Publications by authors named "Zhi Yao"

365 Publications

A Matter of Life or Death: Productively Infected and Bystander CD4 T Cells in Early HIV Infection.

Front Immunol 2020 12;11:626431. Epub 2021 Feb 12.

Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.

CD4 T cell death or survival following initial HIV infection is crucial for the development of viral reservoirs and latent infection, making its evaluation critical in devising strategies for HIV cure. Here we infected primary CD4 T cells with a wild-type HIV-1 and investigated the death and survival mechanisms in productively infected and bystander cells during early HIV infection. We found that HIV-infected cells exhibited increased programmed cell death, such as apoptosis, pyroptosis, and ferroptosis, than uninfected cells. However, productively infected (p24) cells and bystander (p24) cells displayed different patterns of cell death due to differential expression of pro-/anti-apoptotic proteins and signaling molecules. Cell death was triggered by an aberrant DNA damage response (DDR), as evidenced by increases in γH2AX levels, which inversely correlated with telomere length and telomerase levels during HIV infection. Mechanistically, HIV-infected cells exhibited a gradual shortening of telomeres following infection. Notably, p24 cells had longer telomeres compared to p24 cells, and telomere length positively correlated with the telomerase, pAKT, and pATM expressions in HIV-infected CD4 T cells. Importantly, blockade of viral entry attenuated the HIV-induced inhibition of telomerase, pAKT, and pATM as well as the associated telomere erosion and cell death. Moreover, ATM inhibition promoted survival of HIV-infected CD4 T cells, especially p24 cells, and rescued telomerase and AKT activities by inhibiting cell activation, HIV infection, and DDR. These results indicate that productively infected and bystander CD4 T cells employ different mechanisms for their survival and death, suggesting a possible pro-survival, pro-reservoir mechanism during early HIV infection.
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http://dx.doi.org/10.3389/fimmu.2020.626431DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907524PMC
February 2021

Carbon footprint of maize production in tropical/subtropical region: a case study of Southwest China.

Environ Sci Pollut Res Int 2021 Feb 5. Epub 2021 Feb 5.

Key Laboratory of Efficient Utilization of Soil and Fertilizer Resources, Chongqing, 400715, China.

Maize production is critical in tropical/subtropical regions, especially in developing countries where maize is a staple food. However, its environmental costs remain unclear. Southwest China is a tropical/subtropical region with large-scale maize production in each of its sub-regions. In the present study, we used Southwest China as a case study to evaluate the greenhouse gas (GHG) emissions and carbon footprint (CF) of maize production during 1996-2015 using life cycle assessment to identify the driving factors behind the GHG emissions and CF and to propose potential mitigation strategies. The mean GHG emissions of maize production per year during 1996-2015 was 4132 kg CO-eq·ha, and the CF during this period was 961 kg CO-eq·Mg. The GHG emissions and CF in Southwest China were 2-4 times higher than those of other major maize-producing regions worldwide. The GHG emissions and CF were both significantly correlated with the N surplus. The N surplus was also linearly correlated with annual precipitation, annual temperature and growing degree days, but not significantly related with soil pH. Scenario testing showed that the CF of maize production in Southwest China could be reduced by 41%, i.e. to 437 kg CO-eq·Mg, by farmers adopting a comprehensive strategy including recommended fertiliser application rates, innovative fertilisers, and crop management to decrease GHG emissions and achieve the yield potential in the region. Integrated soil and crop management is essential for sustainable maize production in tropical/subtropical regions with complex and changeable ecological conditions, especially in developing countries where maize is a staple food.
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http://dx.doi.org/10.1007/s11356-021-12663-wDOI Listing
February 2021

Transcriptional coregualtor NUPR1 maintains tamoxifen resistance in breast cancer cells.

Cell Death Dis 2021 Feb 4;12(2):149. Epub 2021 Feb 4.

Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin, China.

To support cellular homeostasis and mitigate chemotherapeutic stress, cancer cells must gain a series of adaptive intracellular processes. Here we identify that NUPR1, a tamoxifen (Tam)-induced transcriptional coregulator, is necessary for the maintenance of Tam resistance through physical interaction with ESR1 in breast cancers. Mechanistically, NUPR1 binds to the promoter regions of several genes involved in autophagy process and drug resistance such as BECN1, GREB1, RAB31, PGR, CYP1B1, and regulates their transcription. In Tam-resistant ESR1 breast cancer cells, NUPR1 depletion results in premature senescence in vitro and tumor suppression in vivo. Moreover, enforced-autophagic flux augments cytoplasmic vacuolization in NUPR1-depleted Tam resistant cells, which facilitates the transition from autophagic survival to premature senescence. Collectively, these findings suggest a critical role for NUPR1 as a transcriptional coregulator in enabling endocrine persistence of breast cancers, thus providing a vulnerable diagnostic and/or therapeutic target for endocrine resistance.
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http://dx.doi.org/10.1038/s41419-021-03442-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862277PMC
February 2021

The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging.

Cells 2021 Jan 16;10(1). Epub 2021 Jan 16.

Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.

According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV.
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http://dx.doi.org/10.3390/cells10010174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830696PMC
January 2021

Pd-Catalyzed Coupling of Thioamides with -Tosylhydrazones/Trapping by Esters Cascade Reaction.

Org Lett 2021 Jan 6;23(2):311-316. Epub 2021 Jan 6.

School of Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China.

,-Disubstituted thioamides coupled with -tosylhydrazones under Pd(TFA)/BuXPhos catalyst and NaOBu, and the intermediates from palladium carbene migratory insertion containing hydrogen were trapped by intramolecular esters activated by BF·EtO instead of undergoing H elimination, providing polyfunctional thiophen-3()-ones with sulfur-containing tetrasubstituted carbon centers in moderate to good yields. The reaction features the formation of three bonds in a single operation, odorless, safe, and easily available substrates, wide substrate scope, and excellent functional group tolerance.
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http://dx.doi.org/10.1021/acs.orglett.0c03796DOI Listing
January 2021

Microstructure Analysis and Reconstruction of a Meniscus.

Orthop Surg 2021 Feb 5;13(1):306-313. Epub 2021 Jan 5.

Department of Joint and Orthopaedics, Zhujiang Hospital, Southern Medical University, Guangzhou, China.

Objective: To analyze the characteristics of menicus microstructure and to reconstruct a microstructure-mimicing 3D model of the menicus.

Methods: Human and sheep meniscus were collected and prepared for this study. Hematoxylin-eosin staining (HE) and Masson staining were conducted for histological analysis of the meniscus. For submicroscopic structure analysis, the meniscus was first freeze-dried and then scanned by scanning electron microscopy (SEM). The porosity of the meniscus was determined according to SEM images. A micro-MRI was used to scan each meniscus, immersed in distilled water, and a 3D digital model was reconstructed afterwards. A three-dimensional (3D) resin model was printed out based on the digital model. Before high-resolution micro-CT scanning, each meniscus was freeze-dried. Then, micro-scale two-dimensional (2D) CT projection images were obtained. The porosity of the meniscus was calculated according to micro-CT images. With micro-CT, multiple 2D projection images were collected. A 3D digital model based on 2D CT pictures was also reconstructed. The 3D digital model was exported as STL format. A 3D resin model was printed by 3D printer based on the 3D digital model.

Results: As revealed in the HE and Masson images, a meniscus is mostly composed of collagen, with a few cells disseminated between the collagen fiber bundles at the micro-scale. The SEM image clearly shows the path of highly cross-linked collagen fibers, and massive pores exist between the fibers. According to the SEM images, the porosity of the meniscus was 34.1% (34.1% ± 0.032%) and the diameters of the collagen fibers were varied. In addition, the cross-linking pattern of the fibers was irregular. The scanning accuracy of micro-MRI was 50 μm. The micro-MRI demonstrated the outline of the meniscus, but the microstructure was obscure. The micro-CT clearly displayed microfibers in the meniscus with a voxel size of 11.4 μm. The surface layer, lamellar layer, circumferential fibers, and radial fibers could be identified. The mean porosity of the meniscus according to micro-CT images was 33.92% (33.92% ± 0.03%). Moreover, a 3D model of the microstructure based on the micro-CT images was built. The microscale fibers could be displayed in the micro-CT image and the reconstructed 3D digital model. In addition, a 3D resin model was printed out based on the 3D digital model.

Conclusion: It is extremely difficult to artificially simulate the microstructure of the meniscus because of the irregularity of the diameter and cross-linking pattern of fibers. The micro-MRI images failed to demonstrate the meniscus microstructure. Freeze-drying and micro-CT scanning are effective methods for 3D microstructure reconstruction of the meniscus, which is an important step towards mechanically functional 3D-printed meniscus grafts.
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http://dx.doi.org/10.1111/os.12899DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862168PMC
February 2021

ERK1/2 inhibition reduces vascular calcification by activating miR-126-3p-DKK1/LRP6 pathway.

Theranostics 2021 1;11(3):1129-1146. Epub 2021 Jan 1.

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, China.

: Vascular microcalcification increases the risk of rupture of vulnerable atherosclerotic lesions. Inhibition of ERK1/2 reduces atherosclerosis in animal models while its role in vascular calcification and the underlying mechanisms remains incompletely understood. Levels of activated ERK1/2, DKK1, LRP6 and BMP2 in human calcific aortic valves were determined. ApoE deficient mice received ERK1/2 inhibitor (U0126) treatment, followed by determination of atherosclerosis, calcification and miR-126-3p production. C57BL/6J mice were used to determine the effect of U0126 on Vitamin D (VD)-induced medial arterial calcification. HUVECs, HAECs and HASMCs were used to determine the effects of ERK1/2 inhibitor or siRNA on SMC calcification and the involved mechanisms. : We observed the calcification in human aortic valves was positively correlated to ERK1/2 activity. At cellular and animal levels, U0126 reduced intimal calcification in atherosclerotic lesions of high-fat diet-fed apoE deficient mice, medial arterial calcification in VD-treated C57BL/6J mice, and calcification in cultured SMCs and arterial rings. The reduction of calcification was attributed to ERK1/2 inhibition-reduced expression of ALP, BMP2 and RUNX2 by activating DKK1 and LRP6 expression, and consequently inactivating both canonical and non-canonical Wnt signaling pathways in SMCs. Furthermore, we determined ERK1/2 inhibition activated miR-126-3p production by facilitating its maturation through activation of AMPKα-mediated p53 phosphorylation, and the activated miR-126-3p from ECs and SMCs played a key role in anti-vascular calcification actions of ERK1/2 inhibition. : Our study demonstrates that activation of miR-126-3p production in ECs/SMCs and interactions between ECs and SMCs play an important role in reduction of vascular calcification by ERK1/2 inhibition.
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http://dx.doi.org/10.7150/thno.49771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7738895PMC
January 2021

HCV-Associated Exosomes Upregulate RUNXOR and RUNX1 Expressions to Promote MDSC Expansion and Suppressive Functions through STAT3-miR124 Axis.

Cells 2020 Dec 18;9(12). Epub 2020 Dec 18.

Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.

RUNX1 overlapping RNA (RUNXOR) is a long non-coding RNA and plays a pivotal role in the differentiation of myeloid cells via targeting runt-related transcription factor 1 (RUNX1). We and others have previously reported that myeloid-derived suppressor cells (MDSCs) expand and inhibit host immune responses during chronic viral infections; however, the mechanisms responsible for MDSC differentiation and suppressive functions, in particular the role of RUNXOR-RUNX1, remain unclear. Here, we demonstrated that RUNXOR and RUNX1 expressions are significantly upregulated and associated with elevated levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS) in MDSCs during chronic hepatitis C virus (HCV) infection. Mechanistically, we discovered that HCV-associated exosomes (HCV-Exo) can induce the expressions of RUNXOR and RUNX1, which in turn regulates miR-124 expression via STAT3 signaling, thereby promoting MDSC differentiation and suppressive functions. Importantly, overexpression of RUNXOR in healthy CD33 myeloid cells promoted differentiation and suppressive functions of MDSCs. Conversely, silencing RUNXOR or RUNX1 expression in HCV-derived CD33 myeloid cells significantly inhibited their differentiation and expressions of suppressive molecules and improved the function of co-cultured autologous CD4 T cells. Taken together, these results indicate that the RUNXOR-RUNX1-STAT3-miR124 axis enhances the differentiation and suppressive functions of MDSCs and could be a potential target for immunomodulation in conjunction with antiviral therapy during chronic HCV infection.
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http://dx.doi.org/10.3390/cells9122715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7766103PMC
December 2020

Long Non-Coding RNA Hotairm1 Promotes S100A9 Support of MDSC Expansion during Sepsis.

J Clin Cell Immunol 2020 22;11(6). Epub 2020 Sep 22.

Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, TN 37614, USA.

Myeloid-derived suppressor cells (MDSCs) expand during mouse and human sepsis, but the mechanism responsible for this is unclear. We previously reported that nuclear transport of S100A9 protein programs Gr1CD11b myeloid precursors into MDSCs in septic mice. Here, we show that long non-coding RNA Hotairm1 converts MDSCs from an activator to a repressor state. Mechanistically, increased Hotairm1 expression in MDSCs in mice converted S100A9 from a secreted proinflammatory mediator to an immune repressor by binding to and shuttling it from cytosol to nucleus during late sepsis. High Hotairm1 levels were detected in exosomes shed from MDSCs from late septic mice. These exosomes inhibited lipopolysaccharide-stimulated secretion of S100A9 from early sepsis Gr1CD11b cells. Importantly, Hotairm1 knockdown in late sepsis Gr1CD11b MDSCs prevented S100A9 cytosol to nuclear transfer and decreased repression of proimmune T cells. Notably, ectopic expression of Hotairm1 in early sepsis Gr1CD11b cells shuttled S100A9 to the nucleus and promoted the MDSC repressor phenotype. In support of translating the mechanistic concept to human sepsis, we found that Hotairm1 binds S100A9 protein in CD33CD11bHLA-DR MDSCs during established sepsis. Together, these data support that Hotairm1 is a plausible molecular target for treating late sepsis immune suppression in humans and its immune repressor mechanism may be cell autonomous.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744002PMC
September 2020

LncRNA HOTAIRM1 promotes MDSC expansion and suppressive functions through the HOXA1-miR124 axis during HCV infection.

Sci Rep 2020 12 16;10(1):22033. Epub 2020 Dec 16.

Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.

HOXA transcript antisense RNA myeloid-specific 1 (HOTAIRM1) is a long non-coding RNA (lncRNA) that plays a pivotal role in regulating myeloid cell development via targeting HOXA1 gene expression. We and others have previously shown that myeloid-derived suppressor cells (MDSCs), a heterogeneous population of immature myeloid cells, expand during chronic viral (HCV, HIV) infections. However, the role of HOTAIRM1 in the development and suppression of MDSCs during viral infection remains unknown. In this study, we demonstrate that the expressions of HOTAIRM1 and its target HOXA1 are substantially upregulated to promote the expressions of immunosuppressive molecules, including arginase 1, inducible nitric oxide synthase, signal transducer and activator of transcription 3, and reactive oxygen species, in CD33 myeloid cells derived from hepatitis C virus (HCV)-infected patients. We show that HCV-associated exosomes (HCV-Exo) can modulate HOTAIRM1, HOXA1, and miR124 expressions to regulate MDSC development. Importantly, overexpression of HOTAIRM1 or HOXA1 in healthy CD33 myeloid cells promoted the MDSC differentiation and suppressive functions; conversely, silencing of HOTAIRM1 or HOXA1 expression in MDSCs from HCV patients significantly reduced the MDSC frequency and their suppressive functions. In essence, these results indicate that the HOTAIRM1-HOXA1-miR124 axis enhances the differentiation and suppressive functions of MDSCs and may be a potential target for immunomodulation in conjunction with antiviral therapy during chronic viral infection.
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http://dx.doi.org/10.1038/s41598-020-78786-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745042PMC
December 2020

Telomeric injury by KML001 in human T cells induces mitochondrial dysfunction through the p53-PGC-1α pathway.

Cell Death Dis 2020 12 2;11(12):1030. Epub 2020 Dec 2.

Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA.

Telomere erosion and mitochondrial dysfunction are prominent features of aging cells with progressive declines of cellular functions. Whether telomere injury induces mitochondrial dysfunction in human T lymphocytes, the major component of adaptive host immunity against infection and malignancy, remains unclear. We have recently shown that disruption of telomere integrity by KML001, a telomere-targeting drug, induces T cell senescence and apoptosis via the telomeric DNA damage response (DDR). In this study, we used KML001 to further investigate the role and mechanism of telomere injury in mitochondrial dysregulation in aging T cells. We demonstrate that targeting telomeres by KML001 induces mitochondrial dysfunction, as evidenced by increased mitochondrial swelling and decreased mitochondrial membrane potential, oxidative phosphorylation, mitochondrial DNA content, mitochondrial respiration, oxygen consumption, glycolysis, and ATP energy production. Mechanistically, we found that the KML001-induced telomeric DDR activated p53 signaling, which in turn repressed the expression of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1), leading to T cell mitochondrial dysfunction. These results, forging a direct link between telomeric and mitochondrial biology, shed new light on the human T cell aging network, and demonstrate that the p53-PGC-1α-NRF-1 axis contributes to mitochondrial dysfunction in the setting of telomeric DDR. This study suggests that targeting this axis may offer an alternative, novel approach to prevent telomere damage-mediated mitochondrial and T cell dysfunctions to combat a wide range of immune aging-associated human diseases.
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http://dx.doi.org/10.1038/s41419-020-03238-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710715PMC
December 2020

Tiam1 mediates Rac1 activation and contraction-induced glucose uptake in skeletal muscle cells.

FASEB J 2021 Feb 22;35(2):e21210. Epub 2020 Nov 22.

Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, China.

Contraction-stimulated glucose uptake in skeletal muscle requires Rac1, but the molecular mechanism of its activation is not fully understood. Treadmill running was applied to induce C57BL/6 mouse hind limb skeletal muscle contraction in vivo and electrical pulse stimulation contracted C2C12 myotube cultures in vitro. The protein levels or activities of AMPK or the Rac1-specific GEF, Tiam1, were manipulated by activators, inhibitors, siRNA-mediated knockdown, and adenovirus-mediated expression. Activated Rac1 was detected by a pull-down assay and immunoblotting. Glucose uptake was measured using the 2-NBD-glucose fluorescent analog. Electrical pulse stimulated contraction or treadmill exercise upregulated the expression of Tiam1 in skeletal muscle in an AMPK-dependent manner. Axin1 siRNA-mediated knockdown diminished AMPK activation and upregulation of Tiam1 protein expression by contraction. Tiam1 siRNA-mediated knockdown diminished contraction-induced Rac1 activation, GLUT4 translocation, and glucose uptake. Contraction increased Tiam1 gene expression and serine phosphorylation of Tiam1 protein via AMPK. These findings suggest Tiam1 is part of an AMPK-Tiam1-Rac1 signaling pathway that mediates contraction-stimulated glucose uptake in skeletal muscle cells and tissue.
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http://dx.doi.org/10.1096/fj.202001312RDOI Listing
February 2021

Substrate-Free Multilayer Graphene Electronic Skin for Intelligent Diagnosis.

ACS Appl Mater Interfaces 2020 Nov 22;12(44):49945-49956. Epub 2020 Oct 22.

Institute of Microelectronics and Beijing National Research Center for Information Science and Technology (BNRist), Tsinghua University, Beijing 100084, China.

Current wearable sensors are fabricated with substrates, which limits the comfort, flexibility, stretchability, and induces interface mismatch. In addition, the substrate prevents the evaporation of sweat and is harmful to skin health. In this work, we have enabled the substrate-free laser scribed graphene (SFG) electronic skin (e-skin) with multifunctions. Compared with the e-skin with the substrate, the SFG has good gas permeability, low impedance, and flexibility. Only assisted using water, the SFG can be transferred to almost any objects including silicon and human skin and it can even be suspended. Many through-holes like stomas in leaf can be formed in the SFG, which make it breathable. After designing the pattern, the gauge factor (GF) of graphene electronic skin (GES) can be designed as the strain sensor. Physiological signals such as respiration, human motion, and electrocardiogram (ECG) can be detected. Moreover, the suspended SFG detect vibrations with high sensitivity. Due to the substrate-free structure, the impedance between SFG e-skin and the human body decreases greatly. Finally, an ECG detecting system has been designed based on the GES, which can monitor the body condition in real time. To analyze the ECG signals automatically, a convolutional neural network (CNN) was built and trained successfully. This work has high potential in the field of health telemonitoring.
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http://dx.doi.org/10.1021/acsami.0c12440DOI Listing
November 2020

Scale-dependent effects of habitat fragmentation on the genetic diversity of populations in China.

Hortic Res 2020 13;7:172. Epub 2020 Oct 13.

State Key Laboratory of Environmental Criteria and Risk Assessment, Chinese Research Academy of Environmental Sciences, 8 Dayangfang, 100012 Beijing, China.

Spatial scale partly explains the differentiated effects of habitat fragmentation on plant biodiversity, but the mechanisms remain unclear. To investigate the effects of habitat fragmentation on genetic diversity at different scales, we sampled Planch. at broad and fine scales, China. The broad-scale sampling included five mountain populations and one oceanic island population (Zhoushan Archipelago), and the fine-scale sampling covered 11 lake islands and three neighboring land populations in Thousand-Island Lake (TIL). These populations were genotyped at 30 microsatellite loci, and genetic diversity, gene flow, and genetic differentiation were evaluated. Genetic differentiation was positively related to geographical distance at the broad scale, indicating an isolation-by-distance effect of habitat fragmentation on genetic diversity. The oceanic population differed from the mainland populations and experienced recent bottleneck events, but it showed high gene flow with low genetic differentiation from a mountain population connected by the Yangtze River. At the fine scale, no negative genetic effects of habitat fragmentation were found because seed dispersal with water facilitates gene flow between islands. The population size of was positively correlated with the area of TIL islands, supporting island biogeography theory, but no correlation was found between genetic diversity and island area. Our results highlight the scale-dependent effects of habitat fragmentation on genetic diversity and the importance of connectivity between island-like isolated habitats at both the broad and fine scales.
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http://dx.doi.org/10.1038/s41438-020-00401-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553913PMC
October 2020

The role of disabled-2 (Dab2) in diseases.

Gene 2021 Feb 12;769:145202. Epub 2020 Oct 12.

Department of Biomedical Sciences, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA. Electronic address:

Disabled-2 (Dab2/DOC-2) is a mitogen-responsive adaptor protein required for multiple cellular functions. It is involved in many signaling pathways and plays an integral role in vesicular uptake and trafficking, modulating immune function, protein-protein interactions, cellular homeostasis and differentiation, oncogenesis, and inflammatory processes in organ systems. It contains domains for binding to NPXY motif-containing and SH3 domain-containing adapter proteins, phosphoinositides, glycoprotein 100 (gp100, or megalin), integrins, clathrin, and myosin VI. However, the molecular mechanism(s) of Dab2's biological function still remain to be elucidated. In this review, we provide an extensive up-to-date understanding of the function of Dab2 and its regulation in cardiovascular diseases, immune disorders, tumorigenesis, and central nervous system disorders.
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http://dx.doi.org/10.1016/j.gene.2020.145202DOI Listing
February 2021

Long noncoding RNA HOTAIRM1 promotes myeloid-derived suppressor cell expansion and suppressive functions through up-regulating HOXA1 expression during latent HIV infection.

AIDS 2020 12;34(15):2211-2221

Center of Excellence for Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine.

Objective: Myeloid-derived suppressor cells (MDSCs) contribute to HIV progression by impairing antiviral immunity; however, the mechanisms responsible for MDSC development during HIV infection are incompletely understood. HOX antisense intergenic RNA myeloid 1 (HOTAIRM1) is a long noncoding RNA (lncRNA) that plays a pivotal role in regulating myeloid cell development via targeting HOXA1. The role of HOTAIRM1--HOXA1 in the differentiation and functions of MDSCs during HIV infection remains unclear.

Methods: In this study, we measured MDSC induction and suppressive functions by flow cytometry, RT-PCR, and co-culture experiments using CD33 myeloid cells derived from people living with HIV (PLHIV) on antiretroviral therapy (ART). We also manipulated the HOTAIRM1--HOXA1 axis in myeloid cells using knockdown and overexpression approaches.

Results: We demonstrate that HOTAIRM1 and HOXA1 expressions are reciprocally upregulated and are responsible for increased levels of immunosuppressive molecules, such as arginase 1 (Arg1), inducible nitric oxide synthase (iNOS), signal transducer and activator of transcription 3 (STAT3), and reactive oxygen species (ROS), in CD33 myeloid cells derived from PLHIV on ART. We found that overexpression of HOTAIRM1 or HOXA1 in CD33 cells isolated from healthy individuals promoted the differentiation and suppressive functions of MDSCs, whereas silencing of HOTAIRM1 or HOXA1 expression in MDSCs derived from PLHIV significantly inhibited the frequency of MDSCs and expressions of the immunosuppressive molecules and reduced their immunosuppressive effects on T cells.

Conclusion: These results indicate that the HOTAIRM1--HOXA1 axis enhances differentiation and suppressive functions of MDSCs and could be a potential therapeutic target for immunomodulation during latent HIV infection.
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http://dx.doi.org/10.1097/QAD.0000000000002700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674250PMC
December 2020

DSTYK Promotes Metastasis and Chemoresistance EMT in Colorectal Cancer.

Front Pharmacol 2020 2;11:1250. Epub 2020 Sep 2.

Department of Biomedical Sciences, J. H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, United States.

Objective: Tumor metastasis and resistance to chemotherapy are two critical factors that contribute to the high death rate of colorectal cancer (CRC) patients. Metastasis is facilitated by the epithelial-mesenchymal transition (EMT) of tumor cells, which has emerged not only as a fundamental process during metastasis, but is also a key process leading to chemoresistance of cancer cells. However, the underlying mechanisms of EMT in CRC cell remain unknown. Here, we aim to assess the role of dual serine/threonine and tyrosine protein kinase (DSTYK) in CRC metastasis and chemoresistance.

Methods: To study the role of DSTYK in TGF-β-induced EMT, we employed techniques including Crispr/Cas9 knockout (KO) to generate DSTYK KO cell lines, RT-PCR to detect the mRNA expression, immunofluorescence analyses, and western blots to detect protein levels of DSTYK in the following 4 cell lines: control LS411N-TβRII and LS411N-TβRII/DSTYK KO, control LS513 and LS513/DSTYK KO cells, treated with/without TGF-β. The effects of DSTYK on apoptosis were investigated by MTT assays, flow cytometry assays, and TUNEL assays. The expression of DSTYK in CRC patients and its correlation with EMT markers were determined by bioinformatics analysis. For analysis, both xenograft and orthotopic tumor mouse models were employed to investigate the function of DSTYK in chemoresistance and metastasis of tumors.

Results: In this study, we demonstrate that the novel kinase DSTYK promotes both TGF-β-induced EMT and the subsequent chemoresistance in CRC cells. DSTYK KO significantly attenuates TGF-β-induced EMT and chemoresistance in CRC cells. According to the Gene Expression Omnibus (GEO) database, the expression of DSTYK is not only positively correlated to the expression of TGF-β, but proportional to the death rate of CRC patients as well. Evidently, the expression of DSTYK in the metastatic colorectal cancer samples from patients was significantly higher than that of primary colorectal cancer samples. Further, we demonstrate in mouse models that chemotherapeutic drug treatment suppresses the growth of DSTYK KO tumors more effectively than control tumors.

Conclusion: Our findings identify DSTYK as a novel protein kinase in regulating TGF-β-mediated EMT and chemoresistance in CRC cells, which defines DSTYK as a potential therapeutic target for CRC therapy.
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http://dx.doi.org/10.3389/fphar.2020.01250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493073PMC
September 2020

Corrigendum to "S100A9 maintains myeloid-derived suppressor cells in chronic sepsis by inducing miR-21 and miR-181b" [Mol. Immunol. 112 (August) (2019) 72-81].

Mol Immunol 2020 Nov 12;127:78. Epub 2020 Sep 12.

Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, TN, United States. Electronic address:

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http://dx.doi.org/10.1016/j.molimm.2020.08.013DOI Listing
November 2020

A feedforward circuit shaped by ECT2 and USP7 contributes to breast carcinogenesis.

Theranostics 2020 29;10(23):10769-10790. Epub 2020 Aug 29.

State Key Laboratory of Experimental Hematology, 2011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University General Hospital, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.

A number of guanine nucleotide exchange factors (GEFs) including epithelial cell transforming factor ECT2 are believed to drive carcinogenesis through activating distinct oncogenic GTPases. Yet, whether GEF-independent activity of ECT2 also plays a role in tumorigenesis remains unclear. Immunohistochemical (IHC) staining, colony formation and xenograft assays were used to examine the role of ECT2 in breast carcinogenesis. Co-immunoprecipitation, immunofluorescent stainings, deubiquitination and deubiquitination experiments were performed to examine the physical and functional interaction between ECT2 and ubiquitin-specific protease USP7. High-throughput RNA sequencing, quantitative reverse transcription-PCR and Western blotting were employed to investigate the biological significance of the interplay between ECT2 and USP7. We report that ECT2 plays a tumor-promoting role in breast cancer, and GEF activity-deficient ECT2 is able to alleviate ECT2 depletion associated growth defects in breast cancer cells. Mechanistically, we demonstrated that ECT2 physically interacts with ubiquitin-specific protease USP7 and functionally facilitates USP7 intermolecular self-association, -deubiquitination and -stabilization in a GEF activity-independent manner. USP7 in turn, deubiquitinates and stabilizes ECT2, resulting in a feedforward regulatory circuit that ultimately sustains the expression of oncogenic protein MDM2. Our study uncovers a GEF-independent role of ECT2 in promoting survival of breast cancer cells, provides a molecular insight for the reciprocal regulation of ECT2 and USP7, and supports the pursuit of ECT2/USP7 as potential targets for breast cancer intervention.
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http://dx.doi.org/10.7150/thno.46878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482815PMC
August 2020

Corrigendum to: "HuR promotes miRNA-mediated upregulation of NFI-A protein expression in MDSCs during murine sepsis" (Mol Immunol., 2019, July, 123, 97-105).

Mol Immunol 2020 Nov 11;127:56. Epub 2020 Sep 11.

Department of Internal Medicine, East Tennessee State University College of Medicine, Johnson City, TN, United States. Electronic address:

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http://dx.doi.org/10.1016/j.molimm.2020.08.012DOI Listing
November 2020

Oncoprotein SND1 hijacks nascent MHC-I heavy chain to ER-associated degradation, leading to impaired CD8 T cell response in tumor.

Sci Adv 2020 May 29;6(22). Epub 2020 May 29.

Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Key Laboratory of Cellular and Molecular Immunology, Excellent Talent Project, Department of Biochemistry and Molecular Biology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.

SND1 is highly expressed in various cancers. Here, we identify oncoprotein SND1 as a previously unidentified endoplasmic reticulum (ER) membrane-associated protein. The amino-terminal peptide of SND1 predominantly associates with SEC61A, which anchors on ER membrane. The SN domain of SND1 catches and guides the nascent synthesized heavy chain (HC) of MHC-I to ER-associated degradation (ERAD), hindering the normal assembly of MHC-I in the ER lumen. In mice model bearing tumors, especially in transgenic OT-I mice, deletion of SND1 promotes the presentation of MHC-I in both B16F10 and MC38 cells, and the infiltration of CD8 T cells is notably increased in tumor tissue. It was further confirmed that SND1 impaired tumor antigen presentation to cytotoxic CD8 T cells both in vivo and in vitro. These findings reveal SND1 as a novel ER-associated protein facilitating immune evasion of tumor cells through redirecting HC to ERAD pathway that consequently interrupts antigen presentation.
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http://dx.doi.org/10.1126/sciadv.aba5412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259962PMC
May 2020

Telomere and ATM Dynamics in CD4 T-Cell Depletion in Active and Virus-Suppressed HIV Infections.

J Virol 2020 10 27;94(22). Epub 2020 Oct 27.

Center of Excellence in Inflammation, Infectious Disease and Immunity, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, Tennessee, USA

CD4 T-cell depletion is a hallmark of HIV/AIDS, but the underlying mechanism is still unclear. We have recently shown that ataxia-telangiectasia-mutated (ATM) deficiency in CD4 T cells accelerates DNA damage, telomere erosion, and cell apoptosis in HIV-infected individuals on antiretroviral therapy (ART). Whether these alterations in ART-treated HIV subjects occur in HIV-infected CD4 T cells remains unknown. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the telomeric DNA damage response (DDR) and cellular apoptosis in highly permissive SupT1 cells, followed by the validation of our observations in primary CD4 T cells with active or drug-suppressed HIV infection. Specifically, we established an HIV T-cell culture system with viral replication and raltegravir (RAL; an integrase inhibitor) suppression, mimicking active and ART-controlled HIV infection We demonstrated that HIV-induced, telomeric DDR plays a pivotal role in triggering telomere erosion, premature T-cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This model provides a new tool to investigate HIV pathogenesis, and our results shed new light on the molecular mechanisms of telomeric DDR and CD4 T-cell homeostasis during HIV infection. The hallmark of HIV infection is a gradual depletion of CD4 T cells, with a progressive decline of host immunity. How CD4 T cells are depleted in individuals with active and virus-suppressed HIV infection remains unclear. In this study, we employed a cellular model of HIV infection to characterize the mechanisms underlying CD4 T-cell destruction by analyzing the chromosome end (telomere) DNA damage response (DDR) and cellular apoptosis in a T-cell line (highly permissive SupT1 cells), as well as in primary CD4 T cells with active or drug-suppressed HIV infection. We demonstrated that HIV-induced telomeric DDR plays a critical role in inducing telomere loss, premature cell aging, and CD4 T-cell apoptosis or depletion via dysregulation of the PI3K/ATM pathways. This study sheds new light on the molecular mechanisms of telomeric DDR and its role in CD4 T-cell homeostasis during HIV infection.
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http://dx.doi.org/10.1128/JVI.01061-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592222PMC
October 2020

Reduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity.

J Hepatol 2020 Dec 29;73(6):1482-1495. Epub 2020 Jul 29.

Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China. Electronic address:

Background & Aims: Chronic overconsumption of a high-carbohydrate diet leads to steatosis and its associated metabolic disorder and, eventually, to non-alcoholic fatty liver disease. Carbohydrate-responsive element binding protein (ChREBP) and insulin regulate de novo lipogenesis from glucose. Herein, we studied the effect of reticulon-4 (Nogo) expression on diet-induced metabolic disorders in mice.

Methods: Nogo-deficient (Nogo) and littermate control [wild-type (WT)] mice were fed a high-glucose or high-fructose diet (HGD/HFrD) to induce metabolic disorders. The effects of Nogo small interfering (si) RNA (siRNA) on HFrD-induced metabolic disorders were investigated in C57BL/6J mice.

Results: HGD/HFrD induced steatosis and its associated metabolic disorders in WT mice by activating ChREBP and impairing insulin sensitivity. They also activated Nogo-B expression, which in turn inhibited insulin activity. In response to HGD/HFrD feeding, Nogo deficiency enhanced insulin sensitivity and energy metabolism to reduce the expression of ChREBP and lipogenic molecules, activated AMP-activated catalytic subunit α, peroxisome proliferator activated receptor α and fibroblast growth factor 21, and reduced endoplasmic reticulum (ER) stress and inflammation, thereby blocking HGD/HFrD-induced hepatic lipid accumulation, insulin resistance and other metabolic disorders. Injection of Nogo siRNA protected C57BL/6J mice against HFrD-induced metabolic disorders by ameliorating insulin sensitivity, ChREBP activity, ER stress and inflammation.

Conclusions: Our study identified Nogo as an important mediator of insulin sensitivity and ChREBP activity. Reduction of Nogo expression is a potential strategy for the treatment of high-carbohydrate diet-induced metabolic complications.

Lay Summary: Nogo deficiency blocks high-carbohydrate diet-induced glucose intolerance and insulin resistance, while increasing glucose/lipid utilisation and energy expenditure. Thus, reduction of Nogo expression protects against high-carbohydrate diet-induced body-weight gain, hepatic lipid accumulation and the associated metabolic disorders, indicating that approaches inhibiting Nogo expression can be applied for the treatment of diseases associated with metabolic disorders.
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http://dx.doi.org/10.1016/j.jhep.2020.07.034DOI Listing
December 2020

Nutritional quality and health risk of pepper fruit as affected by magnesium fertilization.

J Sci Food Agric 2021 Jan 7;101(2):582-592. Epub 2020 Aug 7.

College of Resources and Environment, Academy of Agricultural Sciences, Southwest University, Chongqing, China.

Background: Magnesium (Mg) fertilization is a promising practice to improve vegetable yield. However, its impacts on vegetable quality and human health have not been examined. Thus, a field experiment was conducted to investigate the effects of varying Mg fertilization rates on yield and quality of pepper (Capsicum annuum L.) fruit. Furthermore, result of the field experiment was linked to pepper consumption data from the China Health and Nutrition Survey (CHNS) in the disability-adjusted life years (DALYs) framework to evaluate the potential health impact of Mg fertilization for the first time.

Results: Compared to control, Mg fertilization increased the 2-year average pepper yield by 25.6%, whereas there was no significant yield improvement when Mg rates exceeded 112.5 kg MgO ha . Magnesium application increased concentrations of Mg and capsaicinoids, decreased those of calcium (Ca), zinc (Zn) and vitamin C (Vc), and had no effect on potassium (K) and iron (Fe) in pepper fruit. As a result, Mg fertilization decreased the comprehensive nutrition level of pepper by 16.6%. Furthermore, the current health burden of the Chinese adult population associated with pepper consumption is estimated at 21.3 million DALYs per year, with the risk being increased by 5.40 DALYs for per megagram of Mg fertilizer application. Increasing health risk was mainly attributed to decreasing concentrations of Ca and Vc in pepper fruit, though the increased Mg intakes offset the impact of 1.74% to 14.4%.

Conclusion: Magnesium fertilization significantly improved the yield but reduced nutritional quality of pepper fruit, and increased human health risks associated with consumption of pepper fruit. © 2020 Society of Chemical Industry.
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http://dx.doi.org/10.1002/jsfa.10670DOI Listing
January 2021

Three Patients with COVID-19 and Pulmonary Tuberculosis, Wuhan, China, January-February 2020.

Emerg Infect Dis 2020 11 15;26(11):2755-2758. Epub 2020 Jul 15.

During January-February 2020, coronavirus disease (COVID-19) and tuberculosis were diagnosed for 3 patients in Wuhan, China. All 3 patients had COVID-19 pneumonia. One severely ill patient died after acute respiratory distress syndrome developed. Clinicians and public health officials should be aware of underlying chronic infections such as tuberculosis in COVID-19 patients.
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http://dx.doi.org/10.3201/eid2611.201536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588523PMC
November 2020

Identifying key drivers for geospatial variation of grain micronutrient concentrations in major maize production regions of China.

Environ Pollut 2020 Nov 28;266(Pt 2):115114. Epub 2020 Jun 28.

College of Resources and Environmental Sciences, National Academy of Agriculture Green Development, Key Laboratory of Plant-Soil Interactions, Ministry of Education, China Agricultural University, Beijing, 100193, PR China. Electronic address:

Micronutrient deficiencies are prevalent health problems worldwide. The maintenance of adequate concentrations of micronutrients in maize grain is crucial for human health. We investigated the overall status and geospatial variation of micronutrients in Chinese maize grains and identified their key drivers. A field survey was conducted in four major maize production areas of China in 2017 with 980 pairs of soil and grain samples collected from famers' fields. At a national scale, grain zinc (Zn), iron (Fe), manganese (Mn) and copper (Cu) concentrations varied substantially, with average values of 17.4, 17.3, 4.9, and 1.5 mg kg, respectively, suggesting a solid gap between grain Zn and Fe concentrations and the biofortification target values. Significant regional difference in the concentrations of Zn, Mn and Cu, but not Fe, were observed in grain, with much higher levels in Southwest China. The nutritional yields of Zn, Fe and Cu were lower than the energy and Mn yields, indicating an unbalanced output between energy and micronutrients in current maize production system. Grain Zn, Fe, Mn and Cu correlated negatively with maize yield in most test regions. Increased nitrogen (N) rate positively affected grain Zn and Cu, while increased phosphorus (P) rate negatively affects grain Zn and Fe. Apart from Fe, available Zn, Mn and Cu in soil exerted significant positive effects on grain Zn, Mn and Cu concentrations, respectively. Decrease in soil pH and increase in the organic matter content may increase the accumulation of Fe and Mn in grain. Grain Zn and Cu concentrations increased as available soil P decreased. Of the factors considered in this study, grain yield, N and P rates, soil pH and organic matter were the main factors that affect grain micronutrient status and should be more extensively considered in the production and nutritional quality of maize grain.
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http://dx.doi.org/10.1016/j.envpol.2020.115114DOI Listing
November 2020

Isolation, purification, and structural characterization of polysaccharides from Atractylodis Macrocephalae Rhizoma and their immunostimulatory activity in RAW264.7 cells.

Int J Biol Macromol 2020 Nov 30;163:270-278. Epub 2020 Jun 30.

Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnosis, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China. Electronic address:

Three water-soluble polysaccharides (AMAP-1, AMAP-2 and AMAP-3) were isolated and purified from Atractylodis Macrocephalae Rhizoma by using the combination of ion-exchange chromatography and gel permeation chromatography. The structures of the polysaccharides were characterized by chemical derivatization, HPGC, GC-MS, FT-IR, and NMR techniques. Structural analyses show that the three polysaccharides are pectin-type macromolecules consisting of homogalacturonan (HG) and rhamnogalacturonan type I (RG-I) regions in different ratios. Immunostimulatory assay highlighted that the RG-I-rich AMAP-1 and AMAP-2 with high molecular weights can stimulate RAW264.7 macrophages to release nitric oxide, but HG-rich AMAP-3 with a low molecular weight cannot. This finding suggests that the immune activity may be related to the side chains of the RG-I region, which provides a certain theoretical guidance for further exploring the structure-activity relationship. Meanwhile, AMAP-1 and AMAP-2, especially AMAP-2, from Atractylodis Macrocephalae Rhizoma show potential as immune adjuvants.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.06.269DOI Listing
November 2020

Correction: The Relationship Between the Impairment of Endothelial Function and Thyroid Antibodies in Hashimoto's Thyroiditis Patients with Euthyroidism.

Horm Metab Res 2020 Sep 30;52(9):e3. Epub 2020 Jun 30.

Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University. Beijing P.R. China.

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http://dx.doi.org/10.1055/a-1204-0011DOI Listing
September 2020

The Relationship Between the Impairment of Endothelial Function and Thyroid Antibodies in Hashimoto's Thyroiditis Patients with Euthyroidism.

Horm Metab Res 2020 Sep 15;52(9):642-646. Epub 2020 Jun 15.

Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University. Beijing P.R. China.

Endothelial dysfunction is the important early step in the development of atherosclerosis. Hypothyroidism caused by Hashimoto's thyroiditis and other thyroid disease is one of the risk factors of endothelial dysfunction. The present study tried to investigate the endothelial function and its associated factors in Hashimoto thyroiditis with euthyroidism. A total of 95 newly diagnosed Hashimoto's thyroiditis patients with euthyroidism and 45 healthy controls were studied. Hashimoto's patients were divided into 3 subgroups namely, single thyroglobulin antibody (TGAb) positive subgroup, single thyroid peroxidase antibody (TPOAb) positive subgroup, and both TGAb and TPOAb positive subgroup. Endothelial function was tested by the reactive hyperemia index (RHI). Hashimoto's thyroiditis patients had lower RHI than healthy controls (1.73±0.42 vs 1.96±0.51, p<0.05). Hashimoto's thyroiditis with single TGAb positive patients had higher RHI than single TPOAb positive (1.98±0.57 vs. 1.69±0.33, p<0.05) and TGAB + TPOAb positive patients (1.98±0.57 vs. 1.68±0.42, p<0.05). RHI were negatively associated with total cholesterol (TC, r=-0.215, p<0.05), low density lipoprotein cholesterol (LDL-C, r=-0.268, p<0.05), triglyceride (TG, r=-0.192, p<0.05), and TPOAb (r=-0.288, p<0.05). In the regression analysis, LDL-C (β=-0.146, p<0.05), TG (β=-0.034, p<0.05) and TPOAb (β=-0.001, p<0.05) were independently associated with RHI. Hashimoto's patients had poor endothelial function. TPOAb levels were negatively associated with endothelial function.
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http://dx.doi.org/10.1055/a-1178-5882DOI Listing
September 2020

Restoration of miR-340 controls pancreatic cancer cell expression to promote macrophage phagocytosis and enhance antitumor immunity.

J Immunother Cancer 2020 06;8(1)

Guangdong Province Key Laboratory for Biotechnology Drug Candidates, School of Life Sciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China; Department of Immunology and Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironment and Diseases of Educational Ministry of China, Tianjin Key Laboratory of Cellular and Molecular Immunology, Tianjin Medical University, Tianjin, China

Background: Immune checkpoint blockade has emerged as a potential cancer immunotherapy. The "don't eat me" signal in cancer cells binds signal regulatory protein-α on macrophages and prevents their phagocytosis. The role of miR-340 in pancreatic ductal adenocarcinoma (PDAC), especially in tumor immunity, has not been explored. Here, we examined the clinical and biological relevance of miR-340 and the molecular pathways regulated by miR-340 in PDAC.

Methods: and miR-340 expression and the relationship with cancer patient survival were analyzed by bioinformatics. The mechanism of miR-340 action was explored through bioinformatics, luciferase reporter, qRT-PCR and western blot analyses. The effects of miR-340 on cancer cells were analyzed in terms of apoptosis, proliferation, migration and phagocytosis by macrophages. tumorigenesis was studied in orthotopic and subcutaneous models, and immune cells from the peripheral and tumor immune microenvironments were analyzed by flow cytometry. Depletion of macrophages was used to verify the role of macrophages in impacting the function of miR-340 in tumor progression.

Results: miR-340 directly regulates and inversely correlates with and it predicts patient survival in PDAC. The restoration of miR-340 expression in pancreatic cancer cells was sufficient to downregulate and promote phagocytosis of macrophages, further inhibiting tumor growth. The overexpression of miR-340 promoted macrophages to become M1-like phenotype polarized in peripheral and tumor immune microenvironments and increased T cells, especially CD8 T cells, contributing to the antitumor effect of miR-340.

Conclusions: miR-340 is a key regulator of phagocytosis and antitumor immunity, and it could offer a new opportunity for immunotherapy for PDAC.
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http://dx.doi.org/10.1136/jitc-2019-000253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279671PMC
June 2020