Publications by authors named "Fengyuan Chen"

28 Publications

  • Page 1 of 1

LARP7 ameliorates cellular senescence and aging by allosterically enhancing SIRT1 deacetylase activity.

Cell Rep 2021 Nov;37(8):110038

Key Laboratory of Systems Biomedicine, Shanghai Center for Systems Biomedicine, Department of Pediatric Cardiology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dong Chuan Road, Shanghai 200240, China. Electronic address:

Cellular senescence is associated with pleiotropic physiopathological processes, including aging and age-related diseases. The persistent DNA damage is a major stress leading to senescence, but the underlying molecular link remains elusive. Here, we identify La Ribonucleoprotein 7 (LARP7), a 7SK RNA binding protein, as an aging antagonist. DNA damage-mediated Ataxia Telangiectasia Mutated (ATM) activation triggers the extracellular shuttling and downregulation of LARP7, which dampens SIRT1 deacetylase activity, enhances p53 and NF-κB (p65) transcriptional activity by augmenting their acetylation, and thereby accelerates cellular senescence. Deletion of LARP7 leads to senescent cell accumulation and premature aging in rodent model. Furthermore, we show this ATM-LARP7-SIRT1-p53/p65 senescence axis is active in vascular senescence and atherogenesis, and preventing its activation substantially alleviates senescence and atherogenesis. Together, this study identifies LARP7 as a gatekeeper of senescence, and the altered ATM-LARP7-SIRT1-p53/p65 pathway plays an important role in DNA damage response (DDR)-mediated cellular senescence and atherosclerosis.
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http://dx.doi.org/10.1016/j.celrep.2021.110038DOI Listing
November 2021

Copper Adsorption to Microplastics and Natural Particles in Seawater: A Comparison of Kinetics, Isotherms, and Bioavailability.

Environ Sci Technol 2021 10 30;55(20):13923-13931. Epub 2021 Sep 30.

Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China.

The growing use of plastics has led to microplastics (MPs) being ubiquitously distributed in marine environments. Although previous studies have emphasized MPs as important metal-transport vectors, few have considered the differences between these anthropogenic particles and their coexisting natural counterparts in sequestering metals in seawater. Here, we compared Cu adsorption to pristine and naturally aged MPs (polystyrene and polyethylene) with that to algae particles and sediments and assessed the bioavailability of the adsorbed Cu by a gut juice extraction assay. Adsorption kinetics and isotherms consistently showed that natural particles bound far more Cu to their surfaces than MPs. The rougher surfaces, greater specific surface areas, and lower ζ-potentials of natural particles contributed to their stronger Cu adsorption capacity than pristine or aged MPs. Natural particles also contained more diverse functional groups for binding Cu, with oxygen-containing groups playing a dominant role. Adsorbed Cu on natural particles was less extractable by sipunculan gut juice than that on MPs, indicating their higher Cu affinity. Overall, our study suggests that natural particles outcompete MPs in carrying metals in the water column and transferring them to marine organisms in today's environmental context. This work provides new insights for assessing the risks of MPs in marine environments.
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http://dx.doi.org/10.1021/acs.est.1c04278DOI Listing
October 2021

AAV-Containing Exosomes as a Novel Vector for Improved Gene Delivery to Lung Cancer Cells.

Front Cell Dev Biol 2021 13;9:707607. Epub 2021 Aug 13.

Center for Biological Science and Technology, Advanced Institute of Natural Sciences, Beijing Normal University at Zhuhai, Zhuhai, China.

Lung carcinoma is the most common type of cancer and the leading cause of cancer-related death worldwide. Among the numerous therapeutic strategies for the treatment of lung cancer, adeno-associated virus (AAV)-mediated gene transfer has been demonstrated to have the potential to effectively suppress tumor growth or reverse the progression of the disease in a number of preclinical studies. AAV vector has a safety profile; however, the relatively low delivery efficacy to particular subtypes of lung carcinoma has limited its prospective clinical translation. Exosomes are nanosized extracellular vesicles secreted from nearly all known cell types. Exosomes have a membrane-enclosed structure carrying a range of cargo molecules for efficient intercellular transfer of functional entities, thus are considered as a superior vector for drug delivery. In the present study, we developed a novel strategy to produce and purify AAV-containing exosomes (AAVExo) from AAV-packaging HEK 293T cells. The cellular uptake capacity of exosomes assisted and enhanced AAV entry into cells and protected AAV from antibody neutralization, which was a serious challenge for AAV application. We tested a list of lung cancer cell lines representing non-small-cell lung cancer and small-cell lung cancer and found that AAVExo apparently improved the gene transfer efficiency compared to conventional AAV vector. Our results were supported in a lung cancer xenograft rodent model. Additionally, we evaluated the gene delivery efficiency in the presence of neutralizing antibody on lung cancer cells. The results demonstrated that AAVExo-mediated gene transfer was not impacted, while the AAV vectors were significantly blocked by the neutralizing antibody. Taken together, we established an efficient methodology for AAVExo purification, and the purified AAVExo largely enhanced gene delivery to lung cancer cells with remarkable resistance to antibody neutralization.
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http://dx.doi.org/10.3389/fcell.2021.707607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8414974PMC
August 2021

The Versatile Functions of G. Lucidum Polysaccharides and G. Lucidum Triterpenes in Cancer Radiotherapy and Chemotherapy.

Cancer Manag Res 2021 17;13:6507-6516. Epub 2021 Aug 17.

Department of Cellular and Molecular Biology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, People's Republic of China.

G. lucidum has a long history of thousands of years in China and is closely related with the lives of the Chinese people. It is reported to cure various diseases due to its high nutritional value and wide range of uses. The fascinating effects of G. lucidum have tethered a multitude of efforts to explore its effective ingredients and supplement functions. At present, many cancer research studies have reported the G. lucidum polysaccharides (GLPs) and G. lucidum triterpenes (GLTs) as the main active ingredients in G. lucidum, which have shown positive effects on radiotherapy and chemotherapy. GLPs or GLTs treatment synergizes with radiotherapy and chemotherapy through multiple pathways, including oxidative stress, apoptosis, immune microenvironment, etc. Therefore, this review aims to analyze and summarize these complex molecules from G. lucidum in order to create more treatment options for cancer patients in the future.
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http://dx.doi.org/10.2147/CMAR.S319732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8380140PMC
August 2021

Face masks as a source of nanoplastics and microplastics in the environment: Quantification, characterization, and potential for bioaccumulation.

Environ Pollut 2021 Nov 8;288:117748. Epub 2021 Jul 8.

Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen, 518060, China. Electronic address:

Billions of disposable face masks are consumed daily due to the COVID-19 pandemic. The role of these masks as a source of nanoplastics (NPs) and microplastics (MPs) in the environment has not been studied in previous studies. We quantified and characterized face mask released particles and evaluated their potential for accumulation in humans and marine organisms. More than one billion of NPs and MPs were released from each surgical or N95 face mask. These irregularly-shaped particles sized from c. 5 nm to c. 600 μm. But most of them were nano scale sized <1 μm. The middle layers of the masks had released more particles than the outer and inner layers. That MPs were detected in the nasal mucus of mask wearers suggests they can be inhaled while wearing a mask. Mask released particles also adsorbed onto diatom surfaces and were ingested by marine organisms of different trophic levels. This data is useful for assessing the health and environmental risks of face masks.
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http://dx.doi.org/10.1016/j.envpol.2021.117748DOI Listing
November 2021

A review of anti-tumour effects of ginsenoside in gastrointestinal cancer.

J Pharm Pharmacol 2021 Sep;73(10):1292-1301

School of Integrated Traditional Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, China.

Objectives: Gastrointestinal cancer, one of the major causes of cancer-related deaths in the world, refers to malignant conditions of the gastrointestinal (GI) tract and other organs. Although conventional therapy has been successful to some extent in cancer treatment, drug resistance and cancer recurrence still limit the therapeutic efficacy. There is increasing evidence indicating that ginsenoside, as a kind of high nutritional value and widely used traditional Chinese medicine, could contribute to the promotion of treatment in GI cancer, which deserves further investigation.

Key Findings: Based on previous studies, the possible mechanisms mainly include regulation of autophagy, apoptosis, proliferation, migration and angiogenesis. However, no studies recently have conducted a more in-depth review of the anti-cancer effects of ginsenoside in GI cancer.

Summary: Therefore, this review will summarise and analyse the latest developments in the anti-tumour effects of ginsenosides in GI cancer, thus may promote further research of the anti-tumour efficacy of ginsenoside.
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http://dx.doi.org/10.1093/jpp/rgab048DOI Listing
September 2021

Exosome-Based Delivery of Natural Products in Cancer Therapy.

Front Cell Dev Biol 2021 2;9:650426. Epub 2021 Mar 2.

Cancer Research Center, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.

A rapidly growing research evidence has begun to shed light on the potential application of exosome, which modulates intercellular communications. As donor cell released vesicles, exosomes could play roles as a regulator of cellular behaviors in up-taken cells, as well as a delivery carrier of drugs for targeted cells. Natural product is an invaluable drug resources and it is used widely as therapeutic agents in cancers. This review summarizes the most recent advances in exosomes as natural product delivery carriers in cancer therapy from the following aspects: composition of exosomes, biogenesis of exosomes, and its functions in cancers. The main focus is the advantages and applications of exosomes for drug delivery in cancer therapy. This review also summarizes the isolation and application of exosomes as delivery carriers of natural products in cancer therapy. The recent progress and challenges of using exosomes as drug delivery vehicles for five representative anti-cancer natural products including paclitaxel, curcumin, doxorubicin, celastrol, and β-Elemene. Based on the discussion on the current knowledge about exosomes as delivery vehicles for drugs and natural compounds to the targeted site, this review delineates the landscape of the recent research, challenges, trends and prospects in exosomes as delivery vehicles for drugs and natural compounds for cancer treatment.
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http://dx.doi.org/10.3389/fcell.2021.650426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960777PMC
March 2021

How marine diatoms cope with metal challenge: Insights from the morphotype-dependent metal tolerance in Phaeodactylum tricornutum.

Ecotoxicol Environ Saf 2021 Jan 27;208:111715. Epub 2020 Nov 27.

Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China. Electronic address:

Metal tolerance in marine diatoms vary between morphotypes, strains, and species due to their long-term adaptations to stochastic environments. The mechanisms underlying this highly variable trait remain a matter of interest in ecotoxicology. In this study, we used several cutting-edge techniques, including a non-invasive micro-test technique, atomic force microscopy, and X-ray photoelectron spectroscopy to examine cadmium (Cd) accumulation and tolerance in the three morphotypes of Phaeodactylum tricornutum. Subcellular Cd distribution, metal transporter expression, and glutathione and phytochelatin activity were also analyzed to characterize the morphology-dependent Cd homeostasis and detoxification. We found that the oval morphotype accumulated more Cd, but was also more Cd tolerant than the other morphotypes. The greater surface binding of Cd to the oval morphotype is attributable to its smaller spherical form, rougher cell surface, and lower surface potential. Moreover, the oval morphotype was less permeable to Cd ions and contained higher phytochelatin and glutathione levels, which explained its higher metal tolerance. Our study offers new explanations for diatom's adaptations to changing environments that may contribute to its evolutionary success.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111715DOI Listing
January 2021

Long noncoding RNA SAM promotes myoblast proliferation through stabilizing Sugt1 and facilitating kinetochore assembly.

Nat Commun 2020 06 1;11(1):2725. Epub 2020 Jun 1.

Department of Orthaepedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China.

The functional study of lncRNAs in skeletal muscle satellite cells (SCs) remains at the infancy stage. Here we identify SAM (Sugt1 asssociated muscle) lncRNA that is enriched in the proliferating myoblasts. Global deletion of SAM has no overt effect on mice but impairs adult muscle regeneration following acute damage; it also exacerbates the chronic injury-induced dystrophic phenotype in mdx mice. Consistently, inducible deletion of SAM in SCs leads to deficiency in muscle regeneration. Further examination reveals that SAM loss results in a cell-autonomous defect in the proliferative expansion of myoblasts. Mechanistically, we find SAM interacts and stabilizes Sugt1, a co-chaperon protein key to kinetochore assembly during cell division. Loss of SAM or Sugt1 both disrupts kinetochore assembly in mitotic cells due to the mislocalization of two components: Dsn1 and Hec1. Altogether, our findings identify SAM as a regulator of SC proliferation through facilitating Sugt1 mediated kinetochore assembly during cell division.
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http://dx.doi.org/10.1038/s41467-020-16553-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264179PMC
June 2020

Mechanisms underlying silicon-dependent metal tolerance in the marine diatom Phaeodactylum tricornutum.

Environ Pollut 2020 Jul 5;262:114331. Epub 2020 Mar 5.

Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen 518060, China. Electronic address:

Anthropogenic activities have significantly changed the stoichiometry and concentrations of nutrients in coastal waters. Silicon (Si) has become a potential limiting nutrient due to disproportionate nitrogen, phosphorus, and silicate inputs into these areas. The disrupted nutrient ratios can cause changes to metal sensitivity and accumulation in marine diatoms, an important group of eukaryotic phytoplankton that requires silicon for growth. In this study, we examined the effects of Si availability on the metal sensitivity in the diatom P. tricornutum. We found that Si starvation dramatically compromised its cadmium, copper, and lead tolerances. Interestingly, multiple lines of evidence indicated that Si-enriched cells had higher metal adsorption and influx rates than Si-starved cells. Yet Si-enriched cells also had a greater ability to respond to and counteract metal toxicity via elevated expression of membrane and vacuolar metal transporters and greater antioxidant activities which scavenge reactive oxygen species created by metal stress.
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http://dx.doi.org/10.1016/j.envpol.2020.114331DOI Listing
July 2020

Osteopontin-loaded PLGA nanoparticles enhance the intestinal mucosal barrier and alleviate inflammation via the NF-κB signaling pathway.

Colloids Surf B Biointerfaces 2020 Jun 7;190:110952. Epub 2020 Mar 7.

Department of Gastroenterology, Shanghai Fifth People's Hospital, Fudan University, 128 Ruili Road, Shanghai 200240, People's Republic of China. Electronic address:

Osteopontin is a multifunctional glycoprotein that is secreted by a variety of tissues or cells, but the role of osteopontin in the epithelial mucosal barrier has not been clearly established. We loaded osteopontin into hyaluronic acid-functionalized polymeric nanoparticles, which were administered by gavage to a colitis mouse model. The disease activity index, weight gain and colon length were calculated to assess the degree of symptoms. Epithelial permeability was measured using fluorescein isothiocyanate-conjugated dextran. The enzymatic activity of myeloperoxidase in the colon and inflammatory cytokines were assayed to assess the levels of inflammation. The histological appearance of the colon was observed by H&E staining. Tight junction proteins and signaling pathway proteins (NF-κB and phospho-NF-κB) were determined by western blotting. The resultant spherical osteopontin-loaded nanoparticles were characterized by the expected particle size (approximately 272.3 nm) and a slightly negative zeta potential (approximately -5.3 mV). Interestingly, we found that the osteopontin-loaded nanoparticles exerted remedial effects on colitis by both enhancing the intestinal barrier and alleviating inflammation in vivo according to the tested parameters. These results suggest that OPN plays a positive role in protecting the epithelial mucosal barrier and may be a therapeutic drug in gut homeostasis.
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http://dx.doi.org/10.1016/j.colsurfb.2020.110952DOI Listing
June 2020

Neutral monosaccharides and their relationship to metal contamination in mangrove sediments.

Chemosphere 2020 Jul 29;251:126368. Epub 2020 Feb 29.

Shenzhen Key Laboratory of Marine Microbiome Engineering, Institute for Advanced Study, Shenzhen University, Shenzhen, 518060, China. Electronic address:

Mangrove sediments act as an important natural sink and a secondary source for trace metals. The main objective of this study was to investigate metal contamination and its relationship to mangrove-derived carbohydrates in mangrove sediments. Sixteen metals (Be, V, Cr, Co, Ni, Cu, Zn, Ga, As, Sr, Cd, Sn, Sb, Ba, Tl, and Pb)were analyzed in the surface sediments from four sites at different latitudes on the southeast coastline of China. The sedimentary organic matter was characterized by Rock-Eval pyrolysis, and the neutral sugars were examined by gas chromatograph mass spectrometry. Our results from the enrichment factors indicated that the mangrove sediments were no enriched by Ga, Sr, and Ba, minor enriched by Be, V, Cr, Co, Ni, Cu, Zn, As, Sn, Sb, Tl, and Pb, and moderate enriched by Cd. Litterfall was a major source of organic matter in the mangrove sediments, and the neutral sugars were mainly derived from this litterfall. Significant correlations were detected between the total organic carbon, pyrolytic parameters, neutral sugars, and enrichment factors of V, Cr, Co, Ni, Zn, and Cd, suggesting the input of neutral carbohydrates played an important role in enhancing the metal accumulation in the mangrove sediments. The mangrove litterfall itself was a major source of metals for the sediments, and the mangrove-derived organic matter enhanced the sediment's metal accumulation.
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http://dx.doi.org/10.1016/j.chemosphere.2020.126368DOI Listing
July 2020

Essential Role of the ELABELA-APJ Signaling Pathway in Cardiovascular System Development and Diseases.

J Cardiovasc Pharmacol 2020 04;75(4):284-291

Department of Pediatric Cardiology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

ELABELA (ELA), previously classified as a "noncoding" RNA, is a new endogenous peptidic ligand of apelin receptor (APJ/APLNR), a class A (rhodopsin-like) G protein-coupled receptor. It has been identified to play a crucial role in diverse biological processes, especially in the normal and pathological cardiovascular system. In comparison with APJ's first ligand apelin, ELA may play a key role at different time points or heart regions. In this review, we summarized the roles of the ELA-APJ signaling pathway in cardiovascular system development and diseases.
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http://dx.doi.org/10.1097/FJC.0000000000000803DOI Listing
April 2020

Postoperative Radiotherapy Improves Survival in Gastric Signet-Ring Cell Carcinoma: a SEER Database Analysis.

J Gastric Cancer 2019 Dec 5;19(4):393-407. Epub 2019 Nov 5.

Department of Gastroenterology, The Fifth People's Hospital of Shanghai Fudan University, Shanghai, China.

Purpose: To identify the potential therapeutic role of postoperative radiotherapy (RT) in patients with locally advanced (stage II and stage III) gastric signet ring cell carcinoma (SRC).

Materials And Methods: Patients with locally advanced gastric SRC from the Surveillance, Epidemiology, and End Results program database between 2004 and 2012 were included in our study. Univariate and multivariate Cox proportional models were performed, and survival curves were generated to evaluate the prognostic effect of postoperative RT and surgery alone on SRC patients. Propensity score matching (PSM) was used to avoid selection bias among the study cohorts.

Results: We found that patients with postoperative RT had better probability of survival compared with those who did not receive RT (overall survival [OS], P<0.001; cancer-specific survival [CSS], P<0.001). After PSM, analysis of both overall and CSS showed that patients who underwent postoperative RT had better prognosis than those receiving surgery alone in the matched cohort (OS, P=0.00079; CSS, P=0.0036). Multivariate Cox proportional model indicated that postoperative RT had better effect on prognosis compared with surgery alone with respect to both overall (hazard ratio [HR], 0.716; 95% confidence interval [95% CI], 0.590-0.87; P=0.001) and CSS (HR, 0.713; 95% CI, 0.570-0.890; P=0.003).

Conclusions: Postoperative RT had better prognosis compared with surgery alone for both overall and CSS for patients with locally advanced gastric SRC.
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http://dx.doi.org/10.5230/jgc.2019.19.e36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928086PMC
December 2019

LNK protein: Low expression in human colorectal carcinoma and relationship with tumor invasion.

Biomed Pharmacother 2020 Jan 6;121:109467. Epub 2019 Nov 6.

Department of General Surgery, The Fifth People's Hospital of Shanghai, Shanghai, China. Electronic address:

Objective: A large number of studies have explored the function of LNK in hematologic system disease, while that in solid tumors has been rarely investigated. In the present study, we attempted to explore the expression level of LNK in colorectal cancer (CRC) as well as the potential relationship between them.

Materials And Methods: The expression levels of LNK were examined using real-time PCR (RT-PCR) and immunohistochemistry (IHC) in cancer tissues and the matching adjacent normal tissues. Then, clinical data, including gender, age, tumor size, lymph node metastasis, parenteral invasion situation, distant metastasis, and TNM stage, from 32 patients were analyzed. Finally, we detected the effect of LNK on the invasion by performing a transwell assay in HCT 116 cells and HT29 cells.

Results: The RT-PCT results revealed that the expression level of LNK was significantly lower in colorectal cancer tissues than that in normal tissues. After analyzing the clinical pathological characteristics, we discovered that LNK had a negative expression in 56.3% patients with colorectal cancer. Moreover, the LNK negative expression was recorded in 83.3% patients with invasion, which was significantly higher than that in patients with positive LNK (42.9%,P < 0.05). A further study verified that the overexpression of LNK effectively reduced the invasion ability of the tumor cells in the transwell assay.

Conclusion: Our present study reported that LNK as an adaptor protein had low expression in colorectal cancer and was related to tumor invasion, which provided a new potential therapeutic strategy for CRC treatment.
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http://dx.doi.org/10.1016/j.biopha.2019.109467DOI Listing
January 2020

Elevated H3K27ac in aged skeletal muscle leads to increase in extracellular matrix and fibrogenic conversion of muscle satellite cells.

Aging Cell 2019 10 20;18(5):e12996. Epub 2019 Jul 20.

Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China.

Epigenetic alterations occur in various cells and tissues during aging, but it is not known if such alterations are also associated with aging in skeletal muscle. Here, we examined the changes of a panel of histone modifications and found H3K27ac (an active enhancer mark) is markedly increased in aged human skeletal muscle tissues. Further analyses uncovered that the H3K27ac increase and enhancer activation are associated with the up-regulation of extracellular matrix (ECM) genes; this may result in alteration of the niche environment for skeletal muscle stem cells, also called satellite cells (SCs), which causes decreased myogenic potential and fibrogenic conversion of SCs. In mice, treatment of aging muscles with JQ1, an inhibitor of enhancer activation, inhibited the ECM up-regulation and fibrogenic conversion of SCs and restored their myogenic differentiation potential. Altogether, our findings not only uncovered a novel aspect of skeletal muscle aging that is associated with enhancer remodeling but also implicated JQ1 as a potential treatment approach for restoring SC function in aging muscle.
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http://dx.doi.org/10.1111/acel.12996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718601PMC
October 2019

YY1 regulates skeletal muscle regeneration through controlling metabolic reprogramming of satellite cells.

EMBO J 2019 05 12;38(10). Epub 2019 Apr 12.

Department of Orthopedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China

Skeletal muscle satellite cells (SCs) are adult muscle stem cells responsible for muscle regeneration after acute or chronic injuries. The lineage progression of quiescent SC toward activation, proliferation, and differentiation during the regeneration is orchestrated by cascades of transcription factors (TFs). Here, we elucidate the function of TF Yin Yang1 (YY1) in muscle regeneration. Muscle-specific deletion of YY1 in embryonic muscle progenitors leads to severe deformity of diaphragm muscle formation, thus neonatal death. Inducible deletion of YY1 in SC almost completely blocks the acute damage-induced muscle repair and exacerbates the chronic injury-induced dystrophic phenotype. Examination of SC revealed that YY1 loss results in cell-autonomous defect in activation and proliferation. Mechanistic search revealed that YY1 binds and represses mitochondrial gene expression. Simultaneously, it also stabilizes Hif1α protein and activates Hif1α-mediated glycolytic genes to facilitate a metabolic reprogramming toward glycolysis which is needed for SC proliferation. Altogether, our findings have identified YY1 as a key regulator of SC metabolic reprogramming through its dual roles in modulating both mitochondrial and glycolytic pathways.
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http://dx.doi.org/10.15252/embj.201899727DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518041PMC
May 2019

REGγ Controls Hippo Signaling and Reciprocal NF-κB-YAP Regulation to Promote Colon Cancer.

Clin Cancer Res 2018 04 6;24(8):2015-2025. Epub 2018 Feb 6.

Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.

Colorectal cancer is one of the most commonly diagnosed cancers closely associated with inflammation and hyperactive growth. We previously demonstrated a regulatory circuit between the proteasome activator REGγ and NF-kappaB (NF-κB) during colon inflammation, known to be important in the development of colitis-associated cancer as well as sporadic colorectal cancer. How the inflammatory microenvironment affects the Hippo pathway during colorectal cancer development is largely unknown. Here, we used REGγ-deficient colon cancer cell lines, REGγ knockout mice, and human colorectal cancer samples to identify the novel molecular mechanism by which REGγ functions as an oncoprotein in the development of colorectal cancer. REGγ can directly interact with Lats1 and promote its degradation, which facilitates Yes-associated protein (YAP) activation in colon cancer cells. REGγ deficiency significantly attenuated colon cancer growth, associated with decreased YAP activity. Suppression of tumor growth due to REGγ depletion was overcome by constitutively active YAP. Surprisingly, reciprocal activation of the YAP and NF-κB pathways was observed in human colon cancer cells. REGγ overexpression was found in over 60% of 172 colorectal cancer specimens, highly correlating with the elevation of YAP and p65. Postoperative follow-up revealed a significantly lower survival rate in patients with concomitantly high expression of REGγ, YAP, and p-p65. REGγ could be a master regulator during colorectal cancer development to promote YAP signaling and reinforce cross-talks between inflammation and growth pathways, and REGγ might be a new marker for prognosis of colorectal cancer patients. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2986DOI Listing
April 2018

[Role of high mobility group protein B1 in 
IL-1α-induced endothelial cell senescence].

Zhong Nan Da Xue Xue Bao Yi Xue Ban 2017 Dec;42(12):1361-1366

Department of Cardiology, Third Xiangya Hospital; Center for Vascular Disease and Translational Medicine, Central South University, Changsha 410013, China.

Objective: To explore the effect of interleukin-1α (IL-1α) on the senescence of human umbilical vein endothelial cells (HUVECs) and the function of high mobility group protein 1 (HMGB1).
 Methods: HUVECs were randomly divided into a control group, a IL-1α group (10 ng/mL IL-1α), a HMGB1 group (100 ng/mL HMGB1), and a HMGB1+IL-1α group (100 ng/mL of HMGB1 plus 10 ng/mL of IL-1α). Senescence associated β-galactosidase (SA β-gal) staining was used to assess the number of senescent cells, Western blot were performed to detect the protein levels of silent information regulator 1(SIRT1), and quantitative real-time PCR (qRT-PCR) was used to detect the mRNA levels of p53, p21 and p16.
 Results: Compared with the control group, the number of SA β-gal positive cells were significantly increased in the IL-1α group (P<0.05), while the expression of SIRT1 protein significantly decreased (P<0.01). Compared with the IL-1α group, the expression of SA β-gal positive cells in the HMGB1+IL-1α group was decreased and the mRNA levels of p21 and p53 were down-regulated (all P<0.05), however, there was no statistical significance in the mRNA expression of p16 (P>0.05).
 Conclusion: IL-1α can induce the senescence of HUVECs, and HMGB1 may inhibit IL-1α-induced endothelial cell senescence via p53-p21 pathway.
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http://dx.doi.org/10.11817/j.issn.1672-7347.2017.12.002DOI Listing
December 2017

regulates myogenic differentiation and muscle regeneration through modulating MyoD transcriptional activity.

Cell Discov 2017 14;3:17002. Epub 2017 Mar 14.

Department of Orthopaedics and Traumatology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong , Hong Kong, China.

is one of the most abundant long non-coding RNAs in various cell types; its exact cellular function is still a matter of intense investigation. In this study we characterized the function of in skeletal muscle cells and muscle regeneration. Utilizing both and assays, we demonstrate that has a role in regulating gene expression during myogenic differentiation of myoblast cells. Specifically, we found that knockdown of accelerates the myogenic differentiation in cultured cells. Consistently, knockout mice display enhanced muscle regeneration after injury and deletion of in dystrophic mdx mice also improves the muscle regeneration. Mechanistically, in the proliferating myoblasts, recruits Suv39h1 to MyoD-binding loci, causing trimethylation of histone 3 lysine 9 (H3K9me3), which suppresses the target gene expression. Upon differentiation, the pro-myogenic miR-181a is increased and targets the nuclear transcripts for degradation through Ago2-dependent nuclear RNA-induced silencing complex machinery; the decrease subsequently leads to the destabilization of Suv39h1/HP1β/HDAC1-repressive complex and displacement by a Set7-containing activating complex, which allows MyoD trans-activation to occur. Together, our findings identify a regulatory axis of miR-181a--MyoD/Suv39h1 in myogenesis and uncover a previously unknown molecular mechanism of action in gene regulation.
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http://dx.doi.org/10.1038/celldisc.2017.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348715PMC
March 2017

YY1 in Cell Differentiation and Tissue Development.

Crit Rev Oncog 2017 ;22(1-2):131-141

Department of Orthopaedics and Traumotologya, Chinese University of Hong Kong, Hong Kong, China; Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong, China.

Yin Yang1 (YY1) is a ubiquitous expressed transcription factor that modulates a variety of biologic processes with prominent roles in cellular differentiation and tissue development. Recent advances in molecular biology, mouse genetics, and particularly high-throughput sequencing have greatly enhanced our understanding of YY1 functions and underlying mechanisms in regulating transcription and epigenetics. In this review, we summarize findings on the roles of YY1 in cell differentiation and tissue development, in particular in muscle, nerve, and immune cells/tissues.
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http://dx.doi.org/10.1615/CritRevOncog.2017021311DOI Listing
April 2019

The REGγ-proteasome forms a regulatory circuit with IκBɛ and NFκB in experimental colitis.

Nat Commun 2016 Feb 22;7:10761. Epub 2016 Feb 22.

Shanghai Key Laboratory of Regulatory Biology, Shanghai Key Laboratory of Brain Functional Genomics (Ministry of Education), Institute of Biomedical Sciences, East China Normal University, Shanghai 200241, China.

Increasing incidence of inflammatory bowel disorders demands a better understanding of the molecular mechanisms underlying its multifactorial aetiology. Here we demonstrate that mice deficient for REGγ, a proteasome activator, show significantly attenuated intestinal inflammation and colitis-associated cancer in dextran sodium sulfate model. Bone marrow transplantation experiments suggest that REGγ's function in non-haematopoietic cells primarily contributes to the phenotype. Elevated expression of REGγ exacerbates local inflammation and promotes a reciprocal regulatory loop with NFκB involving ubiquitin-independent degradation of IκBɛ. Additional deletion of IκBɛ restored colitis phenotypes and inflammatory gene expression in REGγ-deficient mice. In sum, this study identifies REGγ-mediated control of IκBɛ as a molecular mechanism that contributes to NFκB activation and promotes bowel inflammation and associated tumour formation in response to chronic injury.
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http://dx.doi.org/10.1038/ncomms10761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764899PMC
February 2016

Linc-YY1 promotes myogenic differentiation and muscle regeneration through an interaction with the transcription factor YY1.

Nat Commun 2015 Dec 11;6:10026. Epub 2015 Dec 11.

Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.

Little is known how lincRNAs are involved in skeletal myogenesis. Here we describe the discovery of Linc-YY1 from the promoter of the transcription factor (TF) Yin Yang 1 (YY1) gene. We demonstrate that Linc-YY1 is dynamically regulated during myogenesis in vitro and in vivo. Gain or loss of function of Linc-YY1 in C2C12 myoblasts or muscle satellite cells alters myogenic differentiation and in injured muscles has an impact on the course of regeneration. Linc-YY1 interacts with YY1 through its middle domain, to evict YY1/Polycomb repressive complex (PRC2) from target promoters, thus activating the gene expression in trans. In addition, Linc-YY1 also regulates PRC2-independent function of YY1. Finally, we identify a human Linc-YY1 orthologue with conserved function and show that many human and mouse TF genes are associated with lincRNAs that may modulate their activity. Altogether, we show that Linc-YY1 regulates skeletal myogenesis and uncover a previously unappreciated mechanism of gene regulation by lincRNA.
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http://dx.doi.org/10.1038/ncomms10026DOI Listing
December 2015

Labetalol Prevents Intestinal Dysfunction Induced by Traumatic Brain Injury.

PLoS One 2015 17;10(7):e0133215. Epub 2015 Jul 17.

Department of Gastroenterology, Shanghai Fifth Hospital affiliated Fudan University, Shanghai, China.

Background: Beta-adrenergic blockade has been hypothesized to have a protective effect on intestinal dysfunction and increased intestinal permeability associated with the epinephrine surge after traumatic brain injury (TBI).

Methods: Wister rats were subjected to either a weight drop TBI, and intraperitoneally injected or not with labetalol, or a sham procedure (18 rats per group). After 3, 6, or 12h (6 rats per subgroup), intestinal permeability to 4.4 kDa FITC-Dextran and plasma epinephrine levels were measured as was intestinal tight junction protein ZO-1 expression at 12h. Terminal ileum was harvested to measure levels of intestinal tumor necrosis factor (TNF)-α and to evaluate histopathology.

Results: In TBI group vs. sham group, intestinal permeability (P<0.01) was significantly higher at all time-points, and intestinal ZO-1 expression was lower at 12h. In TBI with vs. without labetalol group, 1) intestinal permeability was significantly lower at 6 and 12h (94.31±7.64 vs. 102.16±6.40 μg/mL; 110.21±7.52 vs. 118.95±7.11 μg/mL, respectively); 2) levels of plasma epinephrine and intestinal TNF-α were significantly lower at 3, 6 and 12h; and 3) intestinal ZO-1 expression was higher at 3, 6 and 12h (p=0.018). Histopathological evaluation showed that labetalol use preserved intestinal architecture throughout.

Conclusion: In a rat model of TBI, labetalol reduced TBI-induced sympathetic hyperactivity, and prevented histopathological intestinal injury accompanied by changes in gut permeability and gut TNF-α expression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0133215PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505891PMC
May 2016

An unusual etiology of abdominal pain and spontaneous pneumomediastinum in a young adult.

Am J Emerg Med 2014 Aug 30;32(8):947.e1-2. Epub 2014 Jan 30.

Department of Gastroenterology, Shanghai Fifth People's Hospital, Fudan University, Shanghai 200240, People's Republic of China.

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http://dx.doi.org/10.1016/j.ajem.2014.01.035DOI Listing
August 2014

Dextran sodium sulfate inhibits the activities of both polymerase and reverse transcriptase: lithium chloride purification, a rapid and efficient technique to purify RNA.

BMC Res Notes 2013 Sep 8;6:360. Epub 2013 Sep 8.

Department of Biology, Center for Diagnostics and Therapeutics, Georgia State University, Atlanta GA 30303, USA.

Background: Dextran sodium sulfate (DSS) is commonly used in mouse studies to induce a very reproducible colitis that effectively mimics the clinical and histological features of human inflammatory bowel disease (IBD) patients, especially ulcerative colitis. However, the mechanisms of action of DSS remain poorly understood, and observations by our laboratory and other groups indicate that DSS contamination of colonic tissues from DSS-treated mice potently inhibits the quantitative reverse-transcription polymerase chain reaction (qRT-PCR) amplification of mRNA.

Results: A prior study used poly-A-mediated mRNA purification to remove DSS from RNA extracts, but we herein report a second efficient and cost-effective approach to counteract this inhibition, using lithium chloride precipitation to entirely remove DSS from RNAs. We also explored how DSS interferes with qRT-PCR process, and we report for the first time that DSS can alter the binding of reverse transcriptase to previously primed RNA and specifically inhibits the enzymatic activities of reverse transcriptase and Taq polymerase in vitro. This likely explains why DSS-treated colonic RNA is not suitable to qRT-PCR amplification without a previous purification step.

Conclusion: In summary, we provide a simple method to remove DSS from colonic RNAs, and we demonstrate for the first time that DSS can inhibit the activities of both polymerase and reverse transcriptase. In order to reliably analyze gene expression in the colonic mucosa of DSS-treated mice, the efficiency rate of qRT-PCR must be the same between all the different experimental groups, including the water-treated control group, suggesting that whatever the duration and the percentage of the DSS treatment, RNAs must be purified.
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http://dx.doi.org/10.1186/1756-0500-6-360DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847706PMC
September 2013

NF-κB pathway in colitis-associated cancers.

Transl Gastrointest Cancer 2013 Jan;2(1):21-29

Colitis-associated cancer is the subtype of colorectal cancer that is associated with inflammatory bowel diseases including ulcerative colitis and Crohn's disease. Colorectal cancer is one of the most commonly diagnosed cancers, and is the third leading cause of cancer death in developed countries. Of the signaling pathways involved in colonic inflammation, that triggered by NF-κB plays a key role. A relationship between inflammation and cancer is now well documented. Moreover, the association between NF-κB activity and cancer development has been intensively investigated. The present review focuses on the activity of the NF-κB signaling pathway in colitis-associated carcinogenesis. The pivotal roles played by this pathway in apoptosis, tumor promotion, and tumor maintenance strongly suggest that inhibitors of the pathway would be powerful anti-cancer agents.
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http://dx.doi.org/10.3978/j.issn.2224-4778.2012.11.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3636557PMC
January 2013

Osteopontin: participation in inflammation or mucosal protection in inflammatory bowel diseases?

Dig Dis Sci 2013 Jun 30;58(6):1569-80. Epub 2013 Jan 30.

Department of Gastroenterology, Shanghai Fifth People's Hospital, Fudan University, 128 Ruili Road, Shanghai, 200240, People's Republic of China.

Background: Osteopontin (OPN) is associated with the Th1 immune response in inflammatory bowel diseases (IBD). While OPN has been shown to play an important role in maintaining the epithelial barrier, its role in IBD remains unclear.

Aim: The aim of this study was to assess OPN function in patients with IBD and in the mouse colitis model.

Methods: Osteopontin expression in colonic samples from IBD patients was determined by a semi-quantitative immunohistochemical staining method. Colitis in BALB/c mice was induced by 5 % dextran sodium sulfate (DSS), followed by treatment with salazosulfapyridine (SASP) and infliximab, respectively. The plasma OPN concentration was measured by an enzyme-linked immunosorbent assay. The expression of OPN in colonic tissues was detected by reverse transcriptase PCR, real-time PCR and Western blot, and the localization of OPN was determined by a semi-quantitative immunohistochemical staining method. The immune function of OPN was investigated by measuring the production of cytokines, and the amount of cytokines produced was then used to determine OPN immune functions.

Results: Osteopontin expression in intestinal epithelial cells was significantly lower in IBD patients than in controls, while its expression in lamina propria exudative cells was significantly higher in IBD patients than in controls. In DSS-induced mice, OPN expression in plasma and colonic tissues increased significantly, and this increase was significantly reduced after the mice were treated with SASP and infliximab. OPN promoted the Th1 immune response and strengthened inflammation in the mouse colitis model.

Conclusions: Our results indicate that OPN plays an important role in the immune response and is also involved in the mucosal protective mechanism in IBD.
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http://dx.doi.org/10.1007/s10620-012-2556-yDOI Listing
June 2013
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