastric cancer, In vitro, 0104 chemical sciences, click chemistry, Click chemistry, Biophysics, Bioorthogonal chemistry, 0210 nano-technology, Peptides, Preclinical imaging, Research Paper, GEBP11
Abstract

The traditional labeling method for targeted NIR fluorescence probes requires directly covalent-bonded conjugation of targeting domains and fluorophores in vitro. Although this strategy works well, it is not sufficient for detecting or treating cancers in vivo, due to steric hindrance effects that relatively large fluorophore molecules exert on the configurations and physiological functions of specific targeting domains. The copper-free, "click-chemistry"-assisted assembly of small molecules in living systems may enhance tumor accumulation of fluorescence probes by improving the binding affinities of the targeting factors. Here, we employed a vascular homing peptide, GEBP11, as a targeting factor for gastric tumors, and we demonstrate its effectiveness for in vivo imaging via click-chemistry-mediated conjugation with fluorescence molecules in tumor xenograft mouse models. This strategy showed higher binding affinities than those of the traditional conjugation method, and our results showed that the tumor accumulation of click-chemistry-mediated probes are 11-fold higher than that of directly labeled probes. The tracking life was prolonged by 12-fold, and uptake of the probes into the kidney was reduced by 6.5-fold. For lesion tumors of different sizes, click-chemistry-mediated probes can achieve sufficient signal-to-background ratios (3.5-5) for in vivo detection, and with diagnostic sensitivity approximately 3.5 times that of traditional labeling probes. The click-chemistry-assisted detection strategy utilizes the advantages of "small molecule" probes while not perturbing their physiological functions; this enables tumor detection with high sensitivity and specific selectivity.

Published
2017

10. Effects of lead exposure on the activation of microglia in mice fed with high‐fat diets.

Author

Wu, Lei, Li, Shuang, Pang, Shulan, Zhang, Bo, Wang, Jierui, He, Bin, Lv, Linyi, Wang, Weixuan, Zhao, Na, and Zhang, Yanshu

Subjects
HIGH-fat diet, COGNITIVE ability, LABORATORY mice, CENTRAL nervous system, MICE
Abstract

Lead (Pb) exposure can cause central nervous system (CNS) damage. The process of Pb neurotoxicity is accompanied by the microglia activation. In addition, microglia activation was observed under the intervention of high‐fat diets (HFD). This study was designed to investigate the effect of Pb on the cognitive function of mice with HFD, with focus on the microglia activation in brain. Male C57BL/6J mice, 8 weeks of age, were randomly divided into control, HFD, Pb, and HFD + Pb groups. The results showed that HFD following Pb exposure could exacerbate the learning and memory impairment in mice. Pb exposure could promote microglia activation and increase the expression of M1 microglia marker and decrease the expression of M2 microglia marker in the hippocampus of mice with HFD. Our finding suggested that Pb exposure may aggravate CNS damage by promoting M1 polarization and inhibiting M2 polarization of hippocampal microglia in HFD mice. [ABSTRACT FROM AUTHOR]

Published
2021
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11. Ivabradine Ameliorates Cardiac Diastolic Dysfunction in Diabetic Mice Independent of Heart Rate Reduction.

Author

Xie, Hao, Shen, Xing-Yi, Zhao, Na, Ye, Peng, Ge, Zhen, and Hu, Zuo-Ying

Subjects
HEART beat, PROLIFERATING cell nuclear antigen, MITOGEN-activated protein kinases, IVABRADINE, MATRIX metalloproteinases, MICE
Abstract

Cardiac fibroblast (CF) proliferation and activation play important roles in cardiac fibrosis and diastolic dysfunction (DD), which are involved in fibrosis-associated cardiovascular diseases. A previous study showed that ivabradine, a specific heart rate (HR)-lowering agent, significantly ameliorated DD in diabetic db/db mice by reducing HR. Herein, we attempted to determine whether ivabradine has antifibrotic and cardioprotective effects in diabetic mice by directly suppressing CF proliferation and activation, independent of a reduction in HR. We found that knockdown of c-Jun N-terminal kinase (JNK) or p38 mitogen-activated protein kinase (MAPK), or treatment with ivabradine, reduced JNK and p38 MAPK phosphorylation and the protein expression of proliferating cell nuclear antigen, collagen I, collagen III, tissue inhibitor of matrix metalloproteinase 2, and α-smooth muscle actin, accompanied with upregulation of matrix metalloproteinase 2 both in high glucose-treated neonatal rat CFs and left ventricular CFs isolated from db/db mice. However, zatebradine (a HR-lowering agent) did not have these effects in vitro or in vivo. In addition, cardiac fibrosis and DD were ameliorated in db/db mice that were intravenously administered lentiviruses carrying short hairpin RNAs targeting JNK and p38 MAPK or administered ivabradine. Taken together, these findings demonstrate that the ivabradine-induced amelioration of cardiac fibrosis, and DD in db/db mice may be at least in part attributable to the suppression of CF proliferation and activation, through the inhibition of JNK and p38 MAPK. [ABSTRACT FROM AUTHOR]

Published
2021
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12. CD39/CD73/A2a Adenosine Metabolic Pathway: Targets for Moxibustion in Treating DSS-Induced Ulcerative Colitis.

Author

Zhu, Yuanbing, Zhuang, Zhiqi, Wu, Qiaofeng, Lin, Sirui, Zhao, Na, Zhang, Qun, Xie, Lushuang, and Yu, Shuguang

Subjects
ULCERATIVE colitis, CYTOKINES, INTERLEUKINS, FLOW cytometry, KRUSKAL-Wallis Test, MOXIBUSTION, ANALYSIS of variance, ANIMAL experimentation, WESTERN immunoblotting, ONE-way analysis of variance, CELL receptors, HYDROLASES, TREATMENT effectiveness, TUMOR necrosis factors, T cells, ADENOSINES, DATA analysis software, DEXTRAN, MICE
Abstract

Ulcerative Colitis (UC) is a chronic inflammation disease, and the incidence of UC is increasing recently. Both clinical trials and animal experiments show that moxibustion is a complementary and alternative treatment for UC. Previous studies showed that moxibustion can improve UC by regulating the balance of Tregs and Th17 (Sun et al., 2017). Treg cells is one subset of CD4 + T cells that exert the immunosuppressive function. CD39 and CD73, expressed on the surface of Tregs, hydrolyze ATP to AMP and are further involved in the immunosuppressive function of Tregs. In this study, we investigated the effect of moxibustion on CD39 + Tregs and CD73 + Tregs in dextran sulfate sodium (DSS) induced UC mice. The A2a receptor (A2aR), one of the targets of adenosine, was also detected. The results showed that moxibustion could increase the expression of CD39, CD73, and A2aR in colonic tissue and improve the proportion of CD39 + Tregs and CD73 + Tregs in peripheral blood, inguinal draining lymph nodes and spleen in the UC model. Additionally, A2aR agonists enhanced the cell viability of colonic epithelial cells and inhibit the production of cytokines IL-6 and TNF- α in vitro, which may further influence the pathway of ATP purine signal metabolism and alleviates the gut inflammation of UC mice. Taken together, this study provides supplemental evidence to reveal the immune related mechanism of moxibustion in the treatment of UC. [ABSTRACT FROM AUTHOR]

Published
2021
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13. Mitochondrial Respiratory Chain and Its Regulatory Elements SIRT1 and SIRT3 Play Important Role in the Initial Process of Energy Conversion after Moxibustion at Local Skin.

Author

Zhang, Ning, Zhao, Na, Xie, Lu-shuang, Huang, Biao, Lin, Si-rui, Zhang, Qun, Zhu, Yuan-bing, Wu, Qiao-feng, and Yu, Shu-guang

Subjects
*MITOCHONDRIAL physiology, *ACUPUNCTURE points, *ANIMAL experimentation, *ENERGY metabolism, *FLUORESCENT antibody technique, *GENE expression, *HEAT, *HYDROLASES, *MICE, *MOXIBUSTION, *SKIN, *SPECTROPHOTOMETRY, *STAINS & staining (Microscopy), *WESTERN immunoblotting
Abstract

Objectives. To study how thermal energy is converted after moxibustion at local skin from the view of mitochondrial respiratory chain and its key regulatory elements of sirtuins 1 (SIRT1) and sirtuins 3 (SIRT3). Methods. Two moxibustion temperatures usually used in clinical practice (38°C and 46°C) were applied to Zusanli (ST36) acupoint for 30 minutes in C57BL/6J mice. Local skin samples were harvested at 30 min and 72 h after moxibustion intervention, respectively. The activity of mitochondrial respiratory chain complexes I–V was detected by spectrophotometry. The expression of SIRT1 and SIRT3 protein was detected by immunofluorescence staining or western blot. Results. Moxibustion at 38°C triggered more significant increase of mitochondrial respiratory chain complexes I–V expression. However, the protein expression of SIRT1 and SIRT3 at 46°C showed more obvious enhancement. In addition, the effect of mitochondrial respiratory chain complexes I–V activity on local skin of ST36 acupoint was more obvious at 30 min after moxibustion, while the expression of SIRT1 and SIRT3 protein was more significant at 72 h after moxibustion. Conclusion. Mitochondrial respiratory chain and its key regulatory element proteins SIRT1 and SIRT3 play important role in the initial process of thermal energy conversion stimulated by different moxibustion temperatures in local skin. [ABSTRACT FROM AUTHOR]

Published
2020
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14. Schisandrin B attenuates bleomycin-induced pulmonary fibrosis in mice through the wingless/integrase-1 signaling pathway.

Author

Wang, Ying, Dong, Xiaoman, Zhao, Na, Su, Xiaoming, Wang, Yueyang, Li, Yanfei, Wen, Meixin, Li, Zhengyi, Wang, Chunmei, Chen, Jianguang, and Zhuang, Wenyue

Subjects
PULMONARY fibrosis, TRANSFORMING growth factors, OXIDANT status, MICE, SUPEROXIDE dismutase
Abstract

Purpose/Aim: Pulmonary fibrosis (PF) is characterized by the progressive and ultimately fatal accumulation of fibroblasts and extracellular matrix in the lung that distorts its architecture and compromises its function. Objective: The present study investigated the potential protective effects of schisandrin B (Sch B) on the Wingless/Integrase-1 (Wnt) signaling pathway in attenuating inflammation and oxidative stress in ICR mice. Methods: Sixty healthy ICR mice were randomly divided into the following groups: control group, bleomycin (BLM) group, Sch B low dose (Sch B-L) group, Sch B medium dose (Sch B-M) group, Sch B high dose (Sch B-H) group, and dexamethasone (DXM) group. The expression of transforming growth factor (TGF)-β1 was examined by ELISA. In addition, the levels of superoxide dismutase (SOD), hydroxyproline (HYP), and the total antioxidant capacity (T-AOC) were determined. The protein and mRNA levels of matrix metalloproteinase 7 (MMP7) and β-catenin in mice were analyzed by western blot and quantitative real -quantitative time PCR (qRT-PCR), respectively. Results: Lung tissues from the BLM group exhibited significantly more inflammatory changes and a significantly greater number of collagen fibers than lung tissues from the control group. In addition, the lung tissues from these BLM-treated mice exhibited slightly increased MMP7 and β-catenin protein expression. Lung tissues from the Sch B-H group exhibited fewer inflammatory changes and fewer collagen fibers than lung tissues from the BLM group. Furthermore, the lung tissues from the Sch B-H mice exhibited decreased HYP and TGF-β1 levels, but increased SOD and T-AOC levels. Conclusions: The present study provided evidence that Sch B may be a potential therapeutic agent for the treatment of PF. [ABSTRACT FROM AUTHOR]

Published
2020
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15. Gut Microbiota: A New Strategy to Study the Mechanism of Electroacupuncture and Moxibustion in Treating Ulcerative Colitis.

Author

Wei, Daneng, Xie, Lushuang, Zhuang, Zhiqi, Zhao, Na, Huang, Biao, Tang, Yong, Yu, Shuguang, Zhou, Qizhi, and Wu, Qiaofeng

Subjects
ANIMAL experimentation, STATISTICAL correlation, ELECTROACUPUNCTURE, GRAM-positive bacteria, LACTOBACILLUS, MICE, MICROBIAL genetics, MOXIBUSTION, SODIUM compounds, STREPTOCOCCUS, T cells, ULCERATIVE colitis, GUT microbiome, SEQUENCE analysis
Abstract

Previous studies have confirmed that acupuncture and moxibustion is an effective way for treating ulcerative colitis (UC). However, the exact mechanism is unclear yet. In this study, DSS-induced UC mice were treated by electroacupuncture and moxibustion, and the genome of intestinal flora was subsequently detected by high-throughput sequencing in order to explore the detailed mechanism in terms of intestinal flora. The results indicated that the alpha diversity indices and beta diversity of intestinal flora were improved by electroacupuncture and moxibustion treatments, especially by the moxibustion treatment. These treatments inhibited Streptococcus, Odoribacter, and Allobaculum whereas it facilitated Lactobacillus on genus level. Further correlation analysis showed that the alpha diversity indices were positively correlated with the percentage of Treg cells in CD4+ cells but negatively correlated with the percentage of Th17 in CD4+ cells. These data indicated that both electroacupuncture and moxibustion can promote the intestinal flora diversity, providing a new view to understand the relationship between host and microbiome when using some external therapies. [ABSTRACT FROM AUTHOR]

Published
2019
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16. Effects of treadmill exercise on mitochondrial fusion and fission in the hippocampus of APP/PS1 mice.

Author

Yan, Qing-Wei, Zhao, Na, Xia, Jie, Li, Bai-Xia, and Yin, Ling-Yu

Subjects
*TREADMILL exercise, *TRANSGENIC mice, *MICE, *ALZHEIMER'S disease
Abstract

Highlights • Treadmill exercise efficiently enhances learning and memory in APP/PS1 mice. • Treadmill exercise improves mitochondrial ultrastructure and functions in the hippocampus of APP/PS1 mice. • Treadmill exercise increased mitochondrial fusion and inhibited mitochondrial fission in the hippocampus of APP/PS1 mice. Abstract Mitochondrial dysfunction is widely recognized as an early event in the pathogenesis of Alzheimer's disease (AD). Defects in mitochondrial fusion and fission have been proposed to lead to learning and memory impairments in AD. The current study aimed to investigate whether exercise-improved learning and memory were associated with improves in mitochondrial function by increased mitochondrial fusion and decreased mitochondrial fission. APP/PS1 transgenic mice were divided into transgenic sedentary (ADC, n = 15) and transgenic exercise (ADE, n = 15) groups. Wild-type mice were also separated into sedentary (WTC, n = 15) and exercise (WTE, n = 15) groups. The WTE and ADE mice were subjected to treadmill exercise for 12 weeks. In this study, learning and memory were significantly decreased in ADC mice compared with those in WTC mice, whereas exercise improved learning and memory in APP/PS1 transgenic mice. Meanwhile, ADC mice displayed defective mitochondrial function as evidenced by a significant increase in swollen mitochondria and vacuoles, loss of mitochondrial cristae, and decreased ATP levels, as well as an imbalance in mitochondrial fusion and fission as evidenced by significantly increased Drp1 and Mff and decreased Mfn1, Mfn2, and Opa1 in the hippocampus. Interestingly, exercise mitigated mitochondrial dysfunction as evidenced by a significant reduction in swollen mitochondria and vacuoles and increased mitochondrial cristae and ATP levels in ADE mice. Coincidentally, exercise promoted the balance of mitochondrial fusion and fission as evidenced by a significantly decreased Drp1 and Mff and increased Mfn1, Mfn2, and Opa1 in the hippocampus. These findings suggest that treadmill exercise efficiently enhances learning and memory in AD by improving mitochondrial dysfunction in APP/PS1 transgenic mice. [ABSTRACT FROM AUTHOR]

Published
2019
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17. Regulating the Balance of Th17/Treg via Electroacupuncture and Moxibustion: An Ulcerative Colitis Mice Model Based Study.

Author

Sun, Jungang, Zhang, Hejiaozi, Wang, Chengyulin, Yang, Mingxiao, Chang, Shyang, Geng, Yu, Yang, Hui, Zhuang, Zhiqi, Wang, Xiang, Xie, Lushuang, Huang, Biao, Zhao, Na, Zhou, Wei, Cheng, Xinhui, Cai, Bei, Wu, Qiaofeng, and Yu, Shu Guang

Subjects
COLITIS treatment, ULCERATIVE colitis, ANIMAL experimentation, CELL receptors, ELECTROACUPUNCTURE, ENZYME-linked immunosorbent assay, FLOW cytometry, GENE expression, IMMUNOHISTOCHEMISTRY, INTERLEUKINS, MICE, MOXIBUSTION, SPLEEN, T cells, TUMOR necrosis factors, WESTERN immunoblotting, DNA-binding proteins
Abstract

Aim. To investigate the relationship between the effects of electroacupuncture/moxibustion and the balance of Th17/Treg in treating ulcerative colitis (UC) and to preliminary compare the effects of the above two methods. Methods. DSS-induced UC mice were treated by electroacupuncture and moxibustion. Disease activity index (DAI) was scored; intestinal pathological structure and ultrastructure were observed. The levels of IL-2, IL-6, IL-10, IL-17A, IL-17F, and TGF-β in plasma were measured by ELISA. The percentages of Treg and Th17 in spleen lymphocytes were analyzed by flow cytometry. Also, the expressions of TLR2, TLR4, RORγt, and FOXP3 in the distal colon were detected by immunohistochemistry or western blot. Results. Both electroacupuncture and moxibustion can relieve UC. These effects are further supported by ELISA results. In addition, the ratio of Treg and Th17 in spleen lymphocytes and the expression of TLR2 and TLR4 are significantly improved. Also, the expression of RORγt and FOXP3 in distal colon were improved. Besides, the effect of moxibustion is better than that of electroacupuncture on TLR2, TLR4, and FOXP3 expression (P<0.05). Conclusion. Both electroacupuncture and moxibustion may ameliorate UC by regulating the balance of Th17/Treg. Whether moxibustion has better efficacy than electroacupuncture needs further study. [ABSTRACT FROM AUTHOR]

Published
2017
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18. Ethno-medicinal study of Artemisia ordosica Krasch. (traditional Chinese/Mongolian medicine) extracts for the treatment of allergic rhinitis and nasosinusitis.

Author

Xiao, Bin, Wang, Jin-Hua, Zhou, Cheng-Yan, Chen, Jun-Miao, Zhang, Na, Zhao, Na, Han, Xiao-Yan, Niu, Yi-Xuan, Feng, Yu-Bao, and Du, Guan-Hua

Subjects
*ANIMAL experimentation, *ANTI-infective agents, *ANTI-inflammatory agents, *CANDIDA, *COMPARATIVE studies, *SEASONAL variations of diseases, *ENZYME-linked immunosorbent assay, *EOSINOPHILS, *ETHANOL, *GUINEA pigs, *ALLERGIC rhinitis, *HERBAL medicine, *HISTAMINE, *LEAVES, *MEDICINAL plants, *CHINESE medicine, *MICE, *NASAL mucosa, *PLANTS, *RHINITIS, *PLANT roots, *SINUSITIS, *STAPHYLOCOCCUS aureus, *PLANT stems, *ETHNOLOGY research, *PHYTOCHEMICALS, *OTITIS, *ALBUMINS, *TREATMENT effectiveness, *DEXAMETHASONE, *BENZENE derivatives, *DESCRIPTIVE statistics, *IN vitro studies, *IN vivo studies, *DRUG administration, *DRUG dosage, *PHARMACODYNAMICS, *THERAPEUTICS
Abstract

Artemisia ordosica Krasch. (AOK) has been used for rheumatic arthritis, cold headache, sore throat, etc. in traditional Chinese/Mongolian medicine and is used for nasosinusitis by local Mongolian "barefoot" doctors. Up to now, their mechanisms are still unclear. To evaluate the in vivo anti-inflammatory and allergic rhinitis (AR) alleviating effect as well as in vitro antimicrobial activities of AOK extracts to verify its ethno-medicinal claims. Crude extracts (methanol/95%-ethanol/ethyl acetate) of AOK root/stem/leaf and fractions (petroleum ether/ethyl acetate/n-butanol/aqueous) of AOK root extract were prepared. Xylene-induced ear swelling model in mouse and ovalbumin (OVA)-induced AR model in guinea pig were established. Ear swelling degrees of mice were measured. The numbers of rubbing movement and sneezes of guinea pigs were counted to evaluate the symptoms of AR. The serum levels of histamine, INF-γ, IL-2/4/10, and VCAM-1 were measured by ELISA assay. The histological changes of nasal mucosa were investigated by light microscope after H&E staining. Antimicrobial activities of AOK extracts were also tested. LC-MS/MS analysis was performed to characterize the constituents of active extract and molecular docking was conducted to predict the biological mechanism. In ear-swelling model, extract (100.00 mg/kg) from the ethyl acetate layer of 95% ethanol (100.00 mg/kg) showed better swelling inhibition in mice than positive control (dexamethasone, 191.91 mg/kg). In AR model, extract from the ethyl acetate layer of 95% ethanol significantly alleviated the AR symptoms in guinea pigs, decreased the serum levels of histamine, INF-γ, IL-2/4/10, and VCAM-1, and reduced the infiltration of eosinophil in nasal mucosa. For Staphylococcus aureus , the ethyl acetate extract of AOK stem showed the highest inhibition (MIC=1.25 mg/mL), for Escherichia coli , n-butanol layer of 95% ethanol extract of AOK root showed the highest inhibition (MIC=15.00 mg/mL), for Candida glabrata , 95%-ethyl acetate extract of AOK leaf showed the best inhibition (MIC=0.064 mg/mL), while ethyl acetate and n-butanol layers showed similar inhibition on MRSA (MIC=7.50 mg/mL). LC-MS/MS characterization showed that dicaffeoylquinic acids account for more than 30% of ethyl acetate layer of AOK extract. Dicaffeoylquinic acids bind with histamine-1 receptor with high affinities and interesting modes. Extracts from AOK had interesting anti-inflammatory activity in mice, alleviating effect against OVA-induced AR in guinea pigs, and antimicrobial activities in vitro , which support the ethno-medicinal use of it. The main constituents in ethyl acetate layer of AOK root extract are dicaffeoylquinic acids and could bind with histamine-1 receptor well. These findings highlighted the importance of natural product chemistry study of AOK. Image 1 [ABSTRACT FROM AUTHOR]

Published
2020
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19. Levo-tetrahydropalmatine attenuates methamphetamine reward behavior and the accompanying activation of ERK phosphorylation in mice.

Author

Su, Hongliang, Sun, Tingting, Wang, Xiao, Du, Yan, Zhao, Na, Zhu, Jie, Yan, Jiangwei, Chen, Teng, and Yun, Keming

Subjects
*DOPAMINE receptors, *CHINESE medicine, *NUCLEUS accumbens, *PHOSPHORYLATION, *MICE
Abstract

• Methamphetamine (METH) induced conditioned place preference (CPP) in mice. • L-THP attenuated METH-induced CPP in mice. • METH induced upregulation of ERK phosphorylation in nucleus accumbens (NAc) and prefrontal cortex (PFc) of mice. • L-THP decreased the high expression of ERK phosphorylation induced by METH in NAc and PFc of mice. Levo-tetrahydropalmatine (L-THP) is the main active ingredient of traditional Chinese herbal medicine Corydalis and Stephania , which have been used for sedative, neuroleptic, and analgesic purposes. Previous studies have demonstrated that L-THP has antagonistic activation on dopamine receptors. Despite its effectiveness on treating drug addiction, L-THP's underlying molecular mechanisms in modulating methamphetamine (METH) reward behavior remain unclear. In order to clarify the mechanisms behind, we designed an experiment of conditioned place preference (CPP) to investigate the effects of L-THP on METH-induced CPP in mice. We then dissected the underlying molecular mechanisms of L-THP in modulating METH-induced CPP by evaluating accompanying changes in expression of phosphorylated extracellular signal-regulated kinase (p-ERK) in reward-relevant brain regions, including nucleus accumbens (NAc), prefrontal cortex (PFc), caudate putamen (CPu), and hippocampus (Hip), which may mediate the effects of L-THP on METH-induced CPP. The results showed that 1.0 mg/kg METH could induce obvious CPP in mice; 10.0 mg/kg L-THP could significantly attenuate METH-induced CPP in mice, though it could not induce CPP or conditioned place aversion by itself. Moreover, the levels of p-ERK in NAc and PFc of the METH group were significantly higher than that of the saline group. Although there was no evident difference between the levels of p-ERK of the L-THP group with that of the saline group, the levels of p-ERK in NAc and PFc of the M + T group were significantly lower than that of the METH group. There was no striking difference among the levels of p-ERK in CPu and Hip of all experimental groups. Our research suggested that NAc and PFc function as circuits contributing to METH addiction, and the activation of the ERK phosphorylation plays an important role in the mechanisms of METH addiction. Besides, L-THP significantly decreased ERK phosphorylation's high expression induced by METH, which suggested that the inhibitory effect of L-THP on modulating METH reward behavior may be related to the suppression of ERK phosphorylation in NAc and PFc of mice. In conclusion, L-THP could suppress the reward properties of METH, therefore, it may be a promising candidate for the treatment of METH addiction. [ABSTRACT FROM AUTHOR]

Published
2020
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