Publications by authors named "Ziyi Yan"

9 Publications

  • Page 1 of 1

RhoA/Rock activation represents a new mechanism for inactivating Wnt/β-catenin signaling in the aging-associated bone loss.

Cell Regen 2021 Mar 3;10(1). Epub 2021 Mar 3.

Department of Pharmacology, Zhejiang University School of Medicine, 866 Yuhangtang Road, Hangzhou, 310058, China.

The Wnt/β-catenin signaling pathway appears to be particularly important for bone homeostasis, whereas nuclear accumulation of β-catenin requires the activation of Rac1, a member of the Rho small GTPase family. The aim of the present study was to investigate the role of RhoA/Rho kinase (Rock)-mediated Wnt/β-catenin signaling in the regulation of aging-associated bone loss. We find that Lrp5/6-dependent and Lrp5/6-independent RhoA/Rock activation by Wnt3a activates Jak1/2 to directly phosphorylate Gsk3β at Tyr216, resulting in Gsk3β activation and subsequent β-catenin destabilization. In line with these molecular events, RhoA loss- or gain-of-function in mouse embryonic limb bud ectoderms interacts genetically with Dkk1 gain-of-function to rescue the severe limb truncation phenotypes or to phenocopy the deletion of β-catenin, respectively. Likewise, RhoA loss-of-function in pre-osteoblasts robustly increases bone formation while gain-of-function decreases it. Importantly, high RhoA/Rock activity closely correlates with Jak and Gsk3β activities but inversely correlates with β-catenin signaling activity in bone marrow mesenchymal stromal cells from elderly male humans and mice, whereas systemic inhibition of Rock therefore activates the β-catenin signaling to antagonize aging-associated bone loss. Taken together, these results identify RhoA/Rock-dependent Gsk3β activation and subsequent β-catenin destabilization as a hitherto uncharacterized mechanism controlling limb outgrowth and bone homeostasis.
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http://dx.doi.org/10.1186/s13619-020-00071-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925793PMC
March 2021

ι-Carrageenan Tetrasaccharide from ι-Carrageenan Inhibits Islet β Cell Apoptosis Via the Upregulation of GLP-1 to Inhibit the Mitochondrial Apoptosis Pathway.

J Agric Food Chem 2021 Jan 22;69(1):212-222. Epub 2020 Dec 22.

College of Food Science and Engineering, Ocean University of China, Qingdao 266003, China.

ι-Carrageenan performs diversified biological activities but has low bioavailability. ι-Carrageenan tetrasaccharide (ιCTs), a novel marine oligosaccharide prepared by the marine enzyme , was investigated for its effects on insulin resistance in high-fat and high-sucrose diet mice. Oral administration of ιCTs (ιCTs-L 30.0 mg/kg·bw, ιCTs-H 90.0 mg/kg·bw) decreased fasting blood glucose by 35.1% ± 1.41 ( < 0.01) and 27.4% ± 0.420 ( < 0.05), and enhanced glucose tolerance. Besides, ιCTs-L ameliorated islet vacuolization, decreased the β cell apoptosis by 21.8% ± 0.200 ( < 0.05), and promoted insulin secretion by 5.41% ± 0.0173 ( < 0.01) through pancreatic hematoxylin and eosin (H&E) staining, TUNEL staining, and insulin-glucagon immunostaining analysis. Interestingly, ιCTs-L and ιCTs-H treatment increased the incretin GLP-1 content in serum by 22.1% ± 0.402 ( < 0.01) and 10.7% ± 0.0935 ( < 0.05) respectively, through regulating the bile acid levels, which contributed to the inhibition of β cell apoptosis. Mechanically, ιCTs upregulated the expression of the GLP-1 receptor (GLP-1R) and protein kinase A (PKA) in the GLP-1/cAMP/PKA signaling pathway, and further inhibited the expression of cytochrome and caspase 3 in the mitochondrial apoptotic pathway. In conclusion, this study suggested that ιCTs alleviated insulin resistance by GLP-1-mediated inhibition of β cell apoptosis and proposed a new strategy for developing potential functional foods that prevent insulin resistance.
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http://dx.doi.org/10.1021/acs.jafc.0c06456DOI Listing
January 2021

CRISPR-based biosensing is prospective for rapid and sensitive diagnosis of pediatric tuberculosis.

Int J Infect Dis 2020 Dec 25;101:183-187. Epub 2020 Sep 25.

Department of Laboratory Medicine, West China Second Hospital, Sichuan University, Chengdu, Sichuan, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, Sichuan, China. Electronic address:

Pediatric tuberculosis (TB) is an important part of global TB prevention and control. Diagnosis of childhood TB still remains challenging when using conventional tests, due to the non-specific clinical manifestations and paucibacillary nature of the specimens. Thus, a sensitive, rapid and low-cost diagnostic test is of great demand. Benefiting from specific and rapid Cas-protein-based catalytic activities, CRISPR-based biosensing platforms (CRISPR platforms) are showing superiority in detecting pathogen nucleic acid traces in clinical samples. Based on their excellent sensitivity, and time and cost saved in existing research, this study aimed to highlight the potential of CRISPR platforms as a tool for diagnosing pediatric TB, and advocate for studies to evaluate its performance in specimens collected from children, especially noninvasive specimens. These platforms are also promising in identifying drug resistance and genotyping. All of the above will help early diagnosis of pediatric TB, thus guide reasonable treatment, and be significant in achieving the World Health Organization End-TB strategy.
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http://dx.doi.org/10.1016/j.ijid.2020.09.1428DOI Listing
December 2020

RACO-1 modulates Hippo signalling in oesophageal squamous cell carcinoma.

J Cell Mol Med 2020 10 7;24(20):11912-11921. Epub 2020 Sep 7.

Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.

Oesophageal cancer is one of the most lethal malignancies worldwide, whereas the 5-year survival is less than 20%. Although the detailed carcinogenic mechanisms are not totally clear, recent genomic sequencing data showed dysregulation of Hippo signalling could be a critical factor for oesophageal squamous cell carcinoma (ESCC) progression. Therefore, understanding of the molecular mechanisms that control Hippo signalling activity is of great importance to improve ESCC diagnostics and therapeutics. Our current study revealed RACO-1 as an inhibitory protein for YAP/TEAD axis. Depletion of RACO-1 increases the protein level of YAP and expression of YAP/TEAD target gene. Besides, RACO-1 silencing could promote ESCC cell invasion and migration, which effect could be rescued by YAP depletion in ESCC cells. Immunoprecipitation showed that RACO-1 associated with YAP and promote ubiquitination and degradation of YAP at k48 poly-ubiquitination site. Our research discovered a new regulator of Hippo signalling via modulating YAP stability. RACO-1 could be a promising factor, which serves cancer diagnostics and therapeutics in ESCC patients.
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http://dx.doi.org/10.1111/jcmm.15811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7579699PMC
October 2020

Regulation of Hippo/YAP signaling and Esophageal Squamous Carcinoma progression by an E3 ubiquitin ligase PARK2.

Theranostics 2020 25;10(21):9443-9457. Epub 2020 Jul 25.

Xinxiang Key Laboratory for Molecular Therapy of Cancer, Xinxiang Medical University, Xinxiang 453003, Henan Province, P.R. China.

Esophageal squamous cell carcinoma (ESCC) is one of the most commonly diagnosed cancer types in China. Recent genomic sequencing analysis indicated the over-activation of Hippo/YAP signaling might play important roles for the carcinogenic process and progression for ESCC patients. However, little is known about the molecular mechanisms that controls Hippo signaling activity in ESCC. Our previous studies indicated that PLCE1-an important risk factor for ESCC-linked to ESCC progression through snail signaling, during this period, we found PARK2 was an important downstream target of PLCE1-snail axis. PARK2 was decreased in ESCC human samples, and correlated with good prognosis in ESCC patients. Further research showed that PARK2 could inhibit YAP, which functions as key downstream effectors of the Hippo pathway. Here, we aim to reveal the molecular mechanisms of PARK2 modulated Hippo pathway in ESCC. To evaluate the function of PARK2 in ESCC, we used a tissue microarray (TMA) of 223 human ESCC patients and immunohistochemistry to analyze the correlation between PARK2 expression and clinicopathologic variables. Depletion of endogenous PARK2 and YAP from ESCC cells using CRISPR/Cas9 technologies. Flow cytometry and EdU cell proliferation assay were used to detect proliferation of ESCC cells. Nude mice subcutaneous injection and Ki-67 staining were used to evaluate tumor growth . Migration and invasion assays were performed. In addition, lung metastasis models in mice were used to validate the function of PARK2 . Identification of PARK2 involved in hippo pathway was achieved by expression microarray screening, double immunofluorescence staining and co-immunoprecipitation assays. The RNA-seq analysis results were validated through quantitative real-time PCR (qRT-PCR) analysis. The protein half-life of YAP was analyzed by Cycloheximide assay, and the TEAD activity was detected by Luciferase reporter assays. Clinical sample of ESCC revealed that low PARK2 expression correlated with late tumor stage (P < 0.001), poor differentiation (P < 0.04), lymph node (P < 0.001) and distant metastasis (P = 0.0087). Multivariate Cox proportional regression analysis further revealed that PARK2 expression (P = 0.032) is an independent prognostic factor for the overall survival of ESCC patients. Besides, the immunohistochemistry results showed that PARK2 negatively correlated with YAP protein level (P 0.001). PARK2 depletion promotes ESCC progression both through Hippo/YAP axis, while PARK2 overexpression suppresses ESCC tumor progression by Hippo signaling. Co-IP and ubiquitination assays revealed that PARK2 could interact with YAP in the cytosol and promotes YAP K48-linked ubiquitination at K90 sites. Clinical sample analysis and mechanistic study have validated PARK2 as a tumor suppressor for ESCC. Multivariate Cox proportional regression analysis further revealed that PARK2 is an independent prognostic factor for the overall survival of ESCC patients. Cellular and molecular mechanisms in this study showed that PARK2 associated with YAP protein in the cytosol, promoted YAP ubiquitination and proteasome-dependent degradation in ESCC cells. Therefore, as a novel modulator for Hippo signaling, modulation of PARK2 activity or gene expression level could be an appealing strategy to treat esophageal.
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http://dx.doi.org/10.7150/thno.46078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449928PMC
July 2020

Saponins from the sea cucumber promotes the osteoblast differentiation in MC3T3-E1 cells through activation of BMP2/Smads pathway.

Curr Pharm Biotechnol 2020 May 19. Epub 2020 May 19.

College of Food Science and Engineering, Ocean University of China, Qingdao, shandong Province. China.

Background: Several studies have shown that plant saponins promoted osteoblast differentiation and improved osteoporosis. In current study, sea cucumber saponins (SCS) with a purity of 80% was extracted from Filipino sea cucumber, with a similar structure to plant saponins.

Objective: This study aims to investigate the effects of SCS on bone formation in vitro and ex vivo.

Results: SCS significantly promoted osteogenic differentiation and mineralization of MC3T3-E1 cells, as well as new osteoid formation in neonatal mouse calvarias ex vivo. qRT-PCR results indicated that SCS markedly down-regulated the expression of C/EBPα* and PPARγ at the levels of transcription, which demonstrate that SCS inhibit the trans-differentiation of MC3T3-E1 cells to an adipocytic phenotype. What is more, further studies revealed that SCS increased the expression levels of Runx2 and OSX. The mechanism revealed that SCS induced the expression of BMP2 and p-Smad1/5, which indicated that SCS facilitated osteogenesis via activating the BMP2/Smads signaling pathway.

Conclusion: SCS promoted osteogenic differentiation of pre-osteoblasts by activating BMP2/Smads molecular pathway, providing theoretical basis for the development of sea cucumber saponins for the treatment to bone loss diseases such as osteoporosis.
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http://dx.doi.org/10.2174/1389201021666200519135446DOI Listing
May 2020

SHARPIN Inhibits Esophageal Squamous Cell Carcinoma Progression by Modulating Hippo Signaling.

Neoplasia 2020 02 26;22(2):76-85. Epub 2019 Dec 26.

Department of Gastroenterology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China; Center for Cancer Research, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China; Xinxiang Key Laboratory for Molecular Therapy of Cancer, Xinxiang Medical University, Xinxiang 453003, Henan Province, PR China. Electronic address:

Esophageal cancer is one of the leading malignancies worldwide, while around sixty percent of newly diagnosed cases are in China. In recent years, genome-wide sequencing studies and cancer biology studies show that Hippo signaling functions a critical role in esophageal squamous cell carcinoma (ESCC) progression, which could be a promising therapeutic targets in ESCC treatment. However, the detailed mechanisms of Hippo signaling dys-regulation in ESCC remain not clear. Here we identify SHARPIN protein as an endogenous inhibitor for YAP protein. SHARPIN depletion significantly decreases cell migration and invasion capacity in ESCC, which effects could be rescued by further YAP depletion. Depletion SHARPIN increases YAP protein level and YAP/TEAD target genes, such as CTGF and CYR61 in ESCC. Immuno-precipitation assay shows that SHARPIN associates with YAP, promoting YAP degradation possibly via inducing YAP K48-dependent poly-ubiquitination. Our study reveals a novel post-translational mechanism in modulating Hippo signaling in ESCC. Overexpression or activation of SHARPIN could be a promising strategy to target Hippo signaling for ESCC patients.
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http://dx.doi.org/10.1016/j.neo.2019.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939053PMC
February 2020

Molecular characterization of Streptococcus pneumoniae in children living in southwest China and assessment of a potential protein vaccine, rPfbA.

Vaccine 2019 01 2;37(5):721-731. Epub 2019 Jan 2.

Department of Laboratory Medicine, West China Second University Hospital, Sichuan University, No. 20, Section 3, South Renmin Road, Chengdu, Sichuan Province 610041, China; Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, No. 17, Section 3, South Renmin Road, Chengdu, Sichuan Province 610041, China. Electronic address:

Background: Few children living in southwest China are vaccinated against Streptococcus pneumoniae (S. pneumoniae), which is an important pathogen in causing high morbidity and high mortality. This study aimed the molecular characterization of S. pneumoniae strains isolated from children and a new vaccine strategy based on a potential protein antigen.

Methods: Molecular characterizations, including serotype, virulence gene and pilus analyses, were performed using PCR. Seven housekeeping genes were sequenced to identify the sequence types (STs), and antibiotic resistance was analysed using the microdilution broth method. In addition, we evaluated the protective effects of recombinant plasmin- and fibronectin-binding protein A (rPfbA) in murine pneumococcal infection models by challenge and passive transfer analyses, and assessed cytokine changes after immunization.

Results: The prevalent serotypes were 19F (31.4%), 19A (21.6%), 6B (13.7%), 14 (11.8%) and 23F (9.8%), and the coverage rates of the 13-valent pneumococcal conjugate vaccine (PCV13) were high in 93.3% of the isolates. The predominant STs were ST271 (23.5%), ST320 (21.6%) and ST876 (11.8%). Most of the S. pneumoniae isolates were resistant to erythromycin (95.1%) and clindamycin (90.2%). The molecular distributions and antibiotic resistance rates of the S. pneumoniae isolates differed between the plateau and the basin regions. More than 93% of the S. pneumoniae isolates carried ply, cbpA, phtD and nanA, and over half of the isolates carried pilus-1, pilus-2 and pfbA. Mucosal immunization with rPfbA induced pneumococcal specific antibody responses which provided to eliminate colonization in lung and nasopharynx, and protection against pneumococcal challenge.

Conclusion: Vaccine strategies based on epidemiological surveillance can be more adaptive to specific areas, reduce costs and protect against changing antigenic sites. We advise that children currently living in southwest China be vaccinated with PCV13.
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http://dx.doi.org/10.1016/j.vaccine.2018.12.021DOI Listing
January 2019

FAM92A1 is a BAR domain protein required for mitochondrial ultrastructure and function.

J Cell Biol 2019 01 7;218(1):97-111. Epub 2018 Nov 7.

Institute of Biotechnology, University of Helsinki, Helsinki, Finland

Mitochondrial function is closely linked to its dynamic membrane ultrastructure. The mitochondrial inner membrane (MIM) can form extensive membrane invaginations known as cristae, which contain the respiratory chain and ATP synthase for oxidative phosphorylation. The molecular mechanisms regulating mitochondrial ultrastructure remain poorly understood. The Bin-Amphiphysin-Rvs (BAR) domain proteins are central regulators of diverse cellular processes related to membrane remodeling and dynamics. Whether BAR domain proteins are involved in sculpting membranes in specific submitochondrial compartments is largely unknown. In this study, we report FAM92A1 as a novel BAR domain protein localizes to the matrix side of the MIM. Loss of FAM92A1 caused a severe disruption to mitochondrial morphology and ultrastructure, impairing organelle bioenergetics. Furthermore, FAM92A1 displayed a membrane-remodeling activity in vitro, inducing a high degree of membrane curvature. Collectively, our findings uncover a role for a BAR domain protein as a critical organizer of the mitochondrial ultrastructure that is indispensable for mitochondrial function.
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http://dx.doi.org/10.1083/jcb.201806191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314547PMC
January 2019