[Research progress in glycogen metabolism reprogramming in sepsis associated immune cells].
[Article in Chinese]
Wang D1, Liu M2, Lyu X2.
Author information
1
Department of Anesthesiology, China-Japan Friendship Hospital of Jilin University, Changchun 130033, Jilin, China.
2
Department of Anesthesiology, Shanghai Pulmonary Hospital of Tongji University, Shanghai 200433, China. Corresponding author: Lyu Xin, Email: xinlv@126.com.
Abstract
Metabolic reprogramming is the response of cells to environmental changes, such as cell activation, proliferation and differentiation, which involves changes in metabolism-related enzymes, metabolites and metabolic pathways. Sepsis-associated immune cells undergo metabolic reprogramming in response to inflammatory signals, which not only provides biological energy and biosynthesis requirements, but also determines cell fate and function in a highly specific way. In this paper, the changes in glycolysis, tricarboxylic acid cycle, oxidative phosphorylation and other glucose metabolism pathways of macrophages, T lymphocytes, dendritic cells, neutrophils and other sepsis related immune cells are described, so as to provide feasibility for future research and metabolic therapy.

PMID: 31657347 DOI: 10.3760/cma.j.issn.2095-4352.2019.09.023
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Select item 31657335
2.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2019 Sep;31(9):1113-1117. doi: 10.3760/cma.j.issn.2095-4352.2019.09.011.
[Changes in coagulation of sepsis rats with protein-malnutrition or energy-malnutrition].
[Article in Chinese]
Li D1, Zou M, Wang L, Li X, Ma X.
Author information
1
Department of Critical Care Medicine, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China. Corresponding author: Ma Xiaochun, Email: xcma2972@sina.com.
Abstract
OBJECTIVE:
To investigate the changes in coagulation of sepsis rats with protein-malnutrition or energy-malnutrition.

METHODS:
108 male Sprague-Dawley (SD) rats were divided into three groups by random number table, with 36 rats in each group. The rats in normal feeding group were given a free diet (27 g/d, containing 18% protein fodder), and the rats in protein-malnutrition group were given a low protein diet (27 g/d, containing 5% protein fodder). The rats in energy-malnutrition group were given a low energy diet (9 g/d, containing 18% protein fodder). After 4 weeks of continuous feeding, 8 rats from each group were sacrificed for malnutrition evaluation. The weights of body, thymus and spleen were measured. The percentages of spleen T lymphocyte subsets and M1 macrophage were determined by flow cytometry. Plasma interleukins (IL-6 and IL-10) levels were determined by enzyme-linked immunosorbent assay (ELISA). The remaining 28 rats in each group were collected for cecal ligation and puncture (CLP) to reproduce the sepsis model, 20 rats of which were used for Kaplan-Meier survival analysis, and the other 8 rats were sacrificed at 8 hours after CLP. The levels of plasma IL-6 and IL-10 were determined by ELISA, and the percentage of spleen M1 macrophages was determined by flow cytometry. The mRNA expressions of tissue factor (TF) and plasminogen activation inhibitor-1 (PAI-1) in liver tissue were determined by reverse transcription-polymerase chain reaction (RT-PCR). Pearson correlation method was used to analyze the correlation between the mRNA expressions of TF and PAI-1 and IL-6 in rats after CLP.

RESULTS:
(1) After 4 weeks of feeding, the rats in the normal feeding group and protein-malnutrition group gained weight, while those in the energy-malnutrition group lost 25% of their initial body weight. The weights of body, thymus and spleen in the protein-malnutrition group and the energy-malnutrition group were significantly lower than those in the normal feeding group. Compared with the normal feeding group and the protein-malnutrition group, the percentages of spleen CD3+T lymphocytes, CD4+T lymphocytes, M1 macrophages and plasma IL-6 levels were significantly increased in the energy-malnutrition group [CD3+T lymphocytes percentage: (52.1±3.7)% vs. (46.9±3.9)%, (44.5±2.2)%; CD4+T lymphocyte percentages: (35.0±3.6)% vs. (26.3±2.2)%, (25.1±2.3)%; M1 macrophage percentages: (8.7±2.0)% vs. (3.2±1.3)%, (4.2±1.1)%; IL-6 (ng/L): 129.4±16.2 vs. 48.1±10.0, 53.0±8.3, all P < 0.05]. (2) Kaplan-Meier survival analysis at 7 days after CLP showed: all rats in the energy-malnutrition group died, and the 7-day cumulative survival rate was significantly lower than that in the normal feeding group and the protein-malnutrition group [0% (0/20) vs. 35% (7/20), 55% (11/20), both P < 0.05]. The mortality of the normal feeding group was 65%, which was consistent with moderate CLP mortality, indicating that the CLP model was successfully prepared. After CLP, the plasma IL-6 level in the protein-malnutrition group was significantly lower than that in the normal feeding group [IL-6 (ng/L): 154.6±34.7 vs. 233.4±41.2, P < 0.05]. Compared with the normal feeding group, the mRNA expressions of TF and PAI-1 in liver and plasma IL-6 levels in the energy-malnutrition group were significantly increased [TF mRNA (2-ΔΔCT): 4.5±2.2 vs. 1.1±0.7, PAI-1 mRNA (2-ΔΔCT): 3.3±1.8 vs. 1.3±0.9, IL-6 (ng/L): 382.7±118.2 vs. 233.4±41.2, all P < 0.05], the percentage of M1 macrophages in spleen was significantly lowered [(8.9±2.4)% vs. (15.2±5.4)%, P < 0.05]. There was no significant difference in plasma IL-10 level among all the groups. Correlation analysis showed that the mRNA expressions of TF and PAI-1 in the liver of rats after CLP were positively correlated with plasma IL-6 level (r1 = 0.644, r2 = 0.574, both P < 0.01).

CONCLUSIONS:
Long-term sustained stress (starvation) leads to sustained chronic inflammatory state, and stimulated the release of related inflammatory factors and activation of the coagulation system after infection. And the inflammatory factors in sepsis rats without sustained stress protein malnutrition were significantly reduced.

PMID: 31657335 DOI: 10.3760/cma.j.issn.2095-4352.2019.09.011
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Select item 31657264
3.
Virulence. 2019 Oct 26. doi: 10.1080/21505594.2019.1685150. [Epub ahead of print]
Antibacterial activity of a Tribolium castaneum defensin in an in vitro infection model of Streptococcus pneumoniae.
Lindhauer NS1, Bertrams W1, Pöppel A2, Herkt CE1, Wesener A1, Hoffmann K1, Greene B3, van der Linden M4, Vilcinskas A2,5, Seidel K1, Schmeck B1,6.
Author information
1
Institute for Lung Research, Universities of Giessen and Marburg Lung Center, Philipps-University Marburg, Member of the German Center for Lung Research (DZL) , Marburg , Germany.
2
Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology , Giessen , Germany.
3
Institute of Medical Bioinformatics and Biostatistics, Universities of Giessen and Marburg, Philipps-University Marburg , Marburg , Germany.
4
German National Reference Center for Streptococci, Department of Medical Microbiology, University Hospital RWTH Aachen , Aachen , Germany.
5
Institute for Insect Biotechnology, Justus-Liebig-University , Giessen , Germany.
6
Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-University, Member of the German Center for Lung Research (DZL) , Marburg , Germany.
Abstract
Streptococcus pneumoniae (S. pneumoniae) is the most common bacterial cause of community-acquired pneumonia. Increasing rates of antibiotic-resistant S. pneumoniae strains impair therapy and necessitate alternative treatment options. In this study we analysed insect-derived antimicrobial peptides (AMPs) for antibacterial effects on S. pneumoniae in a human in vitro infection model. AMP effects on bacterial growth were examined by colony forming unit (CFU)-assays, and growth curve measurements. Furthermore, cytotoxicity to primary human macrophages was detected by measuring lactate-dehydrogenase release to the supernatant. One AMP (Defensin 1) was tested in a model of primary human monocyte-derived macrophages infected with S. pneumoniae strain D39 and a multi-resistant clinical isolate. Inflammatory reactions were characterised by qPCR and multiplex-ELISA. In total, antibacterial effects of 23 AMPs were characterized. Only Tribolium castaneum Defensin 1 showed significant antibacterial effects against S. pneumoniae strain D39 and a multi-resistant clinical isolate. During in vitro infection of primary human macrophages with S. pneumoniae D39, Defensin 1 displayed strong antibacterial effects, and consequently reduced bacteria-induced cytokine expression and release. In summary, Tribolium castaneum Defensin 1 showed profound antibacterial effectivity against Streptococcus pneumoniae D39 and a multi-resistant clinical isolate without unwanted cytotoxic or inflammatory side effects on human blood-derived macrophages.

KEYWORDS:
; Antimicrobial peptides; antibiotic resistance; defensin; inflammation; insect; macrophages

PMID: 31657264 DOI: 10.1080/21505594.2019.1685150
Select item 31657199
4.
Anal Chem. 2019 Oct 28. doi: 10.1021/acs.analchem.9b03731. [Epub ahead of print]
Multicolor fluorescence based on FRET regulated by functional peptides to screen high metastatic potential cancer cells.
Wen Y, Huo F, Wang J, Yin C.
Abstract
The activation and execution of cancer invasion and metastasis involves in a complex network of intracellular, extracellular molecule levels (such as reactive oxygen species, ROS, matrix metalloproteinase, MMPs) and signaling cascades. Obviously, fluorescence sensing is a powerful detection tool for the analytes. However, for imaging the intracellular signal cascades involved multiple molecules, traditional fluorescence probes were unsuitable, because most of them only can determine the change of only species, rather than response multiple species simultaneously. Herein, we constructed a novel probe: H2O2 responding fluorophore donor was linked by MMP2-sensitive peptides tagged a FRET Cy5 acceptor. Upon addition of H2O2, the system was lighted with green fluorescence emission (555 nm), further triggering a brighter red fluorescent emission (672 nm, belong to Cy5 acceptor), owing to FRET. In contrast, in the prescence of MMP2, the FRET was turned off, due to special cleavage of the peptide linker. The stimulation with H2O2 made probe-loaded living cells emit multicolor fluorescence: mainly red fluorescence in normal RAW264.7 cells and poorly-invasive MCF7 cells; only green fluorescence in highly-invasive MDA-MA-231 cells, owing to different expression of MMP2. This means that after activation of H2O2, probe can be used to distinguish MDA-MA-231 cells from RAW264.7 macrophages and MCF7 cells. Therefore, so multicolor fluorescent probe is a powerful tool in monitoring cancer invasion and metastasis, which will provide precision information for cancer control and cure.

PMID: 31657199 DOI: 10.1021/acs.analchem.9b03731
Select item 31656976
5.
Skeletal Radiol. 2019 Oct 28. doi: 10.1007/s00256-019-03325-7. [Epub ahead of print]
Unusual manifestations of diffuse-type tenosynovial giant cell tumor in two patients: importance of radiologic-pathologic correlation.
Dundar A1, Young JR1, Wenger DE1, Inwards CY2, Broski SM3.
Author information
1
Department of Radiology, Mayo Clinic, Charlton Building North, 1st Floor, 200 First Street SW, Rochester, MN, 55905, USA.
2
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA.
3
Department of Radiology, Mayo Clinic, Charlton Building North, 1st Floor, 200 First Street SW, Rochester, MN, 55905, USA. Broski.stephen@mayo.edu.
Abstract
Diffuse-type tenosynovial giant cell tumor (TSGCT) is a rare, locally aggressive neoplasm. It most commonly occurs in the knee, followed by the hip, and has distinctive imaging features, including mass-like foci of low T2 signal intensity, "blooming" on gradient-echo MRI, and pronounced uptake on FDG PET/CT. Histologically, TSGCT demonstrates a neoplastic population of mononuclear cells admixed with hemosiderin-laden macrophages, foamy histiocytes, inflammatory cells, and osteoclast-like giant cells. In cases where diffuse-type TSGCT presents in an uncommon location or with atypical features, the imaging diagnosis may be challenging. Furthermore, because of its polymorphous appearance, it may be mistaken microscopically for other neoplastic and non-neoplastic histiocytic lesions. Herein, we present two cases of diffuse-type TSGCT presenting as large masses, and underscore the importance of radiologic-pathologic correlation for accurate diagnosis.

KEYWORDS:
Histiocytosis; Pigmented villonodular synovitis; Tenosynovial giant cell tumor

PMID: 31656976 DOI: 10.1007/s00256-019-03325-7
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Select item 31656879
6.
J Immunol Regen Med. 2019 Mar;3:26-35. doi: 10.1016/j.regen.2019.01.001. Epub 2019 Feb 1.
Matrix bound nanovesicle-associated IL-33 activates a pro-remodeling macrophage phenotype via a non-canonical, ST2-independent pathway.
Hussey GS1,2, Dziki JL1,2, Lee YC1,3, Bartolacci JG1,3, Behun M1, Turnquist HR1,2,4,5, Badylak SF1,2,3.
Author information
1
McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Suite 300, Pittsburgh, PA 15219-3110, USA.
2
Department of Surgery, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
3
Department of Bioengineering, University of Pittsburgh, 3700 O'Hara Street, Pittsburgh, PA, 15261, USA.
4
Thomas E. Starzl Transplantation Institute, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
5
Department of Immunology, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian Hospital, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
Abstract
The regenerative healing response of injured skeletal muscle is dependent upon an appropriately timed switch from a local type-I to a type-II immune response. Biologic scaffolds derived from extracellular matrix (ECM) have been shown to facilitate a macrophage phenotype transition that leads to downstream site-appropriate functional tissue deposition and myogenesis. However, the mechanisms by which ECM directs the switching of immune cell phenotype are only partially understood. Herein, we provide the first evidence that matrix bound nanovesicles (MBV) embedded within ECM-scaffolds are a rich and stable source of interleukin-33 (IL-33), an alarmin/cytokine with emerging reparative properties. We show that IL-33 encapsulated within MBV bypass the classical IL33/ST2 receptor signaling pathway to direct macrophage differentiation into the reparative, pro-remodeling M2 phenotype, which in turn facilitates myogenesis of skeletal muscle progenitor cells. Our results suggest the potential of IL-33+ MBV as a clinical therapy to augment the restorative efficacy of existing ECM-based and non-ECM based approaches.

KEYWORDS:
Extracellular Matrix; Interleukin-33; Macrophage polarization; Matrix bound nanovesicles

PMID: 31656879 PMCID: PMC6814021 [Available on 2020-03-01] DOI: 10.1016/j.regen.2019.01.001
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Conflict of interest statement
Select item 31656675
7.
J Thorac Dis. 2019 Sep;11(9):4005-4017. doi: 10.21037/jtd.2019.09.03.
Elevation of pulmonary CD163+ and CD204+ macrophages is associated with the clinical course of idiopathic pulmonary fibrosis patients.
Nouno T1, Okamoto M1, Ohnishi K2, Kaieda S1, Tominaga M1, Zaizen Y1, Ichiki M3, Momosaki S4, Nakamura M1, Fujimoto K5, Fukuoka J6, Shimizu S7, Komohara Y2, Hoshino T1.
Author information
1
Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, Asahi-machi, Kurume, Japan.
2
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Honjo, Chuou-ku, Kumamoto, Japan.
3
Department of Respirology, National Hospital Organization Kyushu Medical Center, Jigyohama, Chuou-ku, Fukuoka, Japan.
4
Department of Pathology, National Hospital Organization Kyushu Medical Center, Jigyohama, Chuou-ku, Fukuoka, Japan.
5
Department of Radiology and Center for Diagnostic Imaging, Kurume University School of Medicine, Asahi-machi, Kurume, Japan.
6
Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto, Nagasaki, Japan.
7
Department of Pathology, Kindai University Faculty of Medicine, Ohnohigashi, Osakasayama, Osaka, Japan.
Abstract
BACKGROUND:
M2-like/repair macrophages are thought to contribute to fibrotic process of idiopathic pulmonary fibrosis (IPF). We analyzed the association between pulmonary accumulation of M2-like macrophages and survival in IPF patients.

METHODS:
Lung tissues were obtained by surgical lung biopsy from patients with IPF (n=16), nonspecific interstitial pneumonia (NSIP, n=8) and control subjects (n=14). Samples were also obtained at autopsy from 9 patients who died of acute exacerbation (AE) of IPF. Lung specimens and/or human peripheral blood mononuclear cells-derived macrophages were evaluated by immunohistochemistry for expression of CD68 (pan-macrophage marker), CD163, and CD204 (M2-like macrophage markers), and by in situ mRNA hybridization and ELISA for production of transforming growth factor-β1 (TGF-β1).

RESULTS:
CD68+, CD163+, and CD204+ cell counts and CD163+/CD68+ and CD204+/CD68+ cell ratios were comparable in IPF and NSIP lung tissues and significantly higher than in control tissues. IPF-AE lung samples contained significantly elevated CD68+ and CD163+ cell counts and CD163+/CD68+ cell ratio compared with IPF samples, whereas CD204+ cell counts and CD204+/CD68+ cells ratio did not differ. High CD163+/CD68+ and CD204+/CD68+ cell ratios were significantly associated with shorter overall survival and time-to-AE in IPF patients. In vitro-differentiated human CD163+ and CD204+ macrophages both secreted TGF-β1; however, the novel IPF drug pentraxin 2/serum amyloid protein could suppress secretion only by CD204+ macrophages.

CONCLUSIONS:
Pulmonary accumulation of CD163+ and CD204+ macrophages is associated with worse clinical course in IPF patients. Suppression of macrophage activation and TGF-β1 secretion may be a potential therapeutic target for IPF.

2019 Journal of Thoracic Disease. All rights reserved.

KEYWORDS:
Acute exacerbation (AE); CD163; CD204; idiopathic pulmonary fibrosis (IPF); macrophages; transforming growth factor (TGF)

PMID: 31656675 PMCID: PMC6790423 DOI: 10.21037/jtd.2019.09.03
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Conflict of interest statement
Select item 31656131
8.
Circ Res. 2019 Oct 28. doi: 10.1161/CIRCRESAHA.119.315932. [Epub ahead of print]
Mitochondrial Protein Poldip2 Controls VSMC Differentiated Phenotype by O-Linked GlcNAc Transferase-Dependent Inhibition of a Ubiquitin Proteasome System.
Paredes F1, Williams HC1, Quintana RA1, San Martin A1.
Author information
1
Medicine, Emory University, UNITED STATES.
Abstract
Rationale: The mitochondrial protein polymerase interacting protein 2 (Poldip2) is required for the activity of the tricarboxylic acid (TCA) cycle. As a consequence, Poldip2 deficiency induces metabolic reprograming with repressed mitochondrial respiration and increased glycolytic activity. Though homozygous deletion of Poldip2 is lethal, heterozygous mice are viable and show protection against aneurysm and injury-induced neointimal hyperplasia, diseases linked to loss of VSMC differentiation. Thus, we hypothesize that the metabolic reprograming induced by Poldip2 deficiency controls VSMC differentiation. Objective: To determine the role of Poldip2-mediated metabolic reprograming in phenotypic modulation of VSMC. Methods and Results: We show that Poldip2 deficiency in vascular smooth muscle in vitro and in vivo induces the expression of the serum response factor (SRF), Myocardin, and MRTFA and dramatically represses KLF4. Consequently, Poldip2-deficient VSMC and mouse aorta express high levels of contractile proteins and, more significantly, these cells do not dedifferentiate nor acquire macrophage-like characteristics when exposed to Cholesterol or PDGF. Regarding the mechanism, we found that Poldip2 deficiency upregulates the hexosamine biosynthetic pathway and OGT-mediated protein O-GlcNAcylation. Increased protein glycosylation causes the inhibition of a nuclear UPS responsible for SRF stabilization and KLF4 repression and is required for the establishment of the differentiated phenotype in Poldip2-deficient cells. Conclusions: Our data show that Poldip2 deficiency induces a highly differentiated phenotype in VSMCs through a mechanism that involves regulation of metabolism and proteostasis. Additionally, our study positions mitochondria-initiated signaling as key element of the VSMC differentiation programs that can be targeted to modulate VSMC phenotype during vascular diseases.

KEYWORDS:
OGT; Poldip2

PMID: 31656131 DOI: 10.1161/CIRCRESAHA.119.315932
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Select item 31655989
9.
Bull Exp Biol Med. 2019 Oct 26. doi: 10.1007/s10517-019-04616-8. [Epub ahead of print]
Effect of Apoptotic Neutrophils on the Production of Erythropoietin, MMP-9, and TIMP-1 in Cultures of Human Macrophages.
Sakhno LV1, Shevela EY2, Lykov AP3, Poveshchenko OV3, Ostanin AA2, Chernykh ER2.
Author information
1
Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia. lsahno53@mail.ru.
2
Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia.
3
Research Institute of Clinical and Experimental Lymphology, Affiliated Branch of Federal Research Center Institute of Cytology and Genetics, Novosibirsk, Russia.
Abstract
We studied the effect of apoptotic neutrophils on the production of erythropoietin, MMP-9, and TIMP-1 by GM-CSF-induced human macrophages. GM-CSF-induced macrophages spontaneously produce erythropoietin and secrete MMP-9 and TIMP-1. Polarization of these macrophages towards the M2-like phenotype after exposure to apoptotic neutrophils considerably increased the production of erythropoietin; the MMP-9/TIMP-1 ratio tended to increase under these conditions due to a decrease in TIMP-1.

KEYWORDS:
MMP-9; TIMP-1; efferocytosis; erythropoietin; human macrophages

PMID: 31655989 DOI: 10.1007/s10517-019-04616-8
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Select item 31655617
10.
Retrovirology. 2019 Oct 26;16(1):29. doi: 10.1186/s12977-019-0491-0.
Effect of induced dNTP pool imbalance on HIV-1 reverse transcription in macrophages.
Shepard C1, Xu J1, Holler J1, Kim DH2, Mansky LM3, Schinazi RF1, Kim B4,5.
Author information
1
Department of Pediatrics, School of Medicine, Emory University, 1760 Haygood Drive E432, Atlanta, GA, 30322, USA.
2
School of Pharmacy, Kyung-Hee University, Seoul, South Korea.
3
Institute for Molecular Virology, University of Minnesota, Minneapolis, MN, USA.
4
Department of Pediatrics, School of Medicine, Emory University, 1760 Haygood Drive E432, Atlanta, GA, 30322, USA. baek.kim@emory.edu.
5
Center for Drug Discovery, Children's Healthcare of Atlanta, Atlanta, GA, USA. baek.kim@emory.edu.
Abstract
BACKGROUND:
Terminally differentiated/nondividing macrophages, a key target cell type of HIV-1, harbor extremely low dNTP concentrations established by a host dNTP triphosphohydrolase, SAM domain and HD domain containing protein 1 (SAMHD1). We tested whether the induction of dNTP pool imbalance can affect HIV-1 replication in macrophages. For this test, we induced a large dNTP pool imbalance by treating human primary monocyte derived macrophages with either one or three of the four deoxynucleosides (dNs), which are phosphorylated to dNTPs in cells, to establish two different dNTP imbalance conditions in macrophages.

RESULTS:
The transduction efficiency and 2-LTR circle copy number of HIV-1 GFP vector were greatly diminished in human primary macrophages treated with the biased dN treatments, compared to the untreated macrophages. We also observed the induced dNTP bias blocked the production of infectious dual tropic HIV-1 89.6 in macrophages. Moreover, biochemical DNA synthesis by HIV-1 reverse transcriptase was significantly inhibited by the induced dNTP pool imbalance. Third, the induced dNTP bias increased the viral mutant rate by approximately 20-30% per a single cycle infection. Finally, unlike HIV-1, the single dN treatment did not significantly affect the transduction of SIVmac239-based GFP vector encoding Vpx in macrophages. This is likely due to Vpx, which can elevate all four dNTP levels even with the single dN treatment.

CONCLUSION:
Collectively, these data suggest that the elevated dNTP pool imbalance can induce kinetic block and mutation synthesis of HIV-1 in macrophages.

KEYWORDS:
HIV-1; Macrophages; Mutagenesis; Reverse transcription; SAMHD1; dNTP pool imbalance

PMID: 31655617 DOI: 10.1186/s12977-019-0491-0
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Grant support
Select item 31655481
11.
Food Chem. 2019 Oct 18;308:125666. doi: 10.1016/j.foodchem.2019.125666. [Epub ahead of print]
Organic acid conjugated phenolic compounds of hardy kiwifruit (Actinidia arguta) and their NF-κB inhibitory activity.
Ahn JH1, Park Y2, Jo YH1, Kim SB1, Yeon SW1, Kim JG1, Turk A1, Song JY1, Kim Y1, Hwang BY1, Lee MK3.
Author information
1
College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea.
2
Division of Special Purpose Trees, National Institute of Forest Science, Suwon 16631, Republic of Korea.
3
College of Pharmacy, Chungbuk National University, Cheongju 28160, Republic of Korea. Electronic address: mklee@chungbuk.ac.kr.
Abstract
Nine new compounds, argutinosides A-I (1-9) together with 20 known compounds (10-29), were isolated from the fruits of Actinidia arguta. Using spectral analysis, the structures of the isolated compounds were identified as 10 succinic acid derivatives, 11 quinic acid derivatives, two shikimic acid derivatives and six citric acid derivatives. The NF-κB transcriptional inhibitory activity of the compounds was evaluated using RAW 264.7 macrophages cells induced by lipopolysaccharide. Among four groups of different organic acid derivatives, the quinic acid derivatives inhibited NF-κB transcriptional activity with an IC50 value of 4.0 μM. Fruit is rich in organic acid and secondary metabolites, which differ depending on the type of fruit. Our present study showed the presence of various organic acids conjugates including nine new 2-methylsuccinic acid phenolic conjugates in kiwiberry and compared their biological activities. This will contribute to application of kiwiberry and also the diversity of different fruits.

Copyright © 2019 Elsevier Ltd. All rights reserved.

KEYWORDS:
1,5,6-Trimethyl citrate (PubChem CID: 74112); 2-methylsuccinic acid derivatives; 3-O-trans-p-Coumaroyl shikimic acid (PubChem CID: 5280555); Actinidia arguta; Citric acid derivatives; NF-κB transcriptional inhibitory activity; Quinic acid derivatives; Shikimic acid derivatives

PMID: 31655481 DOI: 10.1016/j.foodchem.2019.125666
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Select item 31655343
12.
Int Immunopharmacol. 2019 Oct 23;77:105944. doi: 10.1016/j.intimp.2019.105944. [Epub ahead of print]
Necroptosis in pulmonary macrophages mediates lipopolysaccharide-induced lung inflammatory injury by activating ZBP-1.
Du XK1, Ge WY2, Jing R3, Pan LH4.
Author information
1
Department of Anesthesiology, Tumor Hospital of Guangxi Medical University, Nanning, China; Laboratory of Perioperative Medicine Research, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: duxueke@gxmu.edu.cn.
2
Department of Anesthesiology, Tumor Hospital of Guangxi Medical University, Nanning, China; Laboratory of Perioperative Medicine Research, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China.
3
Department of Anesthesiology, Tumor Hospital of Guangxi Medical University, Nanning, China; Laboratory of Perioperative Medicine Research, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: jingren890323@outlook.com.
4
Department of Anesthesiology, Tumor Hospital of Guangxi Medical University, Nanning, China; Laboratory of Perioperative Medicine Research, Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, China. Electronic address: plinghui@hotmail.com.
Abstract
Z-DNA combined protein-1 (ZBP-1), an important necroptosis regulator, activates necrosis-associated inflammation and immune response. Increased ZBP-1 expression in necroptosis-associated inflammation correlates with activation of receptor interacting protein kinase (RIPK1)/RIPK3 and nuclear factor (NF)-κB. Here we explored the role of ZBP-1-mediated necroptosis in lipopolysaccharide (LPS)-induced lung injury. Bone marrow-derived macrophages (BMDMs) transfected with a small interfering RNA against ZBP-1 or scrambled control RNA were administered to mice that had been depleted of alveolar macrophages (AMs). Then the animals were treated with E. coli LPS (2.0 mg/kg) or phosphate-buffered saline by intratracheal instillation for 48 h. LPS-induced lung inflammatory injury was verified, and the mRNA and protein expression of ZBP-1, RIPK1/RIPK3 and NF-κB in AMs were then assessed by Western blot and real time-quantitative polymerase chain reaction. In mechanistic studies in vitro, BMDM cultures were treated with different concentrations of LPS for 24 h, and the expression of ZBP-1, RIPK1/RIPK3 and NF-κB were assessed. LPS activated ZBP-1-mediated necroptosis, primarily in AMs. This activation and associated lung inflammatory injury were much weaker after AMs depletion or silencing of ZBP-1 in BMDMs, which correlated with down-regulation of RIPK1/RIPK3. These in vivo findings were confirmed in experiments with cultures of BMDMs. In conclusion, LPS induces lung inflammation and injury by activating ZBP-1-mediated necroptosis and release of pro-inflammatory cytokines by macrophages.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

KEYWORDS:
Lipopolysaccharide-induced lung injury; Necroptosis; ZBP-1; mitochondrial DNA

PMID: 31655343 DOI: 10.1016/j.intimp.2019.105944
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Select item 31655342
13.
Int Immunopharmacol. 2019 Oct 23;77:105956. doi: 10.1016/j.intimp.2019.105956. [Epub ahead of print]
LOX-1 is involved in TLR2 induced RANKL regulation in peri-implantitis.
Zhang Q1, Liu J2, Ma L2, Bai N2, Xu H3.
Author information
1
Department of Prosthodontics, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China. Electronic address: dentistqianzhang@126.com.
2
Department of Prosthodontics, The Affiliated Hospital of Qingdao University, Qingdao, Shandong Province, China.
3
Department of Pathology, ZiBo Central Hospital, ZiBo, Shandong Province, China.
Abstract
PURPOSE:
To explore whether receptor activator of nuclear factor kappa-B ligand (RANKL) is involved in the nosogenesis of peri-implantitis and to reveal the regulatory mechanism in Porphyromonas gingivalis induced RANKL production.

METHODS:
Therefore, we collected peri-implant crevicular fluid (PICF) and gingival tissues from healthy implants and peri-implantitis patients. The expression of RANKL in samples was tested by ELISA, Western blot and immunofluorescence staining. The production of RANKL in THP-1 macrophages stimulated with P. gingivalis was detected by qRT-PCR and Western blot. Then macrophages were pre-treated with neutralizing antibodies of Toll-like receptor 2 (TLR2) or lectin-type oxidized LDL receptor 1 (LOX-1) and inhibitors of TLR2, LOX-1 or Erk1/2 before P. gingivalis stimulation to evaluate the roles of TLR2, LOX-1 and Erk1/2 in RANKL production by qRT-PCR and Western blot.

RESULTS:
The protein level of RANKL was higher in PICF of peri-implantitis patients than healthy implants. We observed increased RANKL expression in P. gingivalis infected macrophages compared to controls. RANKL induced by P. gingivalis stimulation was mediated by TLR2 and Erk1/2 signaling pathway in THP-1 macrophages. LOX-1 is involved in TLR2 induced RANKL expression.

CONCLUSION:
RANKL was involved in peri-implantitis, and regulated by TLR2, LOX-1 and Erk1/2 signaling against P. gingivalis infection. As the novel inflammation pathway triggers, TLR2 and LOX-1 which mediate RANKL production seems to be potential drug targets of peri-implantitis.

Copyright © 2019 Elsevier B.V. All rights reserved.

KEYWORDS:
LOX-1; Porphyromonas gingivalis; RANKL; TLR2; peri-implantitis

PMID: 31655342 DOI: 10.1016/j.intimp.2019.105956
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Select item 31655340
14.
Int Immunopharmacol. 2019 Oct 23;77:105940. doi: 10.1016/j.intimp.2019.105940. [Epub ahead of print]
Macrophages-derived p38α promotes the experimental severe acute pancreatitis by regulating inflammation and autophagy.
Fan HN1, Chen W1, Fan LN2, Wu JT3, Zhu JS4, Zhang J5.
Author information
1
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
2
Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen 361004, China.
3
Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou 310000, China.
4
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: zhujs1803@163.com.
5
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China. Electronic address: jing5522724@163.com.
Abstract
BACKGROUND:
Severe acute pancreatitis (SAP) is a common threat to human health. In the present study, we aimed to investigate the underlying mechanisms by which p38α in macrophages contributes to SAP. We used conditional knockout of p38α in macrophages and p38 MAPK inhibitors to understand the effects of p38α in macrophages on caerulein-induced inflammatory responses in SAP mice models.

METHODS AND MATERIALS:
Wild-type (WT) mice were randomly divided into three groups: a control group, SAP group, and SAP + p38MAPK inhibitor (SB203580) group, and mice with a conditional knockout (KO) of p38α in macrophages were included in a KO + SAP group. We evaluated pancreatic pathology and ultra-structure by hematoxylin and eosin staining and transmission electron microscopy. The pulmonary wet-to-dry weight ratio was calculated. The serum levels of TNF-α and IL-1β were determined by ELISA. The mRNA and protein expression of inflammatory cytokines TNF-α, IL-1β, IL-17, IL-18, MIF, and MCP-1 in pancreatic tissues were tested by qRT-PCR and immunohistochemistry analysis. The protein expression of p38, caspase-1, ULK1, LC3B and p62 in pancreatic tissues was examined by Western blotting.

RESULTS:
The results indicated that the severity of SAP as well as the expression of the cytokines TNF-α, IL-1β, IL-17, IL-18 and MCP-1 were higher in the SAP group than those in the control group, but were lower in the SAP + SB203580 and KO + SAP groups as compared with the SAP group. The protein expression of p38, caspase-1, LC3B and p62 was increased in the SAP group than that in the control group, but this result was reversed in the SAP + SB203580 and KO + SAP groups as compared with the SAP group. In addition, the ULK1 level was significantly lower in the SAP group than that in the control group, but was increased in the SAP + SB203580 and KO + SAP groups as compared with the SAP group.

CONCLUSIONS:
Our findings demonstrated that, macrophage derived p38α promoted the experimental severe acute pancreatitis by regulating inflammation and autophagy.

Copyright © 2019 Elsevier B.V. All rights reserved.

KEYWORDS:
Acute pancreatitis; Autophagy; Inflammation; Macrophages; P38α; ULK1

PMID: 31655340 DOI: 10.1016/j.intimp.2019.105940
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Select item 31655310
15.
Biomed Pharmacother. 2019 Oct 23;120:109523. doi: 10.1016/j.biopha.2019.109523. [Epub ahead of print]
MicroRNA-148b-colony-stimulating factor-1 signaling-induced tumor-associated macrophage infiltration promotes hepatocellular carcinoma metastasis.
Ke M1, Zhang Z2, Cong L3, Zhao S1, Li Y3, Wang X4, Lv Y5, Zhu Y6, Dong J7.
Author information
1
National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi Province, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi Province, China.
2
Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, China.
3
Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi Province, China.
4
Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
5
National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi Province, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi Province, China; Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi Province, China.
6
Department of General Surgery, Huashan Hospital, Cancer Metastasis Institute, Fudan University, 12 Urumqi Road (M), Shanghai 200040, China. Electronic address: xj_zy2009@163.com.
7
Department of Vascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi Province, China; National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi Province, China; Institute of Advanced Surgical Technology and Engineering, The First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, 710061, Shaanxi Province, China. Electronic address: dongjiandoctor@126.com.
Abstract
BACKGROUND:
MicroRNAs (miRNAs) are small non-coding molecules that exhibit important regulatory roles in various biological or cellular functions, including tumor metastasis. However, the detailed mechanisms of the expression and functions of miRNAs in hepatocellular carcinoma (HCC) have not yet been completely investigated.

METHODS:
In this study, the levels of miR-148b in HCC cells and patient specimens were determined using qPCR assays. MiR-148b-overexpressing HCC cells were used to investigate the effect of miR-148b in vitro and in vivo. The relationship between the expression of miR-148b and colony stimulating factor-1 (CSF1) in HCC patients and the infiltration of macrophages into the tumor microenvironment were assessed by immunohistochemical staining.

RESULTS:
MiR-148b expression was decreased in metastatic HCC cells. A positive association between downregulated miR-148b expression and several clinical parameters, including recurrence, metastasis, and poor prognosis, was observed in patients with HCC. The results of bio-functional experiments indicated that the biological characteristics of HCC cells were not affected by miR-148b deficiency in vitro. However, miR-148b deficiency significantly enhanced the progression and metastasis of HCC in nude mice. By analyzing the gene expression profiles, we demonstrated that CSF1 was regulated by miR-148b and that miR-148b deficiency promoted HCC growth and metastasis through CSF1/CSF1 receptor (CSF1R)-mediated tumor-associated macrophage (TAM) infiltration. These results were supported by the negative relationship between miR-148b and CSF1 expression and TAM infiltration in HCC patients. Moreover, HCC patients with low miR-148b levels and high TAM infiltration were associated with poorer prognosis.

CONCLUSION:
MiR-148b-CSF1 signaling-induced TAM infiltration promotes HCC metastasis. Therefore, miR-148b plays a suppressor role in HCC and might be a potential prognostic factor and therapeutic candidate for HCC.

Copyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.

KEYWORDS:
Colony-stimulating factor-1; Macrophage; MicroRNA-148b; Microenvironment

PMID: 31655310 DOI: 10.1016/j.biopha.2019.109523
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Select item 31655269
16.
Fish Shellfish Immunol. 2019 Oct 23. pii: S1050-4648(19)31012-5. doi: 10.1016/j.fsi.2019.10.043. [Epub ahead of print]
Functional characterization of galectin-3 from Nile tilapia (Oreochromis niloticus) and its regulatory role on monocytes/macrophages.
Niu J1, Huang Y2, Liu X1, Luo G1, Tang J2, Wang B2, Lu Y2, Cai J3, Jian J4.
Author information
1
College of Fishery, Guangdong Ocean University, Zhanjiang, 524088, China; Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, China; Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, China.
2
College of Fishery, Guangdong Ocean University, Zhanjiang, 524088, China; Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, China; Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Guangdong Provincial Engineering Research Center for Aquatic Animal Health Assessment, Shenzhen, 518120, China.
3
College of Fishery, Guangdong Ocean University, Zhanjiang, 524088, China; Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, China; Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Guangdong Provincial Engineering Research Center for Aquatic Animal Health Assessment, Shenzhen, 518120, China; Guangxi Key Lab for Marine Biotechnology, Guangxi Institute of Oceanography, Guangxi Academy of Sciences, Beihai, 536000, China. Electronic address: matrix924@foxmail.com.
4
College of Fishery, Guangdong Ocean University, Zhanjiang, 524088, China; Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, China; Guangdong Key Laboratory of Control for Diseases of Aquatic Economic Animals, Zhanjiang, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Guangdong Provincial Engineering Research Center for Aquatic Animal Health Assessment, Shenzhen, 518120, China. Electronic address: jianjc@gdou.edu.cn.
Abstract
Galectin-3 is a kind of β-galactoside-binding lectin involved in host defense against pathogen infection. However, the immune functions of fish galectin-3 remain poorly understood. In this study, the roles of a fish galectin-3 (OnGal-3) from Nile tilapia (Oreochromis niloticus) on the binding activity on bacterial pathogens or PAMPs, the agglutinating activity on bacterial pathogens and the regulatory effects on monocytes/macrophages activity were investigated. After in vitro challenge of Streptococcus agalactiae and Aeromonas hydrophila, OnGal-3 expressions were significantly up-regulated in monocytes/macrophages. In addition, recombinant OnGal-3(rOnGal-3) protein showed strong binding activity on bacterial pathogens or PAMPs. Also, rOnGal-3 agglutinated Gram-positive and Gram-negative bacteria. Moreover, rOnGal-3 could induce the inflammatory factors expressions in monocytes/macrophages and enhance phagocytosis and respiratory burst activity of monocytes/macrophages. These results suggest that fish galectin-3 participates in anti-bacterial immune response through recognizing pathogens and modulating monocytes/macrophages activity.

Copyright © 2019. Published by Elsevier Ltd.

KEYWORDS:
Galectin-3; Inflammation; Monocytes/macrophages; Nile tilapia; Phagocytosis

PMID: 31655269 DOI: 10.1016/j.fsi.2019.10.043
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Select item 31655257
17.
iScience. 2019 Oct 9;21:68-83. doi: 10.1016/j.isci.2019.10.015. [Epub ahead of print]
Tracking Dynamics of Spontaneous Tumors in Mice Using Photon-Counting Computed Tomography.
Cassol F1, Portal L1, Richelme S2, Dupont M1, Boursier Y1, Arechederra M2, Auphan-Anezin N3, Chasson L3, Laprie C3, Fernandez S4, Balasse L4, Lamballe F2, Dono R2, Guillet B4, Lawrence T3, Morel C5, Maina F6.
Author information
1
Aix-Marseille Univ, CNRS/IN2P3, CPPM (Centre de Physique des Particules de Marseille), 163 Avenue de Luminy, case 902, Marseille 13009, France.
2
Aix-Marseille Univ, CNRS, IBDM (Developmental Biology Institute of Marseille), 163 Avenue de Luminy, case 907, Marseille 13009, France.
3
Aix-Marseille Univ, CNRS, INSERM, CIML, Marseille 13009, France.
4
Aix-Marseille Univ, CERIMED, Marseille 13005, France.
5
Aix-Marseille Univ, CNRS/IN2P3, CPPM (Centre de Physique des Particules de Marseille), 163 Avenue de Luminy, case 902, Marseille 13009, France. Electronic address: morel@cppm.in2p3.fr.
6
Aix-Marseille Univ, CNRS, IBDM (Developmental Biology Institute of Marseille), 163 Avenue de Luminy, case 907, Marseille 13009, France. Electronic address: flavio.maina@univ-amu.fr.
Abstract
Computed tomography is a powerful medical imaging modality for longitudinal studies in cancer to follow neoplasia progression and evaluate anticancer therapies. Here, we report the generation of a photon-counting micro-computed tomography (PC-CT) method based on hybrid pixel detectors with enhanced sensitivity and precision of tumor imaging. We then applied PC-CT for longitudinal imaging in a clinically relevant liver cancer model, the Alb-R26Met mice, and found a remarkable heterogeneity in the dynamics for tumors at the initiation phases. Instead, the growth curve of evolving tumors exhibited a comparable exponential growth, with a constant doubling time. Furthermore, longitudinal PC-CT imaging in mice treated with a combination of MEK and BCL-XL inhibitors revealed a drastic tumor regression accompanied by a striking remodeling of macrophages in the tumor microenvironment. Thus, PC-CT is a powerful system to detect cancer initiation and progression, and to monitor its evolution during treatment.

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

KEYWORDS:
Cancer; Optical Imaging; Optics

PMID: 31655257 DOI: 10.1016/j.isci.2019.10.015
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Select item 31655030
18.
Eur J Pharmacol. 2019 Oct 23:172748. doi: 10.1016/j.ejphar.2019.172748. [Epub ahead of print]
Fisetin, via CKIP-1/REGγ, limits oxidized LDL-induced lipid accumulation and senescence in RAW264.7 macrophage-derived foam cells.
Jia Q1, Cao H1, Shen D2, Yan L1, Chen C1, Xing S1.
Author information
1
Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200031, China.
2
Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200031, China. Electronic address: 13818279131@163.com.
Abstract
To test the hypothesis that the flavonoid compound, fisetin, protects macrophages from lipid accumulation and senescence through regulation of casein kinase 2-interacting protein-1 (CKIP-1)/REGγ (11S regulatory particles, 28 kDa proteasome activator, proteasome activator subunit 3) signaling. RAW264.7 macrophage cells were exposed to 100 μg/ml oxidized low-density lipoprotein (ox-LDL) with or without 20 μg/ml fisetin for 24 h. Cell viability was detected by CCK-8 after 1 h. Intracellular lipid accumulation was measured using Oil Red O staining. Total cholesterol (TC) and free cholesterol (FC) contents were measured using assay kits, and cell senescence was inferred by β-gal staining. Protein expression levels of CKIP-1, REGγ, organic cation transporter 1 (Oct-1), lectin-like oxidized LDL receptor-1 (LOX-1), tumor suppressor protein p53 (p53), cell cycle regulatory protein p21 (p21), and multiple tumor suppressor-1 (p16) were detected by immunofluorescence and confirmed by Western blot. Stimulating RAW264.7 macrophage cells with 100 μg/ml ox-LDL for 24 h induced the formation of foam cells, increased intracellular lipid accumulation, increased TC and FC content, and promoted cell senescence. Furthermore, cells induced with 100 μg/ml ox-LDL for 24 h showed decreased CKIP-1 and REGγ protein, while the expressions of Oct-1, LOX-1, p53, p21 and p16 were increased. In contrast, treatment with 20 μg/ml fisetin reversed 100 μg/ml ox-LDL effects to increase cell viability, and decrease β-gal staining, intracellular lipid levels and TC and FC levels. These beneficial effects were associated with increased CKIP-1 and REGγ and decreased Oct-1, LOX-1, p53, p21, and p16 protein expression. Results indicated that fisetin limited ox-LDL-mediated lipid accumulation and senescence in RAW264.7 macrophage-derived foam cells. The mechanism underlying these effects may involve regulation of CKIP-1/REGγ signaling.

Copyright © 2019. Published by Elsevier B.V.

KEYWORDS:
CKIP-1/REGγ signaling; Fisetin; Lipid accumulation; RAW264.7; Senescence

PMID: 31655030 DOI: 10.1016/j.ejphar.2019.172748
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Select item 31654988
19.
Phytomedicine. 2019 Sep 16;65:153091. doi: 10.1016/j.phymed.2019.153091. [Epub ahead of print]
Total Glucosides of Paeony protects against collagen-induced mouse arthritis via inhibiting follicular helper T cell differentiation.
Li H1, Cao XY2, Dang WZ2, Jiang B2, Zou J3, Shen XY4.
Author information
1
School of Kinesiology, Shanghai University of Sport, No. 188, Hengren Road, Yangpu Aera, Shanghai 200438, China; Department of Pharmacology, School of Pharmaceutical Sciences, Fudan University, No. 826, Zhangheng Road, Pudong New Area, Shanghai 201203, China.
2
Department of Pharmacology, School of Pharmaceutical Sciences, Fudan University, No. 826, Zhangheng Road, Pudong New Area, Shanghai 201203, China.
3
School of Kinesiology, Shanghai University of Sport, No. 188, Hengren Road, Yangpu Aera, Shanghai 200438, China. Electronic address: zoujun777@126.com.
4
School of Kinesiology, Shanghai University of Sport, No. 188, Hengren Road, Yangpu Aera, Shanghai 200438, China; Department of Pharmacology, School of Pharmaceutical Sciences, Fudan University, No. 826, Zhangheng Road, Pudong New Area, Shanghai 201203, China. Electronic address: shxiaoy@fudan.edu.cn.
Abstract
BACKGROUND:
The development of rheumatoid arthritis (RA) is related to germinal center (GC) response and autoreactive T cells, which mediate adaptive immunity and play an important role in stimulating the production of autoantibodies and pro-inflammatory cytokines by B cells and macrophages. Total Glucosides of Paeony (TGP) has anti-inflammatory, immunomodulatory and analgesic effects and is widely used to treat RA. However, few studies investigated whether the therapeutic effect of TGP is associated with the inhibition of autoimmune response.

PURPOSE:
The aim of this study was to investigate the effects and mechanisms of TGP on RA.

STUDY DESIGN:
Type II collagen-induced arthritis (CIA) mouse model was used, and TGP and paeoniflorin were intragastrically treated.

METHODS:
DBA/1 mice were divided into 5 groups: control, model, positive drug (paeoniflorin) and high- and low-dose TGP group. After 21 days of intragastric administration, the pathological change, inflammation expression and molecular mechanism of each group of mice were detected by Micro-CT, histochemical analysis, ELLSA, Western blot, RT-qPCR and flow cytometry.

RESULTS:
Our study found that TGP treatment effectively improved inflammation and joint destruction in CIA mice. It reduced the production of serum IgG2a and pro-inflammatory cytokines, including serum interleukin (IL)-21, tumor necrosis factor (TNF)-α and IL-6, and the phosphorylation of NF-κB p65 and STAT3 in a dose-dependent manner. More importantly, TGP could suppress the frequency of germinal center B cells and Tfh cells in the spleen.

CONCLUSION:
TGP can not only improve symptoms, but also inhibit bone destruction. The therapeutic effect of TGP on CIA is mainly achieved by inhibiting spleen Tfh cell differentiation and GC formation through STAT3 signaling pathway.

Copyright © 2019 Elsevier GmbH. All rights reserved.

KEYWORDS:
Follicular helper T cells; Rheumatoid arthritis; STAT3; TGP

PMID: 31654988 DOI: 10.1016/j.phymed.2019.153091
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Select item 31654774
20.
Acta Biomater. 2019 Oct 22. pii: S1742-7061(19)30705-6. doi: 10.1016/j.actbio.2019.10.026. [Epub ahead of print]
Evaluation of a polyurethane-reinforced hydrogel patch in a rat right ventricle wall replacement model.
Tao ZW1, Wu S2, Cosgriff-Hernandez EM2, Jacot JG3.
Author information
1
Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
2
Department of Biomedical Engineering, University of Texas at Austin, Austin, TX, USA.
3
Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pediatrics, Children's Hospital Colorado, Aurora, CO, USA. Electronic address: jeffrey.jacot@ucdenver.edu.
Abstract
Congenital heart defects affect about 1% births in the United States. Many of the defects are treated with surgically implanted patches made from inactive materials or fixed pericardium that do not grow with the patients, leading to an increased risk of arrhythmia, sudden cardiac death, and heart failure. This study investigated an angiogenic poly(ethylene glycol) fibrin-based hydrogel reinforced with an electrospun biodegradable poly(ether ester urethane) urea (BPUR) mesh layer that was designed to encourage cell invasion, angiogenesis, and regenerative remodeling in the repair of an artificial defect created onto the rat right ventricle wall. Electrocardiogram signals were analyzed, heart function was measured, and fibrosis, macrophage infiltration, muscularization, vascularization, and defect size were evaluated at 4- and 8-weeks post surgery. Compared with rats with fixed pericardium patches, rats with BPUR-reinforced hydrogel patches had fewer arrhythmias and greater right ventricular ejection fraction and cardiac output, as well as greater left ventricular ejection fraction, fractional shorting, stroke work and cardiac output. Histology and immunofluorescence staining showed less fibrosis and less patch material remaining in rats with BPUR-reinforced hydrogel patches at 4- and 8-weeks. Rats with BPUR-reinforced hydrogel patches also had a greater volume of granular tissue, a greater volume of muscularized tissue, more blood vessels, and a greater number of leukocytes, pan-macrophages, and M2 macrophages at 8 weeks. Overall, this study demonstrated that the engineered BPUR-reinforced hydrogel patch initiated greater regenerative vascular and muscular remodeling with a limited fibrotic response, resulting in fewer incidences of arrhythmia and improved heart function compared with fixed pericardium patches when applied to heal the defects created on the rat right ventricle wall.

Copyright © 2019. Published by Elsevier Ltd.

KEYWORDS:
Cardiac tissue engineering; Congenital heart defects; Fibrin gel; Poly(ether ester urethane) urea; Poly(ethylene glycol); Surgical correction

PMID: 31654774 DOI: 10.1016/j.actbio.2019.10.026
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