Publications by authors named "Sha Huang"

202 Publications

Proteomic profiling identifies signatures associated with progression of precancerous gastric lesions and risk of early gastric cancer.

EBioMedicine 2021 Nov 21;74:103714. Epub 2021 Nov 21.

State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address:

Background: Molecular features underlining the multistage progression of gastric lesions and development of early gastric cancer (GC) are poorly understood, restricting the ability to GC prevention and management.

Methods: We portrayed proteomic landscape and explored proteomic signatures associated with progression of gastric lesions and risk of early GC. Tissue proteomic profiling was conducted for a total of 324 subjects. A case-control study was performed in the discovery stage (n=169) based on populations from Linqu, a known high-risk area for GC in China. We then conducted two-stage validation, including a cohort study from Linqu (n = 56), with prospective follow-up for progression of gastric lesions (280-473 days), and an independent case-control study from Beijing (n = 99).

Findings: There was a clear distinction in proteomic features for precancerous gastric lesions and GC. We derived four molecular subtypes of gastric lesions and identified subtype-S4 with the highest progression risk. We found 104 positively-associated and 113 inversely-associated proteins for early GC, with APOA1BP, PGC, HPX and DDT associated with the risk of gastric lesion progression. Integrating these proteomic signatures, the ability to predict progression of gastric lesions was significantly strengthened (areas-under-the-curve=0.88 (95%CI: 0.78-0.99) vs. 0.56 (0.36-0.76), Delong's P = 0.002). Immunohistochemistry assays and examination at mRNA level validated the findings for four proteins.

Interpretation: We defined proteomic signatures for progression of gastric lesions and risk of early GC, which may have translational significance for identifying particularly high-risk population and detecting GC at an early stage, improving potential for targeted GC prevention.

Funding: The funders are listed in the Acknowledgement.
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http://dx.doi.org/10.1016/j.ebiom.2021.103714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617343PMC
November 2021

CPT2 downregulation triggers stemness and oxaliplatin resistance in colorectal cancer via activating the ROS/Wnt/β-catenin-induced glycolytic metabolism.

Exp Cell Res 2021 12 21;409(1):112892. Epub 2021 Oct 21.

Department of Abdominal Radiotherapy, Fujian Cancer Hospital, Fujian Medical University Cancer Hospital, Fuzhou, Fujian, 350011, China. Electronic address:

Carnitine palmitoyltransferase 2 (CPT2) has been demonstrated to act as a tumor promotor or suppressor in different types of cancers. However, little is known about the effect of CPT2 on colorectal cancer (CRC). In the present study, we analyzed CPT2 expression in CRC tissues and cells. CPT2 was overexpressed in CRC cell lines (SW480 and RKO), and its effects and molecular mechanism on the proliferation, glycolysis, stemness, and oxaliplatin sensitivity were investigated. The xenograft experiment was used to confirm the influence of CPT2 on CRC tumorigenesis in vivo. We found that CPT2 expression was significantly downregulated in CRC patients, and its lower expression was associated with the poor prognosis, large tumor size, advanced TNM stage, and poor histological grade differentiation of patients. Upregulation of CPT2 significantly inhibited the proliferation, glycolytic metabolism, cancer stem cell properties, and oxaliplatin resistance in CRC cells. Also, the increase of CPT2 inhibited tumorigenesis, stemness and glycolysis, while enhanced oxaliplatin sensitivity in mouse models. Mechanistically, CPT2 functioned via suppressing the activation of Wnt/β-catenin pathway through repressing ROS production. In conclusion, our results demonstrated that CPT2 was decreased in CRC, and CPT2 downregulation could trigger stemness and oxaliplatin resistance in CRC via activating the ROS/Wnt/β-catenin-induced glycolytic metabolism. This study indicates that CPT2 is a potential therapeutic target for CRC.
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http://dx.doi.org/10.1016/j.yexcr.2021.112892DOI Listing
December 2021

Comparative transcriptional profiling of the early host response to infection by typhoidal and non-typhoidal Salmonella serovars in human intestinal organoids.

PLoS Pathog 2021 10 20;17(10):e1009987. Epub 2021 Oct 20.

Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan, United States of America.

Salmonella enterica represents over 2500 serovars associated with a wide-ranging spectrum of disease; from self-limiting gastroenteritis to invasive infections caused by non-typhoidal serovars (NTS) and typhoidal serovars, respectively. Host factors strongly influence infection outcome as malnourished or immunocompromised individuals can develop invasive infections from NTS, however, comparative analyses of serovar-specific host responses have been constrained by reliance on limited model systems. Here we used human intestinal organoids (HIOs), a three-dimensional "gut-like" in vitro system derived from human embryonic stem cells, to elucidate similarities and differences in host responses to NTS and typhoidal serovars. HIOs discriminated between the two most prevalent NTS, Salmonella enterica serovar Typhimurium (STM) and Salmonella enterica serovar Enteritidis (SE), and typhoidal serovar Salmonella enterica serovar Typhi (ST) in epithelial cell invasion, replication and transcriptional responses. Pro-inflammatory signaling and cytokine output was reduced in ST-infected HIOs compared to NTS infections, consistent with early stages of NTS and typhoidal diseases. While we predicted that ST would induce a distinct transcriptional profile from the NTS strains, more nuanced expression profiles emerged. Notably, pathways involved in cell cycle, metabolism and mitochondrial functions were downregulated in STM-infected HIOs and upregulated in SE-infected HIOs. These results correlated with suppression of cellular proliferation and induction of host cell death in STM-infected HIOs and in contrast, elevated levels of reactive oxygen species production in SE-infected HIOs. Collectively, these results suggest that the HIO model is well suited to reveal host transcriptional programming specific to infection by individual Salmonella serovars, and that individual NTS may provoke unique host epithelial responses during intestinal stages of infection.
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http://dx.doi.org/10.1371/journal.ppat.1009987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8570492PMC
October 2021

Knowledge and Attitudes toward Dementia among Undergraduate Health Professional Students in China: A Cross-Sectional Survey.

Teach Learn Med 2021 Sep 26:1-9. Epub 2021 Sep 26.

School of Nursing, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Phenomenon: Dementia is a huge burden to the economic and health care system in China. As the next generation of health care providers, undergraduate health professional students play a pivotal role in caring for dementia patients during their clinical placements and in independent practice. Nevertheless, they may not be adequately prepared to care for patients with dementia by their undergraduate programs. Measuring the knowledge and attitudes of health professional students could be an important step in providing evidence regarding the need to enhance dementia care training in the curriculum. Approach: Responses from 325 Chinese health professional (nursing, medical, and public health) students were included in the analyses. After providing informed consent, students answered questionnaires including a demographic data questionnaire, the Alzheimer's Disease Knowledge Scale (ADKS) and the Dementia Attitudes Scale (DAS). Univariate analyses were performed to test the association between outcomes and potential explanatory variables. Multiple linear regression analysis was used to determine the predictive factors for knowledge and attitudes toward dementia. Findings: Chinese health professional students had a mean ADKS score of 18.92 ( = 3.20). Better knowledge was associated with advanced education, having family members with medical knowledge, having heard of dementia, and having interest in learning about dementia. Students had a mean DAS score of 89.10 ( = 8.93), and their attitudes were significantly associated with majoring in public health and having heard of dementia. Students' knowledge was positively, but weakly related with attitudes ( = 0.122,  = 0.028). Insights: Chinese undergraduate health professional students demonstrate insufficient knowledge and less positive attitudes toward dementia than their counterparts in developed countries. Enhanced dementia care-specific curriculum and training are urgently needed in China to meet the growing demand for dementia care services.
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http://dx.doi.org/10.1080/10401334.2021.1971988DOI Listing
September 2021

Memory Deficit in Patients With Temporal Lobe Epilepsy: Evidence From Eye Tracking Technology.

Front Neurosci 2021 7;15:716476. Epub 2021 Sep 7.

Key Laboratory of Spectral Imaging Technology, Xi'an Institute of Optics and Precision Mechanics of the Chinese Academy of Sciences, Xi'an, China.

To explore quantitative measurements of the visual attention and neuroelectrophysiological relevance of memory deficits in temporal lobe epilepsy (TLE) by eye tracking and electroencephalography (EEG). Thirty-four TLE patients and twenty-eight healthy controls were invited to complete neurobehavioral assessments, cognitive oculomotor tasks, and 24-h video EEG (VEEG) recordings using an automated computer-based memory assessment platform with an eye tracker. Visit counts, visit time, and time of first fixation on areas of interest (AOIs) were recorded and analyzed in combination with interictal epileptic discharge (IED) characteristics from the bilateral temporal lobes. The TLE patients had significantly worse Wechsler Digit Span scores [(1, 58) = 7.49, = 0.008]. In the Short-Term Memory Game with eye tracking, TLE patients took a longer time to find the memorized items [(1, 57) = 17.30, < 0.001]. They had longer first fixation [(1, 57) = 4.06, = 0.049] and more visit counts [(1, 57) = 7.58, = 0.008] on the target during the recall. Furthermore, the performance of the patients in the Digit Span task was negatively correlated with the total number of IEDs [(28) = -0.463, = 0.013] and the number of spikes per sleep cycle [(28) = -0.420, = 0.026]. Eye tracking appears to be a quantitative, objective measure of memory evaluation, demonstrating memory retrieval deficits but preserved visual attention in TLE patients. Nocturnal temporal lobe IEDs are closely associated with memory performance, which might be the electrophysiological mechanism for memory impairment in TLE.
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http://dx.doi.org/10.3389/fnins.2021.716476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453169PMC
September 2021

LINC01559 promotes colorectal cancer via sponging miR-1343-3p to modulate PARP1/PTEN/AKT pathway.

Pathol Res Pract 2021 Aug 8;224:153521. Epub 2021 Jun 8.

Fujian Cancer Hospital & Institute, No 420 Fuma Road, Fuzhou, Fujian, 350014, China. Electronic address:

Background: Colorectal cancer (CRC) is considered as one of the commonest tumors and is the major reason of cancer-related deaths around the world. Plentiful evidences have validated that long non-coding RNAs (lncRNAs) play a significant part in various cancers, including CRC. LINC01559 is implicated in the development of various cancers. However, the detailed function of LINC01559 in CRC has not been illustrated.

Methods: LINC01559 expression was examined via RT-qPCR, and a series of functional experiments were conducted to explore the role of LINC01559 in CRC progression. Mechanism experiments were carried out to examine the underlying mechanism of LINC01559.

Results: LINC01559 expression was increased in CRC cells and tissues, and LINC01559 depletion restrained the biological behaviors of CRC cells. Also, LINC01559 sponged miR-1343-3p in CRC, and PARP1 was the target of miR-1343-3p. Besides, miR-1343-3p overexpression or PARP1 down-regulation affected the biological behaviors of CRC cells. In addition, up-regulation of PARP1 or adding SC79 (AKT pathway activator) could remedy the repressive effects of LINC01559 silencing on CRC cell biological behaviors.

Conclusions: LINC01559 promotes CRC through sponging miR-1343-3p to modulate PARP1/PTEN/AKT pathway, which may be conducive to offering a new idea for CRC therapeutic treatment.
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http://dx.doi.org/10.1016/j.prp.2021.153521DOI Listing
August 2021

Effect of ABT-263 on Intestinal Fibrosis in Human Myofibroblasts, Human Intestinal Organoids, and the Mouse Salmonella typhimurium Model.

Inflamm Bowel Dis 2021 Jul 24. Epub 2021 Jul 24.

Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.

Background: Intestinal fibrosis and subsequent intestinal obstruction are common complications of Crohn's disease (CD). Current therapeutics combat inflammation, but no pharmacological therapy exists for fibrostenotic disease. Pathological persistence of activated intestinal myofibroblasts is a key driver of fibrosis in CD. In other organ systems, BH-3 mimetic drugs that affect Bcl-2 apoptotic pathways induce apoptosis in activated myofibroblasts and reduce fibrogenic gene expression, thereby reducing fibrosis.

Methods: We evaluated the proapoptotic and antifibrotic efficacy of several classes of BH-3 mimetics in 2 in vitro fibrogenesis models. The candidate molecule, ABT-263, was advanced to a 3-dimensional human intestinal organoid (HIO) model. Finally, the therapeutic efficacy of ABT-263 was evaluated in the mouse Salmonella typhimurium intestinal fibrosis model.

Results: The BH-3 mimetics induced apoptosis, repressed fibrotic protein expression, and reduced fibrogenic gene expression in normal human intestinal myofibroblasts. The BH-3 mimetics that target Bcl-2 and Bcl-xl demonstrated the greatest efficacy in vitro. The ABT-199 and ABT-263 induced apoptosis and ameliorated fibrogenesis in the in vitro myofibroblast models. In the HIO model, ABT-263 inhibited fibrogenesis and induced apoptosis. In the mouse S. typhimurium model, dose-dependent reduction in macroscopic pathology, histological inflammation, inflammatory and fibrotic gene expression, and extracellular matrix protein expression indicated ABT-263 may reduce intestinal fibrosis.

Conclusions: In vitro, the antifibrotic efficacy of BH-3 mimetics identifies the Bcl-2 pathway as a druggable target and BH-3 mimetics as putative therapeutics. Reduction of inflammation and fibrosis in the mouse intestinal fibrosis model by ABT-263 indicates BH-3 mimetics as potential, novel antifibrotic therapeutics for Crohn's disease.
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http://dx.doi.org/10.1093/ibd/izab166DOI Listing
July 2021

The role of CTHRC1 in hair follicle regenerative capacity restored by plantar dermis homogenate.

Biochem Biophys Res Commun 2021 09 20;571:14-19. Epub 2021 Jul 20.

Research Center for Tissue Repair and Regeneration, Medical Innovation Research Department and the Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Chinese PLA General Hospital, Beijing, 100853, China; Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, Beijing, 100048, China. Electronic address:

Restoration of hair follicle (HF) regenerative capacity is the cornerstone in tissue engineering for the loss of regenerative capacity during in vitro expansion of skin-derived precursors (SKPs). Microenvironmental cues facilitated tissue or organ regeneration offers a potential strategy to overcome this difficulty. In our previous work, plantar dermis matrix homogenate (PD) has been proved to induce sweat glands regeneration both in vivo and in vitro. Here, we found PD also restore regenerative capacity of culture impaired HF spheroids (IHFS). Further, followed by our previous iTRAQ results, the CTHRC1 was identified as a potential regulator in PD facilitated restorative effects in HF regeneration. Knockout of Cthrc1 impaired HF regenerative capacity in spheroids, decreased the diameter of HF in 28 postnatal days mice and shortened invagination of HF bud in 18 days of gestation mice. In IHFS and Cthrc1-/- spheroids, PD partially restored HF regenerative capacity while Cthrc1-/- PD (PDKO) has less or no effect. Taken together, PD is an effective microenvironmental cues for HF regenerative capacity restoration and CTHRC1 played an important role in HF regeneration.
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http://dx.doi.org/10.1016/j.bbrc.2021.07.056DOI Listing
September 2021

Using bioprinting and spheroid culture to create a skin model with sweat glands and hair follicles.

Burns Trauma 2021 4;9:tkab013. Epub 2021 May 4.

Research Center for Tissue Repair and Regeneration, Medical Innovation Research Department and the Fourth Medical Center, Chinese PLA General Hospital and PLA Medical College, Beijing 100048, China.

Background: Sweat glands (SGs) and hair follicles (HFs) are two important cutaneous appendages that play crucial roles in homeostatic maintenance and thermoregulation, and their interaction is involved in wound healing. SGs can be regenerated from mesenchymal stem cell-laden 3D bioprinted scaffolds, based on our previous studies, whereas regeneration of HFs could not be achieved in the same model. Due to the lack of an model, the underlying molecular mechanism of the interaction between SGs and HFs in regeneration could not be fully understood. The purpose of the present study was to establish an model of skin constructs with SGs and HFs and explore the interaction between these two appendages in regeneration.

Methods: To investigate the interaction effects between SGs and HFs during their regeneration processes, a combined model was created by seeding HF spheroids on 3D printed SG scaffolds. The interaction between SG scaffolds and HF spheroids was detected using RNA expression and immunofluorescence staining. The effects of microenvironmental cues on SG and HF regeneration were analysed by altering seed cell types and plantar dermis homogenate in the scaffold.

Results: According to this model, we overcame the difficulties in simultaneously inducing SG and HF regeneration and explored the interaction effects between SG scaffolds and HF spheroids. Surprisingly, HF spheroids promoted both SG and HF differentiation in SG scaffolds, while SG scaffolds promoted SG differentiation but had little effect on HF potency in HF spheroids. Specifically, microenvironmental factors (plantar dermis homogenate) in SG scaffolds effectively promoted SG and HF genesis in HF spheroids, no matter what the seed cell type in SG scaffolds was, and the promotion effects were persistent.

Conclusions: Our approach elucidated a new model for SG and HF formation and provided an applicable platform to investigate the interaction between SGs and HFs . This platform might facilitate 3D skin constructs with multiple appendages and unveil the spatiotemporal molecular program of multiple appendage regeneration.
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http://dx.doi.org/10.1093/burnst/tkab013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240535PMC
May 2021

Identification and Validation of Plasma Metabolomic Signatures in Precancerous Gastric Lesions That Progress to Cancer.

JAMA Netw Open 2021 Jun 1;4(6):e2114186. Epub 2021 Jun 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China.

Importance: Metabolic deregulation plays an important role in gastric cancer (GC) development. To date, no studies have comprehensively explored the metabolomic profiles along the cascade of gastric lesions toward GC.

Objective: To draw a metabolic landscape and define metabolomic signatures associated with the progression of gastric lesions and risk of early GC.

Design, Setting, And Participants: A 2-stage, population-based cohort study was initiated in 2017 in Linqu County, Shandong Province, China, a high-risk area for GC. Prospective follow-up was conducted during the validation stage (June 20, 2017, to May 27, 2020). A total of 400 individuals were included based on the National Upper Gastrointestinal Cancer Early Detection Program in China. The discovery stage involved 200 individuals with different gastric lesions or GC (high-grade intraepithelial neoplasia or invasive GC). The validation stage prospectively enrolled 152 individuals with gastric lesions who were followed up for 118 to 1063 days and 48 individuals with GC.

Exposures: Metabolomic profiles and metabolite signatures were examined based on untargeted plasma metabolomics assay.

Main Outcomes And Measures: The risk of GC overall and early GC (high-grade intraepithelial neoplasia), and progression of gastric lesions.

Results: Of the 400 participants, 124 of 200 (62.0%) in the discovery set were men; mean (SD) age was 56.8 (7.5) years. In the validation set, 136 of 200 (68.0%) were men; mean (SD) age was 57.5 (8.1) years. Distinct metabolomic profiles were noted for gastric lesions and GC. Six metabolites, including α-linolenic acid, linoleic acid, palmitic acid, arachidonic acid, sn-1 lysophosphatidylcholine (LysoPC)(18:3), and sn-2 LysoPC(20:3) were significantly inversely associated with risk of GC overall and early GC (high-grade intraepithelial neoplasia). Among these metabolites, the first 3 were significantly inversely associated with gastric lesion progression, especially for the progression of intestinal metaplasia (α-linolenic acid: OR, 0.42; 95% CI, 0.18-0.98; linoleic acid: OR, 0.43; 95% CI, 0.19-1.00; and palmitic acid: OR, 0.32; 95% CI, 0.13-0.78). Compared with models including only age, sex, Helicobacter pylori infection, and gastric histopathologic findings, integrating these metabolites significantly improved the performance for predicting the progression of gastric lesions (area under the curve [AUC], 0.86; 95% CI, 0.70-1.00 vs AUC, 0.69; 95% CI, 0.50-0.88; P = .02) and risk of early GC (AUC, 0.83; 95% CI, 0.58-1.00 vs AUC, 0.61; 95% CI, 0.31-0.91; P = .03).

Conclusions And Relevance: This study defined metabolite signatures that might serve as meaningful biomarkers for assessing high-risk populations and early diagnosis of GC, possibly advancing targeted GC prevention and control.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.14186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220475PMC
June 2021

Bioactive nanoparticle reinforced alginate/gelatin bioink for the maintenance of stem cell stemness.

Mater Sci Eng C Mater Biol Appl 2021 Jul 19;126:112193. Epub 2021 May 19.

Research Center for Tissue Repair and Regeneration affiliated to the Medical Innovation Research Department, PLA General Hospital, 51 Fu Cheng Road, Beijing 100048, PR China. Electronic address:

Mesenchymal cells (MSCs) are an attractive option as seed cells for bioprinting. However, loss of stemness and undesired differentiation reduces their effectiveness. In this study, 12 nm bioactive nanoparticles (BNPs) which could release silicon (Si) ions were used to enhance the properties of alginate/gelatin hydrogel bioink to maintain MSC stemness. By specifically leveraging biochemical signals of BNPs, bioink with defined stiffness towards osteogenic and adipogenic potential, independent of pore structure, were designed by incorporating with different concentration of BNPs. These bioink were characterized by printability, mechanical and rheological properties as well as osteogenic and adipogenic potentials. Notably, the effect of 2% BNPs addition in alginate/gelatin hydrogel on MSC stemness maintenance was confirmed by the expression of stemness markers. At higher concentrations of BNPs (5%), printability was impacted by the gelling process. We further confirmed the enhanced stemness maintenance by sweat gland lineage commitment of bioprinted MSCs in vitro. Overall, our study proved that alginate/gelatin hydrogel bioink reinforced by BNPs in the optimal concentrations could retain MSC stemness as well as support MSC growth and prolong the desired differentiation. These findings may provide a new approach to achieve the ideal therapeutic potential of MSCs in 3D bioprinting application.
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http://dx.doi.org/10.1016/j.msec.2021.112193DOI Listing
July 2021

Interactive effects of natural and anthropogenic factors on heterogenetic accumulations of heavy metals in surface soils through geodetector analysis.

Sci Total Environ 2021 Oct 24;789:147937. Epub 2021 May 24.

Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China. Electronic address:

The rapid socioeconomic development has led to severe pollution of urban soils by heavy metals. It is vital to identify and quantify the factors that affect trace-element pollution for better preventing and managing soil pollution. In this study, we collected 179 surface soil samples from Zhangzhou City in a coastal area of south China to determine the concentration of seven heavy metals (As, Cr, Cu, Hg, Ni, Pb, and Zn) and used the Nemerow Pollution Index (P) to estimate the level of heavy metal pollution in soils. Eighteen environmental factors, including six natural factors (e.g. soil properties, surface topography) and twelve anthropogenic factors (e.g. industry, road network, land use types and landscape pattern), were evaluated with the geodetector statistical method. The results indicate that the heavy metal contamination of soils in Zhangzhou City was highly heterogeneous. We found that the primary influencing factors for heavy metal concentrations were soil organic matter content, agriculture activities, and landscape pattern. Furthermore, the nonlinear relationship between the primary factors and their interaction factors enhanced soil contamination by the heavy metals. Among the anthropogenic factors, landscape pattern enhanced P the most when interacting with natural factor. In addition, the buffer zone should be considered when evaluating the effects of factors such as land use and landscape pattern, because the interactions between landscape pattern and slope aspect produce a maximum effect, accounting for 31.0% of the P value on the scale of 800 m. Based on this analysis, we identified the key factors of heavy metal pollution in the soils of Zhangzhou City and proposed strategic procedures for effective soil pollution prevention and treatment in the future.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147937DOI Listing
October 2021

Charting human development using a multi-endodermal organ atlas and organoid models.

Cell 2021 Jun 20;184(12):3281-3298.e22. Epub 2021 May 20.

Institute of Molecular and Clinical Ophthalmology Basel, 4031 Basel, Switzerland; Department of Ophthalmology, University of Basel, 4031 Basel, Switzerland. Electronic address:

Organs are composed of diverse cell types that traverse transient states during organogenesis. To interrogate this diversity during human development, we generate a single-cell transcriptome atlas from multiple developing endodermal organs of the respiratory and gastrointestinal tract. We illuminate cell states, transcription factors, and organ-specific epithelial stem cell and mesenchyme interactions across lineages. We implement the atlas as a high-dimensional search space to benchmark human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) under multiple culture conditions. We show that HIOs recapitulate reference cell states and use HIOs to reconstruct the molecular dynamics of intestinal epithelium and mesenchyme emergence. We show that the mesenchyme-derived niche cue NRG1 enhances intestinal stem cell maturation in vitro and that the homeobox transcription factor CDX2 is required for regionalization of intestinal epithelium and mesenchyme in humans. This work combines cell atlases and organoid technologies to understand how human organ development is orchestrated.
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http://dx.doi.org/10.1016/j.cell.2021.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208823PMC
June 2021

Salmonella enterica Serovar Typhimurium SPI-1 and SPI-2 Shape the Global Transcriptional Landscape in a Human Intestinal Organoid Model System.

mBio 2021 05 18;12(3). Epub 2021 May 18.

Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA

The intestinal epithelium is a primary interface for engagement of the host response by foodborne pathogens, like Typhimurium. While the interaction of Typhimurium with the mammalian host has been well studied in transformed epithelial cell lines or in the complex intestinal environment , few tractable models recapitulate key features of the intestine. Human intestinal organoids (HIOs) contain a polarized epithelium with functionally differentiated cell subtypes, including enterocytes and goblet cells and a supporting mesenchymal cell layer. HIOs contain luminal space that supports bacterial replication, are more amenable to experimental manipulation than animals and are more reflective of physiological host responses. Here, we use the HIO model to define host transcriptional responses to Typhimurium infection, also determining host pathways dependent on pathogenicity island-1 (SPI-1)- and -2 (SPI-2)-encoded type 3 secretion systems (T3SS). Consistent with prior findings, we find that Typhimurium strongly stimulates proinflammatory gene expression. Infection-induced cytokine gene expression was rapid, transient, and largely independent of SPI-1 T3SS-mediated invasion, likely due to continued luminal stimulation. Notably, Typhimurium infection led to significant downregulation of host genes associated with cell cycle and DNA repair, leading to a reduction in cellular proliferation, dependent on SPI-1 and SPI-2 T3SS. The transcriptional profile of cell cycle-associated target genes implicates multiple miRNAs as mediators of Typhimurium-dependent cell cycle suppression. These findings from -infected HIOs delineate common and distinct contributions of SPI-1 and SPI-2 T3SSs in inducing early host responses during enteric infection and reinforce host cell proliferation as a process targeted by serovar Typhimurium ( Typhimurium) causes a significant health burden worldwide, yet host responses to initial stages of intestinal infection remain poorly understood. Due to differences in infection outcome between mice and humans, physiological human host responses driven by major virulence determinants of have been more challenging to evaluate. Here, we use the three-dimensional human intestinal organoid model to define early responses to infection with wild-type Typhimurium and mutants defective in the SPI-1 or SPI-2 type-3 secretion systems. While both secretion system mutants show defects in mouse models of oral infection, the specific contributions of each secretion system are less well understood. We show that Typhimurium upregulates proinflammatory pathways independently of either secretion system, while the downregulation of the host cell cycle pathways relies on both SPI-1 and SPI-2. These findings lay the groundwork for future studies investigating how SPI-1- and SPI-2-driven host responses affect infection outcome and show the potential of this model to study host-pathogen interactions with other serovars to understand how initial interactions with the intestinal epithelium may affect pathogenesis.
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http://dx.doi.org/10.1128/mBio.00399-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8262845PMC
May 2021

Two bHLH transcription factors, bHLH48 and bHLH60, associate with phytochrome interacting factor 7 to regulate hypocotyl elongation in Arabidopsis.

Cell Rep 2021 05;35(5):109054

State Key Laboratory of Genetic Engineering and Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200438, People's Republic of China. Electronic address:

The basic helix-loop-helix (bHLH) transcription factor PHYTOCHROME-INTERACTING FACTOR 7 (PIF7) is a central regulator that promotes stem growth by activating growth-related gene expression during shade-avoidance responses. Studying the co-factors of PIF7 can facilitate understanding of the mechanism of PIFs and light signal transduction. Here, we describe the identification of two bHLH transcription factors, bHLH48 and bHLH60 (bHLH48/bHLH60), as essential partners for PIF7-dependent modulation of hypocotyl elongation and function downstream of phytochrome B. These two bHLH factors display DNA binding activity and interact with PIF7. Genetic analysis indicated that bHLH48/bHLH60 and PIF7 are interdependent in promoting hypocotyl elongation. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis identified the substantially overlapping downstream targets of bHLH60 and PIF7. Biochemical analysis revealed that bHLH48/bHLH60 enhance the DNA binding ability of PIF7. These results provide evidence that bHLH48/bHLH60 act as positive partners of PIF7 for mutual benefit in the regulation of hypocotyl elongation.
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http://dx.doi.org/10.1016/j.celrep.2021.109054DOI Listing
May 2021

Rural Morphology and Forces Driving Change in Rapidly Urbanizing Areas: A Case Study in Fujian, China.

Int J Environ Res Public Health 2021 04 26;18(9). Epub 2021 Apr 26.

School of Environmental and Geographical Sciences, Shanghai Normal University, Shanghai 200234, China.

Rapid urbanization in China has transformed many rural areas from agriculture-dominated to diverse systems, but studies of rural morphology are limited compared to studies of urban settlement. This paper uses a fractal dimension (FD) value to analyze the change in rural morphology in Fujian Province, a region with a long history of rural settlement and rapid recent urbanization, and to explore the factors that influenced this change. We found that the rural FD value increased from 2000 to 2012 and that rural morphology was spatially heterogeneous. FD was generally lower than in urban areas but very close to a typical urban area value in the southeast coastal region. A structural equation model was used to identify key factors influencing rural morphology, which were natural conditions, rurality and economic development, while historic administration had the smallest positive effect. With a long history and unique administrative system, the spatial morphology of Chinese rural areas has shown characteristics distinct from compact urban or scattered rural areas. The urban planning method adopted by rural planners is not suitable in rural regions, because the planning potential of rural areas with high and low FD values varies. Although rural planning currently uses a very similar approach to urban planning, it should use a local, flexible and adaptive policy based on rural morphological characteristics.
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http://dx.doi.org/10.3390/ijerph18094590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123589PMC
April 2021

NH-terminal deletion of specific phosphorylation sites on PHOX2B disrupts the formation of enteric neurons in vivo.

Am J Physiol Gastrointest Liver Physiol 2021 06 21;320(6):G1054-G1066. Epub 2021 Apr 21.

Developmental Biology and Regenerative Medicine Program, The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California.

Mutations in the paired-like homeobox 2 b () gene are associated with congenital central hypoventilation syndrome (CCHS), which is a rare condition in which both autonomic dysregulation with hypoventilation and an enteric neuropathy may occur. The majority of patients with CCHS have a polyalanine repeat mutation (PARM) in PHOX2B, but a minority of patients have nonpolyalanine repeat mutations (NPARMs), some of which have been localized to exon 1. A nonsense mutation previously generated in a human pluripotent stem cell (hPSC) line results in an NH-terminus truncated product missing the first 17 or 20 amino acids, possibly due to translational reinitiation at an alternate ATG start site. This NH-terminal truncation in the PHOX2B protein results in the loss of two key phosphorylation residues. Though the deletion does not affect the potential for PHOX2B mutant hPSC to differentiate into enteric neural crest cells (ENCCs) in culture, it impedes in vivo development of neurons in an in vivo model of human aganglionic small intestine. A mutation that affects only 17-20 NH-terminal amino acids in the paired-like homeobox 2 b () gene hinders the subsequent in vivo establishment of intestinal neuronal cells, but not the in vitro differentiation of these cells.
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http://dx.doi.org/10.1152/ajpgi.00073.2021DOI Listing
June 2021

Biophysical and Biochemical Cues of Biomaterials Guide Mesenchymal Stem Cell Behaviors.

Front Cell Dev Biol 2021 25;9:640388. Epub 2021 Mar 25.

Research Center for Tissue Repair and Regeneration, Medical Innovation Research Department and the Fourth Medical Center, Chinese PLA General Hospital, PLA Medical College, Beijing, China.

Mesenchymal stem cells (MSCs) have been widely used in the fields of tissue engineering and regenerative medicine due to their self-renewal capabilities and multipotential differentiation assurance. However, capitalizing on specific factors to precisely guide MSC behaviors is the cornerstone of biomedical applications. Fortunately, several key biophysical and biochemical cues of biomaterials that can synergistically regulate cell behavior have paved the way for the development of cell-instructive biomaterials that serve as delivery vehicles for promoting MSC application prospects. Therefore, the identification of these cues in guiding MSC behavior, including cell migration, proliferation, and differentiation, may be of particular importance for better clinical performance. This review focuses on providing a comprehensive and systematic understanding of biophysical and biochemical cues, as well as the strategic engineering of these signals in current scaffold designs, and we believe that integrating biophysical and biochemical cues in next-generation biomaterials would potentially help functionally regulate MSCs for diverse applications in regenerative medicine and cell therapy in the future.
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http://dx.doi.org/10.3389/fcell.2021.640388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027358PMC
March 2021

Ginsenoside Rb1 Alleviates Alcohol-Induced Liver Injury by Inhibiting Steatosis, Oxidative Stress, and Inflammation.

Front Pharmacol 2021 26;12:616409. Epub 2021 Feb 26.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.

Alcoholic liver disease (ALD) has become a heavy burden on health worldwide. Ginsenoside Rb1 (GRb1), extracted from L, has protective effects on many diseases, but the effect and mechanisms of GRb1 on ALD remain unknown. This study aimed to investigate the protective effects of GRb1 on ALD and to discover the potential mechanisms. Zebrafish larvae were exposed to 350 mM ethanol for 32 h to establish a model of acute alcoholic liver injury, and the larvae were then treated with 6.25, 12.5, or 25 μM GRb1 for 48 h. The human hepatocyte cell line was stimulated by 100 mM ethanol and meanwhile incubated with 6.25, 12.5, and 25 μM GRb1 for 24 h. The lipid changes were detected by Oil Red O staining, Nile Red staining, and triglyceride determination. The antioxidant capacity was assessed by fluorescent probes , and the expression levels of inflammatory cytokines were detected by immunohistochemistry, immunofluorescence, and quantitative real-time PCR. The results showed that GRb1 alleviated lipid deposition in hepatocytes at an optimal concentration of 12.5 μM . GRb1 reversed the reactive oxygen species accumulation caused by alcohol consumption and partially restored the level of glutathione. Furthermore, GRb1 ameliorated liver inflammation by inhibiting neutrophil infiltration in the liver parenchyma and downregulating the expression of nuclear factor-kappa B pathway-associated proinflammatory cytokines, including tumor necrosis factor-α and interleukin-1β. This study revealed that GRb1 has a protective effect on alcohol-induced liver injury due to its resistance to lipid deposition as well as antioxidant and anti-inflammatory actions. These findings suggest that GRb1 may be a promising candidate against ALD.
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http://dx.doi.org/10.3389/fphar.2021.616409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952325PMC
February 2021

Lupeol ameliorates LPS/D-GalN induced acute hepatic damage by suppressing inflammation and oxidative stress through TGFβ1-Nrf2 signal pathway.

Aging (Albany NY) 2021 03 11;13(5):6592-6605. Epub 2021 Mar 11.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong, China.

Acute hepatic damage is a severe condition characterized by inflammation and oxidative stress, which is a serious threat to people's life and health. But there are few effective treatments for acute liver injury. Therefore, safe and effective therapeutic approaches for preventing acute liver damage are urgently needed. Lupeol is a natural compound, which has significant antioxidant and anti-inflammatory properties in liver disease. However, the protective mechanism of lupeol against acute liver injury remains unclear. Here, zebrafish and mutant mice were utilized to investigate the protective effects of lupeol against lipopolysaccharide (LPS)/ D-galactosamine(D-GalN) -induced liver injury and the underlying mechanisms. We found that pretreatment with lupeol attenuated the LPS/D-GalN-induced liver injury by decreasing the infiltration of inflammatory cells and reducing pro-inflammatory cytokines. We also demonstrated that lupeol could protect injured liver from oxidative stress by downregulating the expression of TGFβ1 and upregulating Nrf2. Notably, our experimental results provided the support that lupeol effectively protected against LPS/D-GalN-induced acute liver injury via suppression of inflammation response and oxidative stress, which were largely dependent on the upregulation of the Nrf2 pathway via downregulating TGFβ1.
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http://dx.doi.org/10.18632/aging.202409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993700PMC
March 2021

Ginsenoside-Rg1 acts as an IDO1 inhibitor, protects against liver fibrosis via alleviating IDO1-mediated the inhibition of DCs maturation.

Phytomedicine 2021 Apr 20;84:153524. Epub 2021 Feb 20.

School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong 510515, PR China. Electronic address:

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) has been reported as a hallmark of hepatic fibrosis. Ginseng Rg1(G-Rg1) is a characterized bioactive component isolated from a traditional Chinese medicinal herb Panax ginseng C. A. Meyer (Ginseng) that used in China widely. However, the anti-hepatic fibrosis property of G-Rg1 and the underlying mechanisms of action are poorly reported.

Purpose: Here, we researched the effect of G-Rg1 on experimental liver fibrosis in vivo and in vitro.

Study Design And Methods: We applied a CCL4-induced liver fibrosis in mice (wild-type and those overexpressing IDO1 by in vivo AAV9 vector) and HSC-T6 cells to detect the anti-hepatic fibrosis effect of G-Rg1 in vivo and in vitro.

Results: We found that G-Rg1 reduced serum levels of AST and ALT markedly. Histologic examination indicated that G-Rg1 dramatically improved the extent of liver fibrosis and suppressed the hepatic levels of fibrotic marker α-SMA in vivo and in vitro. The proliferation of HSC-T6 was significantly inhibited by G-Rg1 in vitro. Both TUNEL staining and flow cytometry demonstrated that G-Rg1 attenuated the levels of hepatocyte apoptosis in fibrotic mice. Additionally, G-Rg1 up-regulated the maturation of hepatic DCs via reducing the expression level of hepatic IDO1, which played an inverse role in the maturation of DCs. Furthermore, oral administration of G-Rg1 ameliorated IDO1 overexpression-induced worsen liver fibrosis as well as IDO1 overexpression-mediated more apparent inhibition of maturation of DCs.

Conclusion: These results suggest that G-Rg1, which exerts its antifibrotic properties via alleviating IDO1-mediated the inhibition of DCs maturation, may be a potential therapeutic drug in treating liver fibrosis.
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http://dx.doi.org/10.1016/j.phymed.2021.153524DOI Listing
April 2021

Clinical Perspectives on Liquid Biopsy in Metastatic Colorectal Cancer.

Front Genet 2021 28;12:634642. Epub 2021 Jan 28.

Department of Molecular Pathology, Fujian Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, China.

Liquid biopsy, which generally refers to the analysis of biological components such as circulating nuclear acids and circulating tumor cells in body fluids, particularly in peripheral blood, has shown good capacity to overcome several limitations faced by conventional tissue biopsies. Emerging evidence in recent decades has confirmed the promising role of liquid biopsy in the clinical management of various cancers, including colorectal cancer, which is one of the most prevalent cancers and the second leading cause of cancer-related deaths worldwide. Despite the challenges and poor clinical outcomes, patients with metastatic colorectal cancer can expect potential clinical benefits with liquid biopsy. Therefore, in this review, we focus on the clinical prospects of liquid biopsy in metastatic colorectal cancer, specifically with regard to the recently discovered various biomarkers identified on liquid biopsy. These biomarkers have been shown to be potentially useful in multiple aspects of metastatic colorectal cancer, such as auxiliary diagnosis of metastasis, prognosis prediction, and monitoring of therapy response.
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http://dx.doi.org/10.3389/fgene.2021.634642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876389PMC
January 2021

Metformin reverses chemoresistance in non-small cell lung cancer via accelerating ubiquitination-mediated degradation of Nrf2.

Transl Lung Cancer Res 2020 Dec;9(6):2337-2355

Department of Thoracic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Background: The therapeutic efficacy of cisplatin-based chemotherapy for non-small cell lung cancer (NSCLC) is limited by drug resistance. In NSCLC, hyperactivation of nuclear factor erythroid 2-related factor 2 (Nrf2) counteracts oxidative stress to promote chemoresistance. Metformin-mediated downregulation of Nrf2 plays a pivotal role in overcoming drug resistance in NSCLC cells. Therefore, a deeper understanding of the molecular mechanisms of combination therapy and the role of Nrf2 in chemotherapeutic response is critical to clinical translation.

Methods: The effects of combination therapy with metformin and cisplatin on cell proliferation and apoptosis, intracellular reactive oxygen species (ROS) levels, and xenograft tumor formation were analyzed in NSCLC cells. Co-immunoprecipitation (co-IP) and Phos-tag assays were used to explore the mechanism of metformin-mediated Nrf2 suppression. Immunohistochemical (IHC) staining was performed to detect Nrf2 expression in matched tumor samples before and after neoadjuvant chemotherapy.

Results: Metformin was observed to synergistically augment cisplatin-induced cytotoxicity by strongly inhibiting the level of Nrf2, thereby weakening the antioxidant system and detoxification ability of Nrf2 and enhancing ROS-mediated apoptosis in NSCLC. The synergistic antitumor effect of combination therapy is blocked by treatment with the ROS scavenger N-acetyl cysteine (NAC) as well as overexpression of Nrf2 and its downstream antioxidant protein. Mechanistically, metformin extensively dephosphorylates Nrf2 by attenuating the interaction between Nrf2 and extracellular signal-regulated kinases 1/2 (ERK1/2), which then restores its polyubiquitination and accelerates its proteasomal degradation. Moreover, for the first time, an association of non-decreased Nrf2 expression in patients after neoadjuvant chemotherapy with poor survival and chemoresistance in NSCLC was revealed.

Conclusions: Our findings illustrate the mechanism of metformin-mediated Nrf2 degradation through posttranslational modifications (PTMs), which weakens the ROS defense system in NSCLC. Fluctuations in Nrf2 expression have a strong predictive ability for chemotherapeutic response in neoadjuvant NSCLC patients. Targeting of the Nrf2 pathway could be a therapeutic strategy for overcoming chemoresistance, with metformin as the first choice for this strategy.
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http://dx.doi.org/10.21037/tlcr-20-1072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815349PMC
December 2020

Indoleamine 2,3-dioxygenase 1 limits hepatic inflammatory cells recruitment and promotes bile duct ligation-induced liver fibrosis.

Cell Death Dis 2021 01 7;12(1):16. Epub 2021 Jan 7.

School of Traditional Chinese Medicine, Southern Medical University, 510515, Guangzhou, Guangdong, People's Republic of China.

Liver fibrosis is a course of chronic liver dysfunction, can develop into cirrhosis and hepatocellular carcinoma. Inflammatory insult owing to pathogenic factors plays a crucial role in the pathogenesis of liver fibrosis. Indoleamine 2,3-dioxygenase 1 (IDO1) can affect the infiltration of immune cells in many pathology processes of diseases, but its role in liver fibrosis has not been elucidated completely. Here, the markedly elevated protein IDO1 in livers was identified, and dendritic cells (DCs) immune-phenotypes were significantly altered after BDL challenge. A distinct hepatic population of CD11cDCs was decreased and presented an immature immune-phenotype, reflected by lower expression levels of co-stimulatory molecules (CD40, MHCII). Frequencies of CD11cCD80, CD11cCD86, CD11cMHCII, and CD11cCD40 cells in splenic leukocytes were reduced significantly. Notably, IDO1 overexpression inhibited hepatic, splenic CD11cDCs maturation, mature DCs-mediated T-cell proliferation and worsened liver fibrosis, whereas above pathological phenomena were reversed in IDO1 mice. Our data demonstrate that IDO1 affects the process of immune cells recruitment via inhibiting DCs maturation and subsequent T cells proliferation, resulting in the promotion of hepatic fibrosis. Thus, amelioration of immune responses in hepatic and splenic microenvironment by targeting IDO1 might be essential for the therapeutic effects on liver fibrosis.
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http://dx.doi.org/10.1038/s41419-020-03277-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791029PMC
January 2021

Chromatin regulatory dynamics of early human small intestinal development using a directed differentiation model.

Nucleic Acids Res 2021 01;49(2):726-744

Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.

The establishment of the small intestinal (SI) lineage during human embryogenesis ensures functional integrity of the intestine after birth. The chromatin dynamics that drive SI lineage formation and regional patterning in humans are essentially unknown. To fill this knowledge void, we apply a cutting-edge genomic technology to a state-of-the-art human model of early SI development. Specifically, we leverage chromatin run-on sequencing (ChRO-seq) to define the landscape of active promoters, enhancers and gene bodies across distinct stages of directed differentiation of human pluripotent stem cells into SI spheroids with regional specification. Through comprehensive ChRO-seq analysis we identify candidate stage-specific chromatin activity states, novel markers and enhancer hotspots during the directed differentiation. Moreover, we propose a detailed transcriptional network associated with SI lineage formation or regional patterning. Our ChRO-seq analyses uncover a previously undescribed pattern of enhancer activity and transcription at HOX gene loci underlying SI regional patterning. We also validated this unique HOX dynamics by the analysis of single cell RNA-seq data from human fetal SI. Overall, the results lead to a new proposed working model for the regulatory underpinnings of human SI development, thereby adding a novel dimension to the literature that has relied almost exclusively on non-human models.
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http://dx.doi.org/10.1093/nar/gkaa1204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826262PMC
January 2021

Nrf2 Mediates Metabolic Reprogramming in Non-Small Cell Lung Cancer.

Front Oncol 2020 26;10:578315. Epub 2020 Nov 26.

Department of Thoracic Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Nuclear factor erythroid-2-related factor-2 (NFE2L2/Nrf2) is a transcription factor that regulates the expression of antioxidant genes. Both Kelch-like ECH-associated protein 1 (Keap1) mutations and Nrf2 mutations contribute to the activation of Nrf2 in non-small cell lung cancer (NSCLC). Nrf2 activity is associated with poor prognosis in NSCLC. Metabolic reprogramming represents a cancer hallmark. Increasing studies reveal that Nrf2 activation promotes metabolic reprogramming in cancer. In this review, we discuss the underlying mechanisms of Nrf2-mediated metabolic reprogramming and elucidate its role in NSCLC. Inhibition of Nrf2 can alter metabolic processes, thus suppress tumor growth, prevent metastasis, and increase sensitivity to chemotherapy in NSCLC. In conclusion, Nrf2 may serve as a therapeutic target for the treatment of NSCLC.
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http://dx.doi.org/10.3389/fonc.2020.578315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726415PMC
November 2020

AtINO80 represses photomorphogenesis by modulating nucleosome density and H2A.Z incorporation in light-related genes.

Proc Natl Acad Sci U S A 2020 12 14;117(52):33679-33688. Epub 2020 Dec 14.

State Key Laboratory of Genetic Engineering and Institute of Plant Biology, Institute of Plant Biology, School of Life Sciences, Fudan University, Shanghai 200438, People's Republic of China;

Photomorphogenesis is a critical developmental process bridging light-regulated transcriptional reprogramming with morphological changes in organisms. Strikingly, the chromatin-based transcriptional control of photomorphogenesis remains poorly understood. Here, we show that the () ortholog of ATP-dependent chromatin-remodeling factor AtINO80 represses plant photomorphogenesis. Loss of AtINO80 inhibited hypocotyl cell elongation and caused anthocyanin accumulation. Both light-induced genes and dark-induced genes were affected in the mutant. Genome-wide occupancy of the H2A.Z histone variant and levels of histone H3 were reduced in In particular, AtINO80 bound the gene body of (), resulting in lower chromatin incorporations of H2A.Z and H3 at in Genetic analysis revealed that AtINO80 acts in a phytochrome B- and HY5-dependent manner in the regulation of photomorphogenesis. Together, our study elucidates a mechanism wherein AtINO80 modulates nucleosome density and H2A.Z incorporation and represses the transcription of light-related genes, such as , to fine tune plant photomorphogenesis.
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http://dx.doi.org/10.1073/pnas.2001976117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7777152PMC
December 2020

The stiffness of hydrogel-based bioink impacts mesenchymal stem cells differentiation toward sweat glands in 3D-bioprinted matrix.

Mater Sci Eng C Mater Biol Appl 2021 Jan 22;118:111387. Epub 2020 Aug 22.

Research Center for Tissue Repair and Regeneration affiliated to the Medical Innovation Research Department, PLA General Hospital and PLA Medical College, 28 Fu Xing Road, Beijing 100853, PR China; PLA Key Laboratory of Tissue Repair and Regenerative Medicine and Beijing Key Research Laboratory of Skin Injury, Repair and Regeneration, Research Unit of Trauma Care, Tissue Repair and Regeneration, Chinese Academy of Medical Sciences, 2019RU051, 51 Fu Cheng Road, Beijing 100048, PR China. Electronic address:

Mechanical aspects of printable hydrogels can impact cell behavior in 3D-bioprinted constructs, and in this context the stiffness of hydrogel-based bioink can serve as an important physical cue in regulating cell differentiation. Here we bioprinted mesenchymal stem cells (MSCs) by the commonly used bioink alginate-gelatin (Alg-Gel) blends and investigated the influence of stiffness on MSC differentiation toward sweat glands. Mechanical properties were assessed through compression testing and it was found that higher compressive modulus was associated with the higher Alg-Gel concentrations. Using these Alg-Gel blends for bioprinting, we demonstrated that stiffness variance cannot cause differences in cell spreading, adhesion and viability. However, MSCs bioprinted by stiffer hydrogels were found to further upregulate the protein and gene expression of sweat gland cell phenotype, function and development of signaling pathways. Furthermore, we found that the increased Yes-associated protein (YAP) localization of nuclei in MSCs when bioprinted by stiffer hydrogels. These results illustrated that the stiffness of Alg-Gel blends is a potent regulator of MSC differentiation, which was possibly achieved through a YAP-dependent mechanotransduction mechanism.
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http://dx.doi.org/10.1016/j.msec.2020.111387DOI Listing
January 2021

Advances in 3D bioprinting technology for cardiac tissue engineering and regeneration.

Bioact Mater 2021 May 10;6(5):1388-1401. Epub 2020 Nov 10.

Department of Cardiac Surgery, and Department of Medical Sciences, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, 510100, China.

Cardiovascular disease is still one of the leading causes of death in the world, and heart transplantation is the current major treatment for end-stage cardiovascular diseases. However, because of the shortage of heart donors, new sources of cardiac regenerative medicine are greatly needed. The prominent development of tissue engineering using bioactive materials has creatively laid a direct promising foundation. Whereas, how to precisely pattern a cardiac structure with complete biological function still requires technological breakthroughs. Recently, the emerging three-dimensional (3D) bioprinting technology for tissue engineering has shown great advantages in generating micro-scale cardiac tissues, which has established its impressive potential as a novel foundation for cardiovascular regeneration. Whether 3D bioprinted hearts can replace traditional heart transplantation as a novel strategy for treating cardiovascular diseases in the future is a frontier issue. In this review article, we emphasize the current knowledge and future perspectives regarding available bioinks, bioprinting strategies and the latest outcome progress in cardiac 3D bioprinting to move this promising medical approach towards potential clinical implementation.
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http://dx.doi.org/10.1016/j.bioactmat.2020.10.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658327PMC
May 2021
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