Publications by authors named "Xiaomeng Ren"

57 Publications

GBP5 promotes liver injury and inflammation by inducing hepatocyte apoptosis.

FASEB J 2022 01;36(1):e22119

HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.

Liver injury is the first step in causing fibrosis, cirrhosis, and liver cancer, leading to mortality. However, the drivers of progressive liver injury are still incompletely defined. Here, we identify GBP5 as a major factor causing liver injury and inflammation. We show that the expression of GBP5 is abnormally elevated in the damaged liver, and its expression depends at least partially on the NF-κB-inducing kinase (NIK)/NF-κB2 signaling pathway. Knockout of Gbp5 ameliorates D-galactosamine/lipopolysaccharide (GalN/LPS)-induced liver injury and inflammation. Conversely, liver-specific overexpression of GBP5 induces liver injury and inflammation. Mechanistically, GBP5 induces hepatocyte apoptosis through the activation of both calpain/caspase 12/caspase 3 and TNFα/caspase 8/caspase 3 signaling pathways. Inhibition of either calpain activity or caspase 3 prevents GBP5-induced cell death. Our data demonstrate that GBP5 expression is induced by toxins or the NIK signaling pathway, which promotes both extrinsic and intrinsic apoptosis signaling pathways and further induces liver injury, providing a novel drug target for the treatment of liver injury and inflammation.
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http://dx.doi.org/10.1096/fj.202101448RDOI Listing
January 2022

Dietary Acrylamide Intake Alters Gut Microbiota in Mice and Increases Its Susceptibility to Typhimurium Infection.

Foods 2021 Dec 3;10(12). Epub 2021 Dec 3.

Collaborative Innovation Center of Seafood Deep Processing, National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian 116304, China.

Acrylamide (AA) has been extensively examined for its potential toxicological effects on humans and animals, but its impacts on gut microbiota and effects on hosts' susceptibility to enteric infection remain elusive. The present study was designed to evaluate the effect of AA on gut microbiota of mice and susceptibility of mice to . Typhimurium infection. After four weeks' intervention, mice fed with AA exhibited significantly decreased body weight. Meanwhile, 16S rRNA gene sequencing showed reduced relative abundance of Firmicutes and increased abundance of Bacteroidetes in AA-treated mice prior to infection. In addition, we observed high relative abundance of and , more specifically the genus and , respectively, in AA-treated mice before infection. Subsequently, the mice were orally infected with . Typhimurium. The histological changes, systemic dissemination of . Typhimurium, and inflammatory responses were examined. Compared to mice fed with normal diet, mice fed AA exhibited higher level of bacterial counts in liver, spleen, and ileum, which was consistent with exacerbated tissue damage determined by histological analyses. In addition, higher expression of pro-inflammaroty cytokines, p-IκBα, and p-P65 and lower mRNA expressions of , , , , and were detected in AA-treated mice. These findings provide novel insights into the potential health impact of AA consumption and the detailed mechanism for its effect on . Typhimurium infection merit further exploration.
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http://dx.doi.org/10.3390/foods10122990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8700958PMC
December 2021

NOP56 negatively regulates MyD88-mediated NF-κB signaling in miiuy croaker, Miichthys miiuy.

Fish Shellfish Immunol 2022 Jan 11;120:75-81. Epub 2021 Nov 11.

Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China; Laboratory of Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, China; National Pathogen Collection Center for Aquatic Animals, Shanghai Ocean University, China. Electronic address:

MyD88 is a critical adaptor in the TLRs signaling pathway, which can activate NF-κB signaling pathway and promote proinflammatory cytokines production. However, the molecular mechanisms that modulate MyD88 expression, especially in teleost, remain largely unknown. In this study, we showed that NOP56 serve as a negative regulator of the MyD88-mediated NF-κB signaling pathway. NOP56 overexpression inhibited the protein expression of MyD88. Whereas, siRNA knockdown of NOP56 had opposite effect. Furthermore, we found that the NOSIC domain is responsible for the suppressive effect of NOP56 in MyD88 expression at protein level. Therefore, we identified NOP56 as a negative regulator of MyD88-mediated NF-κB signaling by inhibiting MyD88 expression and provided new insight into the regulation mechanism in teleost fish.
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http://dx.doi.org/10.1016/j.fsi.2021.11.011DOI Listing
January 2022

A mitochondrial-metabolism-regulatable carrier-free nanodrug to amplify the sensitivity of photothermal therapy.

Chem Commun (Camb) 2021 Sep 6;57(71):8993-8996. Epub 2021 Sep 6.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.

The oxidative phosphorylation inhibitor atovaquone (ATO) and the photosensitizer new indocyanine green (IR820) were self-assembled into carrier-free nanodrugs (IR820/ATO NPs) to achieve superior photothermal therapy (PTT), offering an attractive mitochondrial metabolism-regulatable approach for breast cancer treatment, where adenosine triphosphate (ATP) was downregulated along with downregulating the expression of heat shock proteins (HSPs) to amplify the sensitivity of PTT.
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http://dx.doi.org/10.1039/d1cc02755gDOI Listing
September 2021

Platelet-armored nanoplatform to harmonize janus-faced IFN-γ against tumor recurrence and metastasis.

J Control Release 2021 10 13;338:33-45. Epub 2021 Aug 13.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China. Electronic address:

Interferon-γ (IFN-γ) plays contradictory roles in tumor immunology: (I) to activate positive host's immunity for eliminating tumor; (II) to induce negative adaptive immune resistance via up-regulating programmed death ligand-1 (PD-L1) expression for tumors to evade immune surveillance. The negative feedback loop between the IFN-γ recovery and the IFN-γ-induced PD-L1 up-regulation puts postoperative adjuvant chemotherapy into a dilemma. It is of great significance but challenging to manipulate the double-edge effects of IFN-γ against postoperative tumor progression. Herein, a platelet-engineered nanoplatform ([email protected] NPs) capable of harmonizing janus-faced nature of IFN-γ was designed via uniquely co-assembling doxorubicin (Dox) and cyclin-dependent kinase 5 inhibitor roscovitine (Rosco) with platelet membrane fragment (PMF) as the particulate stabilizer. With [email protected] NPs navigated by PMF to residual tumor, the Dox-activated immune response recovered IFN-γ secretion for positive host's immunity, while the IFN-γ-induced negative adaptive immune resistance was potently overcome by Rosco via disabling PD-L1 expression without dependence of IFN-γ stimulation. The negative feedback loop between IFN-γ recovery and PD-L1 up-regulation was thus potently disrupted in postoperative adjuvant chemotherapy. Our [email protected] NPs not only harmonized janus-faced nature of IFN-γ to effectively regulate postoperative tumor progression, but also illustrated an innovative strategy for high-drug-loading biomimic nanoplatform.
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http://dx.doi.org/10.1016/j.jconrel.2021.08.020DOI Listing
October 2021

TSLP disease-associated genetic variants combined with airway TSLP expression influence asthma risk.

J Allergy Clin Immunol 2022 Jan 7;149(1):79-88. Epub 2021 Jun 7.

Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address:

Background: Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine important in initiation of allergic inflammation. Single nucleotide polymorphisms (SNPs) in TSLP are associated with asthma, yet studies have shown inconsistent associations between circulating TSLP and asthma. Studies that integrate the combined effects of TSLP genotype, TSLP mRNA, circulating TSLP levels, and asthma outcome are lacking.

Objectives: This study sought to recruit a novel cohort based on asthma-relevant TSLP SNPs and determine their impact on TSLP mRNA expression and TSLP circulating protein levels, and their individual and combined effects on asthma.

Methods: This study developed an algorithm to prioritize TSLP SNPs and recruited 51 carriers and noncarriers based on TSLP genotypes. TSLP mRNA was quantified in nasal epithelial cells and circulating TSLP levels in plasma. This study determined the associations of defined TSLP risk genotypes and/or TSLP mRNA and protein levels with asthma.

Results: TSLP mRNA expression, but not circulating TSLP, was significantly increased in people who are asthmatic compared with in people who are nonasthmatic (P = .007; odds ratio, 1.44). Notably, 90% of children with the defined TSLP risk genotypes and high nasal TSLP mRNA expression (top tertile) had asthma compared with 40% of subjects without risk genotypes and with low TSLP expression (bottom tertile) (P = .024). No association between circulating TSLP and asthma was observed.

Conclusions: Collectively, these data suggest childhood asthma is modified by the combined effects of TSLP genotype and TSLP expression in the nasal epithelium. The increased asthma risk likely manifests when genetic variation enables expression quantitative trait loci in the TSLP locus to elevate TSLP. It is important to consider both biomarkers when factoring asthma risk.
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http://dx.doi.org/10.1016/j.jaci.2021.05.033DOI Listing
January 2022

Generation of Pulmonary Endothelial Progenitor Cells for Cell-based Therapy Using Interspecies Mouse-Rat Chimeras.

Am J Respir Crit Care Med 2021 08;204(3):326-338

Center for Lung Regenerative Medicine.

Although pulmonary endothelial progenitor cells (EPCs) hold promise for cell-based therapies for neonatal pulmonary disorders, whether EPCs can be derived from pluripotent embryonic stem cells (ESCs) or induced pluripotent stem cells remains unknown. To investigate the heterogeneity of pulmonary EPCs and derive functional EPCs from pluripotent ESCs. Single-cell RNA sequencing of neonatal human and mouse lung was used to identify the heterogeneity of pulmonary EPCs. CRISPR/Cas9 gene editing was used to genetically label and purify mouse pulmonary EPCs. Functional properties of the EPCs were assessed after cell transplantation into neonatal mice with mutation, a mouse model of alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interspecies mouse-rat chimeras were produced through blastocyst complementation to generate EPCs from pluripotent ESCs for cell therapy in ACDMPV mice. We identified a unique population of EPCs, FOXF1cKIT EPCs, as a subset of recently described general capillary cells (gCAPs) expressing SMAD7, ZBTB20, NFIA, and DLL4 but lacking mature arterial, venous, and lymphatic markers. FOXF1cKIT gCAPs are reduced in ACDMPV, and their transcriptomic signature is conserved in mouse and human lungs. After cell transplantation into the neonatal circulation of ACDMPV mice, FOXF1cKIT gCAPs engraft into the pulmonary vasculature, stimulate angiogenesis, improve oxygenation, and prevent alveolar simplification. FOXF1cKIT gCAPs, produced from ESCs in interspecies chimeras, are fully competent to stimulate neonatal lung angiogenesis and alveolarization in ACDMPV mice. Cell-based therapy using donor or ESC/induced pluripotent stem cell-derived FOXF1cKIT endothelial progenitors may be considered for treatment of human ACDMPV.
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http://dx.doi.org/10.1164/rccm.202003-0758OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8513594PMC
August 2021

An injectable hydrogel using an immunomodulating gelator for amplified tumor immunotherapy by blocking the arginase pathway.

Acta Biomater 2021 04 30;124:179-190. Epub 2021 Jan 30.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China. Electronic address:

Arginase 1 (ARG1) inactivates T cells by degrading L-arginine, severely reducing the immunotherapeutic efficacy. Effectively blocking the ARG1 pathway remains a challenge. L-norvaline is a very cheap and negligible side effects inhibitor of ARG1. However, its blockage efficacy for ARG1 is impeded by its high half-maximal-inhibitory concentration (IC50) requiring high drug loading content of L-norvaline in carriers. Moreover its high water solubility results in bursting and uncontrolled release. Herein we reported an injectable hydrogel strategy via an L-norvaline-based immunomodulating gelator that could effectively block ARG1 pathway. The designed gelator was a diblock copolymer containing L-norvaline-based polypeptide block, which could construct a thermally responsive injectable hydrogel by its self-gelation in tumor microenvironments. The hydrogel not only ensures high drug loading of L-norvaline, but also ensures controlled release of L-norvaline through responsive peptide bond cleavage, thereby solving the problems encountered by L-norvaline. The injectable hydrogel in combination with doxorubicin hydrochloride demonstrated a potent immunotherapy for removal of primary tumors, suppression of abscopal tumors and inhibition of pulmonary metastasis by combining the blockage of ARG1 pathway and the immunogenic cell death. Our immunomodulating gelator strategy provides a robust injectable hydrogel platform to efficiently reverse ARG1 immunosuppressive environments for amplified immunotherapy. STATEMENT OF SIGNIFICANCE: We designed an injectable hydrogel via an L-norvaline-based immunomodulating gelator. The designed gelator, a diblock copolymer containing an L-norvaline-based polypeptide block, enabled a thermally responsive injectable hydrogel by its self-gelation in tumor microenvironments. The injectable hydrogel not only guarantees high drug loading of L-norvaline, but also ensures controlled release of L-norvaline through responsive peptide bonds cleavage, thereby solving the problems encountered by L-norvaline. By further introducing doxorubicin hydrochloride in the hydrogel for inducing immunogenic cell death, the hydrogel showed remarkable immunotherapeutic efficacy towards ablation of primary tumors, suppression of abscopal tumors and inhibition of pulmonary metastasis. Our immunomodulating gelator strategy provides a new concept to efficiently reverse Arginase 1 immunosuppressive environments for amplified immunotherapy.
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http://dx.doi.org/10.1016/j.actbio.2021.01.041DOI Listing
April 2021

Impact of dietary components on enteric infectious disease.

Crit Rev Food Sci Nutr 2021 Jan 18:1-26. Epub 2021 Jan 18.

National Engineering Research Center of Seafood, School of Food Science and Technology, Dalian Polytechnic University, Dalian, Liaoning, China.

Diets impact host health in multiple ways and an unbalanced diet could contribute to the initiation or progression of a variety of diseases. Although a wealth of information exists on the connections between diet and chronic metabolic diseases such as cardiovascular disease, diabetes mellitus, etc., how diet influences enteric infectious disease still remain underexplored. The review summarizes the current findings on the link between various dietary components and diverse enteric infectious diseases. Dietary ingredients discussed include macronutrients (carbohydrates, lipids, proteins), micronutrients (vitamins, minerals), and other dietary ingredients (phytonutrients and probiotic supplements). We first describe the importance of enteric infectious diseases and the direct and indirect relationship between diet and enteric infectious diseases. Then we discuss the effects of different dietary components on the susceptibility to or progression of enteric infectious disease. Finally, we delineate current knowledge gap and highlighted future research directions. The literature review revealed that different dietary components affect host resistance to enteric infections through a variety of mechanisms. Dietary components may directly inhibit or bind to enteric pathogens, or indirectly influence enteric infections through modulating immune function and gut microbiota. Elucidating the unique repercussions of different diets on enteric infections in this review may help provide dietary guidelines or design dietary interventions to prevent or alleviate enteric infectious diseases.
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http://dx.doi.org/10.1080/10408398.2021.1871587DOI Listing
January 2021

microRNA-128 inhibits the inflammatory responses by targeting TAB2 in miiuy croaker, Miichthysmiiuy.

Dev Comp Immunol 2021 04 24;117:103976. Epub 2020 Dec 24.

Laboratory of Fish Molecular Immunology, College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China; Key Laboratory of Exploration and Utilization of Aquatic Genetic Resources (Shanghai Ocean University), Ministry of Education, China. Electronic address:

The inflammatory response is a self-defense process that fights the pathogen invasion by eliminating harmful stimuli. However, excessive inflammation may disrupt immune homeostasis, even causing chronic inflammation or autoimmune diseases. MicroRNAs (miRNAs) are a crucial regulator that can negatively regulate gene expression and participate in multiple biological processes of growth, development, and immune response in organisms. However, the miRNA-mediated modulation networks of inflammatory responses remain largely unclear in lower vertebrates. In this study, miR-128 was identified as a negative regulator to participate in the NF-κB signaling pathway by targeting TAB2 in miiuy croaker. First, we predicted target genes of miR-128 through the bioinformatics software programs and found that TAB2 is a direct target of miR-128. We also found that miR-128 can inhibit TAB2 expression at the mRNA and protein levels. Besides, upon LPS stimulation, miR-128 inhibits the expression of inflammatory cytokines by targeting TAB2 to avoid excessive inflammation. Particularly, we found that miR-128 can regulate TAB2-mediated NF-κB signaling pathways. In summary, our results indicate that miR-128 plays a critical role in suppressing inflammatory responses by regulating the TAB2-mediated NF-κB signaling pathway in miiuy croaker.
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http://dx.doi.org/10.1016/j.dci.2020.103976DOI Listing
April 2021

Engineering a photosensitizer nanoplatform for amplified photodynamic immunotherapy via tumor microenvironment modulation.

Nanoscale Horiz 2021 02 18;6(2):120-131. Epub 2020 Nov 18.

Department of Pharmaceutics, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.

Photosensitizer-based photodynamic therapy (PDT) can not only kill tumor cells by the generated cytotoxic reactive oxygen species (ROS), but also trigger immunogenic cell death (ICD) and activate an immune response for immunotherapy. However, such photodynamic immunotherapy suffers from major obstacles in the tumor microenvironment. The hypoxic microenvironment greatly weakens PDT, while the immunosuppressive tumor microenvironment caused by aberrant tumor blood vessels and indoleamine 2,3-dioxygenase (IDO) leads to a significant reduction in immunotherapy. To overcome these obstacles, herein, an engineered photosensitizer nanoplatform is designed for amplified photodynamic immunotherapy by integrating chlorin e6 (Ce6, a photosensitizer), axitinib (AXT, a tyrosine kinase inhibitor) and dextro-1-methyl tryptophan (1MT, an IDO inhibitor). In our nanoplatform, AXT improves the tumor microenvironment by normalizing tumor blood vessels, which not only promotes PDT by reducing the level of hypoxia of the tumor microenvironment, but also promotes immunotherapy through facilitating infiltration of immune effector cells into the tumor and reversing the immunosuppressive effect of vascular endothelial growth factor (VEGF). Moreover, 1MT effectively inhibits the activity of IDO, further reducing the immunosuppressive nature of the tumor microenvironment. Therefore, this nanoplatform demonstrates an amplified photodynamic immunotherapy via tumor microenvironment modulation, exhibiting outstanding therapeutic efficacy against tumor growth and metastasis with negligible side toxicity. The current concept of engineering photosensitizer nanoplatforms for overcoming photodynamic immunotherapy obstacles provides a promising strategy against tumors.
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http://dx.doi.org/10.1039/d0nh00480dDOI Listing
February 2021

Fish oil extracted from Coregonus peled improves obese phenotype and changes gut microbiota in a high-fat diet-induced mouse model of recurrent obesity.

Food Funct 2020 Jul;11(7):6158-6169

School of Food Science and Technology, Dalian Polytechnic University, Dalian 116304, Liaoning, PR China. and National Engineering Research Center of Seafood, Dalian 116304, Liaoning, PR China and Collaborative Innovation Center of Seafood Deep Processing, Dalian 116304, Liaoning, PR China.

Recurrent obesity is rapidly emerging as a public health problem. Previous studies have confirmed that fish oil supplementation can alleviate obesity in mice; however, the effect of fish oil on recurrent obesity remains unclear. In the present study, the modulatory effects of fish oil extracted from Coregonus peled on the phenotypes and gut microbiota of recurrent obese mice were evaluated by MRI, OGTT, and bioinformatics analysis. We found that fish oil supplementation could significantly reduce the body weight gain, net weight gain, body fat distribution, and glucose tolerance. In addition, the composition and structure of gut microbiota were significantly shifted toward those of the control group by fish oil treatment. Moreover, the relative abundance of gut microbiota, such as Bacteroidetes, Bacteroidia, Lachnospiraceae, and Bifidobacterium, was markedly responding to the rapid dietary changes between fish oil and high-fat diet. Overall, our results confirmed that the alleviation of recurrent obesity using fish oil supplementation might be modulated by altering the hysteretic behavior and memory-like function of gut microbiota. We proposed that further studies are needed to elucidate the modulation mechanism.
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http://dx.doi.org/10.1039/d0fo00911cDOI Listing
July 2020

Loss of FOXM1 in macrophages promotes pulmonary fibrosis by activating p38 MAPK signaling pathway.

PLoS Genet 2020 04 9;16(4):e1008692. Epub 2020 Apr 9.

Division of Pulmonary Biology, the Perinatal Institute of Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease with high mortality and is refractory to treatment. Pulmonary macrophages can both promote and repress fibrosis, however molecular mechanisms regulating macrophage functions during fibrosis remain poorly understood. FOXM1 is a transcription factor and is not expressed in quiescent lungs. Herein, we show that FOXM1 is highly expressed in pulmonary macrophages within fibrotic lungs of IPF patients and mouse fibrotic lungs. Macrophage-specific deletion of Foxm1 in mice (myFoxm1-/-) exacerbated pulmonary fibrosis. Inactivation of FOXM1 in vivo and in vitro increased p38 MAPK signaling in macrophages and decreased DUSP1, a negative regulator of p38 MAPK pathway. FOXM1 directly activated Dusp1 promoter. Overexpression of DUSP1 in FOXM1-deficient macrophages prevented activation of p38 MAPK pathway. Adoptive transfer of wild-type monocytes to myFoxm1-/- mice alleviated bleomycin-induced fibrosis. Altogether, contrary to known pro-fibrotic activities in lung epithelium and fibroblasts, FOXM1 has anti-fibrotic function in macrophages by regulating p38 MAPK.
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http://dx.doi.org/10.1371/journal.pgen.1008692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173935PMC
April 2020

Nanoparticle Delivery of Proangiogenic Transcription Factors into the Neonatal Circulation Inhibits Alveolar Simplification Caused by Hyperoxia.

Am J Respir Crit Care Med 2020 07;202(1):100-111

Department of Pediatrics, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

: Advances in neonatal critical care have greatly improved the survival of preterm infants, but the long-term complications of prematurity, including bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. Although VEGF (vascular endothelial growth factor) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in patients with BPD.: To test whether nanoparticle delivery of proangiogenic transcription factor FOXM1 (forkhead box M1) or FOXF1 (forkhead box F1), both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury.: Newborn mice were exposed to 75% O for the first 7 days of life before being returned to a room air environment. On Postnatal Day 2, polyethylenimine-(5) myristic acid/polyethylene glycol-oleic acid/cholesterol nanoparticles containing nonintegrating expression plasmids with or cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry, and the flexiVent small-animal ventilator.: The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or FOXF1 did not protect endothelial cells from apoptosis caused by hyperoxia but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and FOXF1 improved elastin fiber organization, decreased alveolar simplification, and preserved lung function in mice reaching adulthood.: Nanoparticle delivery of FOXM1 or FOXF1 stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.
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http://dx.doi.org/10.1164/rccm.201906-1232OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328311PMC
July 2020

Fucoxanthin alleviates palmitate-induced inflammation in RAW 264.7 cells through improving lipid metabolism and attenuating mitochondrial dysfunction.

Food Funct 2020 Apr;11(4):3361-3370

School of Food Science and Technology, National Engineering Research Center of Seafood, Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian, Liaoning 116034, China. and College of Food Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

In this study, we aimed to examine the effects of fucoxanthin on inflammation triggered by palmitate in macrophages. Raw 264.7 cells were treated with palmitate with or without fucoxanthin co-treatment. Fucoxanthin greatly alleviated palmitate-induced decrease in cell viability and loss of mitochondrial membrane potential. Fucoxanthin also significantly attenuated the palmitate-induced transcriptional expression of Il-6, Il-1β, Tnfα and Nlrp3 inflammasomes and increased the expression of Tgfb. In addition, fucoxanthin decreased triglyceride accumulation induced by palmitate through enhancing the expression of Cpt1a, Pparg and other lipid metabolism genes. Inhibition of CPT1a by etomoxir attenuated the anti-inflammatory effect of fucoxanthin. Furthermore, fucoxanthin increased AMPK phosphorylation and AMPKa1 knockdown by its specific siRNA diminished protective function. In addition, fucoxanthin restored palmitate-mediated mitochondrial dysfunction and improved mitophagy-related gene expression. These findings suggest that fucoxanthin could attenuate free fatty acid-induced inflammation in macrophages through modulating lipid metabolism and mitigating mitochondrial dysfunction.
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http://dx.doi.org/10.1039/d0fo00442aDOI Listing
April 2020

The distribution characteristics of intestinal microbiota in children with community-acquired pneumonia under five Years of age.

Microb Pathog 2020 Feb 11;142:104062. Epub 2020 Feb 11.

Department of Biotechnology, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China. Electronic address:

Pneumonia is the leading cause of morbidity and mortality in children under five years of age worldwide. Over the past decades, studies have shown that the upper respiratory pathogens are closely related to the occurrence of pneumonia. However, the co-occurrence of gut microbiome dysbiosis may have clinical manifestation in the prognosis of childhood pneumonia. The aim of the present study is to investigate the differences in gut microbial communities between children's diagnosed community-acquired pneumonia (CAP) under five compared to healthy controls in Inner Mongolia. Fecal samples were collected from children with CAP and healthy controls (<5 years old) and the genomic microbiome 16S rRNA was amplified using the hypervariable V4 region and subjected to MiSeq Illumina sequencing, and then analyzed for microbiota composition and phenotype. Finally functional profiling was performed by KEGG pathways analyses. Our results revealed a gut microbiota dysbiosis in children with CAP. Distinct gut microbiome composition and structure were associated with childhood CAP between two age categories compared to healthy controls. In addition, the phylogenic phenotype's prediction was found to be significantly different between the groups. The prominent genera in age group of 0-3 were Bifidobacterium and Enterococcus. On the contrary, Escherichia-Shigella, Prevotella, Faecalibacterium and Enterobacter were remarkably decreased in most of the fecal samples from CAP patients in age group of 0-3 compared to the control. At the genus level, the CAP children in the age group of 4-5 showed an increase in the abundance of Escherichia/Shigella, Bifidobacterium, Streptococcus and Psychrobacter and, a decrease in the abundance of Faecalibacterium, Bacteroides, Lachnospiraceae and Ruminococcus compared with the matched healthy controls. Moreover, CAP children in both age groups exhibited distinct profiles in the KEGG functional analysis. Our data revealed that the gut microbiota differ between CAP patients and health children and certain gut microbial species are associated with CAP. Further research to identify specific microbial species which may contribute to the development CAP are merited. In addition, rectification of microbiota dysbiosis may provide supplemental benefits for treatment of the childhood CAP.
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http://dx.doi.org/10.1016/j.micpath.2020.104062DOI Listing
February 2020

Postnatal Alveologenesis Depends on FOXF1 Signaling in c-KIT Endothelial Progenitor Cells.

Am J Respir Crit Care Med 2019 11;200(9):1164-1176

Center for Lung Regenerative Medicine.

Disruption of alveologenesis is associated with severe pediatric lung disorders, including bronchopulmonary dysplasia (BPD). Although c-KIT endothelial cell (EC) progenitors are abundant in embryonic and neonatal lungs, their role in alveolar septation and the therapeutic potential of these cells remain unknown. To determine whether c-KIT EC progenitors stimulate alveologenesis in the neonatal lung. We used single-cell RNA sequencing of neonatal human and mouse lung tissues, immunostaining, and FACS analysis to identify transcriptional and signaling networks shared by human and mouse pulmonary c-KIT EC progenitors. A mouse model of perinatal hyperoxia-induced lung injury was used to identify molecular mechanisms that are critical for the survival, proliferation, and engraftment of c-KIT EC progenitors in the neonatal lung. Pulmonary c-KIT EC progenitors expressing PECAM-1, CD34, VE-Cadherin, FLK1, and TIE2 lacked mature arterial, venal, and lymphatic cell-surface markers. The transcriptomic signature of c-KIT ECs was conserved in mouse and human lungs and enriched in FOXF1-regulated transcriptional targets. Expression of FOXF1 and c-KIT was decreased in the lungs of infants with BPD. In the mouse, neonatal hyperoxia decreased the number of c-KIT EC progenitors. Haploinsufficiency or endothelial-specific deletion of in mice increased apoptosis and decreased proliferation of c-KIT ECs. Inactivation of either or caused alveolar simplification. Adoptive transfer of c-KIT ECs into the neonatal circulation increased lung angiogenesis and prevented alveolar simplification in neonatal mice exposed to hyperoxia. Cell therapy involving c-KIT EC progenitors can be beneficial for the treatment of BPD.
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http://dx.doi.org/10.1164/rccm.201812-2312OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888649PMC
November 2019

The conserved cysteine residues in Bacillus thuringiensis Cry1Ac protoxin are not essential for the bipyramidal crystal formation.

J Invertebr Pathol 2019 05 27;163:82-85. Epub 2019 Mar 27.

College of Life Science, State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha 410081, PR China. Electronic address:

To evaluate the function of conserved cysteine residues in Cry1Ac protoxin, we constructed a series of Cry1Ac mutants in which single or multiple cysteine residues were replaced with serine. It was found that cysteine substitution had little effect on the protoxin expression and bipyramidal crystal formation. Bioassays using Plutella xylostella larvae showed that two mutants with fourteen cysteine residues in the C-terminal half and all sixteen residues replaced had similar toxicity as wildtype Cry1Ac protoxin. Our study suggests that the conserved cysteine resudues in the Cry1Ac protoxin are not essential for deposition into a bipyramidal crystal even though the C-terminal half was directly involved in crystal formation.
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http://dx.doi.org/10.1016/j.jip.2019.03.009DOI Listing
May 2019

Solubility enhancement of Cry2Aa crystal through carboxy-terminal extension and synergism between the chimeric protein and Cry1Ac.

Appl Microbiol Biotechnol 2019 Mar 8;103(5):2243-2250. Epub 2019 Jan 8.

College of Life Science, State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha, 410081, People's Republic of China.

It was reported that the highly conserved C-terminal region of Bacillus thuringiensis Cry1A protoxins was very important for parasporal crystal formation and solubility feature in alkaline environment. In order to improve the solubilization efficiency of Cry2Aa crystal, the coding sequences of Cry2Aa protein and the C-terminal half of Cry1Ac were fused seamlessly through Red/ET homologous recombination and expressed in an acrystalliferous B. thuringiensis strain under the control of the cry1Ac promoter and terminator. Microscopic observation revealed that the recombinant strain containing the chimeric gene cry2Aa-1Ac produced distinct parasporal inclusion with semispherical to approximately cuboidal shape during sporulation. SDS-PAGE analysis showed that this strain expressed stable 130-kDa Cry2Aa-1Ac chimeric protein, which was confirmed to be the correctly expressed product by LC-MS/MS. The chimeric protein inclusion could be effectively dissolved at pH 10.5 and activated by trypsin like the parental Cry1Ac crystal. While, the parental Cry2Aa crystal exhibited very low solubility under this condition. Bioassays against third-instar larvae of Helicoverpa armigera proved that the chimeric protein was more toxic than Cry2Aa. Additionally, synergistic effect was clearly detected between the chimeric protein and Cry1Ac against H. armigera, while there was only additive effect for the combination of wild Cry2Aa and Cry1Ac. These results indicated that the developed chimeric protein might serve as a potent insecticidal toxin used in the field against lepidopteran pests.
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http://dx.doi.org/10.1007/s00253-018-09606-wDOI Listing
March 2019

Islet α-cell Inflammation Induced By NF-κB inducing kinase (NIK) Leads to Hypoglycemia, Pancreatitis, Growth Retardation, and Postnatal Death in Mice.

Theranostics 2018 13;8(21):5960-5971. Epub 2018 Nov 13.

HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.

Islet α-cell dysfunction has been shown to contribute to type 2 diabetes; however, whether islet α-cell inflammation is involved in the occurrence of pancreatitis is largely unknown. The aims of this study were to investigate how NF-κB inducing kinase (NIK) regulates pancreatic α-cell function, both and , and to assess how islet α-cell inflammation induced by NIK affects the development of pancreatitis. We utilized adenovirus-mediated NIK overexpression, ELISA, qPCR, RNA-seq, and Western blot analyses to study the role of NIK in islet α cells . Islet α-cell-specific NIK overexpressing (α-NIK-OE) mice were generated, and pancreatic α/β-cell function and the occurrence of pancreatitis in these mice were assessed ELISA, qPCR, and immunohistochemical analyses. The LTβR/noncanonical NF-κB signaling pathway is present in islet α cells. Overexpression of NIK in αTC1-6 cells induces inflammation and cell death, contributing to a decrease in the expression and secretion of glucagon. Additionally, α-cell specific overexpression of NIK (α-NIK-OE) results in α-cell death, lower serum glucagon levels, and hypoglycemia in mice. Strikingly, α-NIK-OE mice also display a reduced β-cell mass, growth retardation, pancreatitis, and postnatal death. Islet α-cell specific overexpression of NIK results in islet α-cell dysfunction and causes islet β-cell death and pancreatitis, which are most likely due to paracrine secretion of cytokines and chemokines from islet α cells, thus leading to hypoglycemia, growth retardation, and postnatal death in mice.
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http://dx.doi.org/10.7150/thno.28960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299425PMC
September 2019

Key Role of the Membrane Trafficking of Nav1.5 Channel Protein in Antidepressant-Induced Brugada Syndrome.

Front Physiol 2018 5;9:1230. Epub 2018 Sep 5.

Department of Cardiology, Chinese People's Liberation Army General Hospital, Beijing, China.

Anti-depressant treatment has been found to be associated with the development of Brugada syndrome (BrS) through poorly defined mechanisms. Herein, this study aimed to explore the molecular basis for amitriptyline-induced BrS. The effects of long-term treatments of amitriptyline on Nav1.5 were investigated using neonatal rat ventricular myocytes. The electrophysiological properties, expression and distribution of Nav1.5 were studied using the patch clamp, Western blot and confocal laser microscopy assays. Interactions between Nav1.5 and its interacting proteins, including ankyrin-G and dystrophin, were evaluated by co-immunoprecipitation. A larger decrease in the peak I occurred after long-term treatments to amitriptyline (56.64%) than after acute exposure to amitriptyline (28%). Slow recovery from inactivation of Nav1.5 was observed after acute or long-term treatments to amitriptyline. The expression of Nav1.5 on the cell membrane showed a larger decrease by long-term treatments to amitriptyline than by acute exposure to amitriptyline. After long-term treatments to amitriptyline, we observed reduced Nav1.5 proteins on the cell membrane and the disrupted co-localization of Nav1.5 and ankyrin-G or dystrophin. Co-immunoprecipitation experiments further testified that the combination of Nav1.5 and ankyrin-G or dystrophin was severely weakened after long-term treatments to amitriptyline, implying the failed interaction between Nav1.5 and ankyrin-G or dystrophin. Our data suggest that the long-term effect of amitriptyline serves as an important contribution to BrS induced by amitriptyline. The mechanisms of BrS induced by amitriptyline were related to Nav1.5 trafficking and could be explained by the disrupted interaction of ankyrin-G, dystrophin and Nav1.5.
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http://dx.doi.org/10.3389/fphys.2018.01230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134322PMC
September 2018

Mechanisms and Treatments of Oxidative Stress in Atrial Fibrillation.

Curr Pharm Des 2018 ;24(26):3062-3071

Guang'an men Hospital, Chinese Academy of Chinese Medical Sciences, Beijing 100053, China.

Atrial fibrillation (AF) is a frequent cardiac arrhythmia. It is a common major cause of serious diseases and is an increasing health-care burden. AF is associated with an excess amount of reactive oxygen species. In this review, we summarize several possible reactive oxygen species pathways that induce AF based on atrial electrical and structural remodeling data. The sources and factors implicated in AF-related oxidative stress include NADPH oxidase activation, calcium overloading and mitochondrial damage, angiotensin system activation, nitric oxide synthase uncoupling, and xanthine oxidase activation-associated cardiovascular conditions. Scavenging oxidative stress markers and related substances are essential aspects of these molecular mechanisms, and may be a therapeutic target in AF.
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http://dx.doi.org/10.2174/1381612824666180903144042DOI Listing
October 2019

The Mechanism of Exosomes Function in Neurological Diseases: A Progressive Review.

Curr Pharm Des 2018 ;24(24):2855-2861

Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing 100700, China.

Exosomes are extracellular microparticles (≈30-100 nm in diameter) secreted from nearly all types of cells, containing a whole set of biological information including proteins, ribonucleic acid (RNA) and lipids. Latest studies show that exosomes contribute to cell-cell communication and are considered closely related with the modulation of angiogenesis and neurogenesis in many neurological diseases. In the past decade, numerous researchers were devoted to exosomes study, but the mechanism of exosomes function and delivery is uncertain. In this review, we summarized several potential mechanisms of exosomes function in angiogenesis, neurogenesis and Blood Brain Barrier (BBB) delivery, and differentiate various sources of exosomes in stroke, tumor, Traumatic Brain Injury (TBI) and Alzheimer's Disease (AD) aimed to report the most advanced mechanical theories in related past three years to provide a new sight for this research area.
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http://dx.doi.org/10.2174/1381612824666180903113136DOI Listing
October 2019

A Polysaccharide Isolated from Dictyophora indusiata Promotes Recovery from Antibiotic-Driven Intestinal Dysbiosis and Improves Gut Epithelial Barrier Function in a Mouse Model.

Nutrients 2018 Jul 31;10(8). Epub 2018 Jul 31.

Department of Biotechnology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, Liaoning, China.

Despite the tremendous biological activity of polysaccharides from the mushroom , its role in the restoration of gut microbiota has not yet been explored. The present study aimed to investigate whether polysaccharide (DIP) could modulate the recovery of gut microbiota composition and intestinal barrier function after broad-spectrum antibiotic-driven dysbiosis. Alteration and restoration in the microbial communities were elucidated by the Illumina MiSeq platform. Colon histology, expression of tight-junction associated proteins, and serum/tissue endotoxin and cytokine levels were evaluated. Two-week daily oral administration of clindamycin and metronidazole resulted in reduced bacterial diversity and richness, and perturbed the microbial flora at various taxonomic levels (altered Firmicutes/Bacteroidetes ratio and increased relative abundance of harmful flora (Proteobacteria, and )), whereas DIP administration reversed the dysbiosis and increased beneficial flora, including Lactobacillaceae (lactic acid-producing bacteria), and Ruminococaceae (butyrate-producing bacteria). In addition, it resulted in the reduction of endotoxemia (through lipopolysaccharides (LPSs)) and pro-inflammatory cytokine (tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1β (IL-1β)) levels, with the increased expression of tight-junction associated proteins (claudin-1, occludin, and zonula occludens-1). These findings not only suggested a comprehensive understanding of the protective effects of a DIP in the restoration of gut microbiota but also highlighted its role in the enhancement of gut barrier integrity, reduction of inflammation and lowering of endotoxin levels in mice.
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http://dx.doi.org/10.3390/nu10081003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115818PMC
July 2018

FOXF1 Inhibits Pulmonary Fibrosis by Preventing CDH2-CDH11 Cadherin Switch in Myofibroblasts.

Cell Rep 2018 Apr;23(2):442-458

Divisions of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Hospital Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229, USA. Electronic address:

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant accumulation of collagen-secreting myofibroblasts. Development of effective therapies is limited due to incomplete understanding of molecular mechanisms regulating myofibroblast expansion. FOXF1 transcription factor is expressed in resident lung fibroblasts, but its role in lung fibrosis remains unknown due to the lack of genetic mouse models. Through comprehensive analysis of human IPF genomics data, lung biopsies, and transgenic mice with fibroblast-specific inactivation of FOXF1, we show that FOXF1 inhibits pulmonary fibrosis. FOXF1 deletion increases myofibroblast invasion and collagen secretion and promotes a switch from N-cadherin (CDH2) to Cadherin-11 (CDH11), which is a critical step in the acquisition of the pro-fibrotic phenotype. FOXF1 directly binds to Cdh2 and Cdh11 promoters and differentially regulates transcription of these genes. Re-expression of CDH2 or inhibition of CDH11 in FOXF1-deficient cells reduces myofibroblast invasion in vitro. FOXF1 inhibits pulmonary fibrosis by regulating a switch from CDH2 to CDH11 in lung myofibroblasts.
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http://dx.doi.org/10.1016/j.celrep.2018.03.067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947867PMC
April 2018

The full-length Cry1Ac protoxin without proteolytic activation exhibits toxicity against insect cell line CF-203.

J Invertebr Pathol 2018 02 3;152:25-29. Epub 2018 Feb 3.

College of Life Science, State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Normal University, Changsha 410081, PR China. Electronic address:

The new dual model for Bacillus thuringiensis insecticidal mechanism proposed that Cry1A protoxins without proteolytic activation could bind to insect midgut receptors to exert toxicity. To evaluate insecticidal potency of Cry1Ac protoxin at precluding interference of midgut proteases, the cytotoxicity of Cry1Ac protoxin against midgut cell line CF-203 derived from Choristoneura fumiferana was analyzed. It was revealed that Cry1Ac protoxin was toxic to CF-203 cells and there existed certain differences in the cytological changes when treated with protoxin and toxin. Our cell-based study provided direct evidence for the proposed dual model and shed light on exploring the difference between two toxic pathways elicited by intact protoxin and activated toxin.
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http://dx.doi.org/10.1016/j.jip.2018.01.004DOI Listing
February 2018

The Effects of Tai Chi Training in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

Front Physiol 2017 7;8:989. Epub 2017 Dec 7.

Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, Beijing, China.

Heart Failure (HF) is associated with significantly high morbidity and mortality. We performed a meta-analysis and updated new evidences from randomized controlled trials (RCTs) to determine the effects of Tai Chi (TC) in patients with HF. Electronic literature search of Medline, PubMed, EMBASE, the Cochrane Library, China national knowledge infrastructure (CNKI), and Wan Fang Database was conducted from inception of their establishment until 2017. And we also searched Clinical Trials Registries (https://clinicaltrials.gov/ and www.controlled-trials.com) for on-going studies. A total of 11 trials with 656 patients were available for analysis. The results suggested that TC was associated with an obviously improved 6-min walk distance [6MWD, weighted mean difference (WMD) 65.29 m; 95% CI 32.55-98.04] and quality of life (Qol, WMD -11.52 points; 95% CI -16.5 to -6.98) and left ventricular ejection fraction (LVEF, WMD 9.94%; 95% CI 6.95 to 12.93). TC was shown to reduce serum B-type natriuretic peptide [BNP, standard mean difference (SMD) -1.08 pg/mL; 95% CI -1.91 to -0.26] and heart rate (HR, WMD -2.52 bpm; 95% CI -3.49 to -1.55). In summary, our meta-analysis demonstrated the clinical evidence about TC for HF is inconclusive. TC could improve 6MWD, Qol and LVEF in patients with HF and may reduce BNP and HR. However, there is a lack of evidence to support TC altering other important long-term clinical outcomes so far. Further larger and more sustainable RCTs are urgently needed to investigate the effects of TC.
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http://dx.doi.org/10.3389/fphys.2017.00989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770613PMC
December 2017

Oxidative Stress-Mediated Atherosclerosis: Mechanisms and Therapies.

Front Physiol 2017 23;8:600. Epub 2017 Aug 23.

Key Laboratory of Chinese Internal Medicine of the Ministry of Education, Dongzhimen Hospital, Beijing University of Chinese MedicineBeijing, China.

Atherogenesis, the formation of atherosclerotic plaques, is a complex process that involves several mechanisms, including endothelial dysfunction, neovascularization, vascular proliferation, apoptosis, matrix degradation, inflammation, and thrombosis. The pathogenesis and progression of atherosclerosis are explained differently by different scholars. One of the most common theories is the destruction of well-balanced homeostatic mechanisms, which incurs the oxidative stress. And oxidative stress is widely regarded as the redox status realized when an imbalance exists between antioxidant capability and activity species including reactive oxygen (ROS), nitrogen (RNS) and halogen species, non-radical as well as free radical species. This occurrence results in cell injury due to direct oxidation of cellular protein, lipid, and DNA or via cell death signaling pathways responsible for accelerating atherogenesis. This paper discusses inflammation, mitochondria, autophagy, apoptosis, and epigenetics as they induce oxidative stress in atherosclerosis, as well as various treatments for antioxidative stress that may prevent atherosclerosis.
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http://dx.doi.org/10.3389/fphys.2017.00600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572357PMC
August 2017

FOXF1 transcription factor promotes lung regeneration after partial pneumonectomy.

Sci Rep 2017 09 6;7(1):10690. Epub 2017 Sep 6.

Center for Lung Regenerative Medicine, Cincinnati Children's Research Foundation, Cincinnati, Ohio, USA.

FOXF1, a member of the forkhead box family of transcription factors, has been previously shown to be critical for lung development, homeostasis, and injury responses. However, the role of FOXF1 in lung regeneration is unknown. Herein, we performed partial pneumonectomy, a model of lung regeneration, in mice lacking one Foxf1 allele in endothelial cells (PDGFb-iCre/Foxf1 mice). Endothelial cell proliferation was significantly reduced in regenerating lungs from mice deficient for endothelial Foxf1. Decreased endothelial proliferation was associated with delayed lung regeneration as shown by reduced respiratory volume in Foxf1-deficient lungs. FACS-sorted endothelial cells isolated from regenerating PDGFb-iCre/Foxf1 and control lungs were used for RNAseq analysis to identify FOXF1 target genes. Foxf1 deficiency altered expression of numerous genes including those regulating extracellular matrix remodeling (Timp3, Adamts9) and cell cycle progression (Cdkn1a, Cdkn2b, Cenpj, Tubb4a), which are critical for lung regeneration. Deletion of Foxf1 increased Timp3 mRNA and protein, decreasing MMP14 activity in regenerating lungs. ChIPseq analysis for FOXF1 and histone methylation marks identified DNA regulatory regions within the Cd44, Cdkn1a, and Cdkn2b genes, indicating they are direct FOXF1 targets. Thus FOXF1 stimulates lung regeneration following partial pneumonectomy via direct transcriptional regulation of genes critical for extracellular matrix remodeling and cell cycle progression.
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http://dx.doi.org/10.1038/s41598-017-11175-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587533PMC
September 2017

E. coli O124 K72 alters the intestinal barrier and the tight junctions proteins of guinea pig intestine.

Biomed Pharmacother 2017 Oct 2;94:468-473. Epub 2017 Aug 2.

Department of Biotechnology, Dalian Medical University, Dalian 116044, China. Electronic address:

Our research group previously isolated and identified a strain of pathogenic Escherichia coli from clinical samples called E. coli O124 K72. The present study was aimed at determining the potential effects of E. coli O124 K72 on intestinal barrier functions and structural proteins integrity in guinea pig. Guinea pigs were grouped into three groups; control (CG); E. coli O124 K72 (E. coli); and probiotics Lactobacillus rhamnosus (LGG). Initially, we create intestinal dysbiosis by giving all animals Levofloxacin for 10days, but the control group (CG) received the same volume of saline. Then, the animals received either E. coli O124 K72 (E. coli) or Lactobacillus rhamnosus (LGG) according to their assigned group. E. coli O124 K72 treatment significantly affected colon morphology and distorted intestinal barrier function by up-regulating Claudin2 and down-regulating Occludin. In addition, E. coli upregulated the mRNA expression of MUC1, MUC2, MUC13 and MUC15. Furthermore, suspected tumor was found in the E. coli treated animals. Our results suggested that E. coli O124 K72 strain has adverse effects on intestinal barrier functions and is capable of altering integrity of structural proteins in guinea pig model while at same time it may have a role in colon carcinogenesis.
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http://dx.doi.org/10.1016/j.biopha.2017.07.123DOI Listing
October 2017
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