48 results on '"Guo, Chang"'
Search Results
2. Sectm1a Facilitates Protection against Inflammation-Induced Organ Damage through Promoting TRM Self-Renewal.
- Author
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Mu X, Fan H, Wang P, Li Y, Domenico K, Li Q, Wang X, Essandoh K, Chen J, Peng T, and Fan GC
- Subjects
- Animals, Glucocorticoid-Induced TNFR-Related Protein genetics, Homeostasis, Membrane Proteins genetics, Mice, Multiple Organ Failure etiology, T-Lymphocytes, Helper-Inducer immunology, Glucocorticoid-Induced TNFR-Related Protein metabolism, Immunologic Memory immunology, Inflammation complications, Macrophages immunology, Membrane Proteins metabolism, Monocytes immunology, Multiple Organ Failure prevention & control
- Abstract
Tissue-resident macrophages (TRMs) are sentinel cells for maintaining tissue homeostasis and organ function. In this study, we discovered that lipopolysaccharide (LPS) administration dramatically reduced TRM populations and suppressed their self-renewal capacities in multiple organs. Using loss- and gain-of-function approaches, we define Sectm1a as a novel regulator of TRM self-renewal. Specifically, at the earlier stage of endotoxemia, Sectm1a deficiency exaggerated acute inflammation-induced reduction of TRM numbers in multiple organs by suppressing their proliferation, which was associated with more infiltrations of inflammatory monocytes/neutrophils and more serious organ damage. By contrast, administration of recombinant Sectm1a enhanced TRM populations and improved animal survival upon endotoxin challenge. Mechanistically, we identified that Sectm1a-induced upregulation in the self-renewal capacity of TRM is dependent on GITR-activated T helper cell expansion and cytokine production. Meanwhile, we found that TRMs may play an important role in protecting local vascular integrity during endotoxemia. Our study demonstrates that Sectm1a contributes to stabling TRM populations through maintaining their self-renewal capacities, which benefits the host immune response to acute inflammation. Therefore, Sectm1a may serve as a new therapeutic agent for the treatment of inflammatory diseases., (Copyright © 2020 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
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3. Sectm1a deficiency aggravates inflammation-triggered cardiac dysfunction through disruption of LXRα signalling in macrophages.
- Author
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Li Y, Deng S, Wang X, Huang W, Chen J, Robbins N, Mu X, Essandoh K, Peng T, Jegga AG, Rubinstein J, Adams DE, Wang Y, Peng J, and Fan GC
- Subjects
- Animals, Cytokines genetics, Cytokines metabolism, Diet, High-Fat, Disease Models, Animal, Gene Expression Regulation, Heart Diseases etiology, Heart Diseases genetics, Heart Diseases physiopathology, Inflammation etiology, Inflammation genetics, Inflammation physiopathology, Inflammation Mediators metabolism, Lipopolysaccharides, Liver X Receptors genetics, Male, Membrane Proteins genetics, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, RAW 264.7 Cells, Rats, Sprague-Dawley, Signal Transduction, Rats, Heart Diseases metabolism, Inflammation metabolism, Liver X Receptors metabolism, Macrophages metabolism, Membrane Proteins deficiency, Ventricular Function, Left
- Abstract
Aims: Cardiac dysfunction is a prevalent comorbidity of disrupted inflammatory homeostasis observed in conditions such as sepsis (acute) or obesity (chronic). Secreted and transmembrane protein 1a (Sectm1a) has previously been implicated to regulate inflammatory responses, yet its role in inflammation-associated cardiac dysfunction is virtually unknown., Methods and Results: Using the CRISPR/Cas9 system, we generated a global Sectm1a-knockout (KO) mouse model and observed significantly increased mortality and cardiac injury after lipopolysaccharide (LPS) injection, when compared with wild-type (WT) control. Further analysis revealed significantly increased accumulation of inflammatory macrophages in hearts of LPS-treated KO mice. Accordingly, ablation of Sectm1a remarkably increased inflammatory cytokines levels both in vitro [from bone marrow-derived macrophages (BMDMs)] and in vivo (in serum and myocardium) after LPS challenge. RNA-sequencing results and bioinformatics analyses showed that the most significantly down-regulated genes in KO-BMDMs were modulated by LXRα, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRα was disrupted in KO-BMDMs when treated with GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines, compared to GW3965-treated WT-cells. Furthermore, using chronic inflammation model of high-fat diet (HFD) feeding, we observed that infiltration of inflammatory monocytes/macrophages into KO-hearts were greatly increased and accordingly, worsened cardiac function, compared to WT-HFD controls., Conclusion: This study defines Sectm1a as a new regulator of inflammatory-induced cardiac dysfunction through modulation of LXRα signalling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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4. Environmentally Relevant Iron Oxide Nanoparticles Produce Limited Acute Pulmonary Effects in Rats at Realistic Exposure Levels.
- Author
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Guo C, Weber RJM, Buckley A, Mazzolini J, Robertson S, Delgado-Saborit JM, Rappoport JZ, Warren J, Hodgson A, Sanderson P, Chipman JK, Viant MR, and Smith R
- Subjects
- Acute Lung Injury chemically induced, Aerosols chemistry, Aerosols toxicity, Air Pollutants toxicity, Animals, Cell Line, Humans, Inflammation chemically induced, Inhalation Exposure, Lung pathology, Particulate Matter toxicity, Rats, Rats, Sprague-Dawley, Acute Lung Injury physiopathology, Inflammation physiopathology, Lung drug effects, Magnetic Iron Oxide Nanoparticles toxicity
- Abstract
Iron is typically the dominant metal in the ultrafine fraction of airborne particulate matter. Various studies have investigated the toxicity of inhaled nano-sized iron oxide particles (FeO
x NPs) but their results have been contradictory, with some indicating no or minor effects and others finding effects including oxidative stress and inflammation. Most studies, however, did not use materials reflecting the characteristics of FeOx NPs present in the environment. We, therefore, analysed the potential toxicity of FeOx NPs of different forms (Fe3 O4 , α-Fe2 O3 and γ-Fe2 O3 ) reflecting the characteristics of high iron content nano-sized particles sampled from the environment, both individually and in a mixture (FeOx -mix). A preliminary in vitro study indicated Fe3 O4 and FeOx -mix were more cytotoxic than either form of Fe2 O3 in human bronchial epithelial cells (BEAS-2B). Follow-up in vitro (0.003, 0.03, 0.3 µg/mL, 24 h) and in vivo (Sprague-Dawley rats, nose-only exposure, 50 µg/m3 and 500 µg/m3 , 3 h/d × 3 d) studies therefore focused on these materials. Experiments in vitro explored responses at the molecular level via multi-omics analyses at concentrations below those at which significant cytotoxicity was evident to avoid detection of responses secondary to toxicity. Inhalation experiments used aerosol concentrations chosen to produce similar levels of particle deposition on the airway surface as were delivered in vitro. These were markedly higher than environmental concentrations. No clinical signs of toxicity were seen nor effects on BALF cell counts or LDH levels. There were also no significant changes in transcriptomic or metabolomic responses in lung or BEAS-2B cells to suggest adverse effects.- Published
- 2021
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5. Tissue-Resident Macrophages in the Control of Infection and Resolution of Inflammation.
- Author
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Mu X, Li Y, and Fan GC
- Subjects
- Homeostasis physiology, Humans, Inflammation pathology, Inflammation etiology, Macrophages physiology
- Abstract
Abstract: Macrophage, as an integral component of the immune system and the first responder to local damage, is on the front line of defense against infection. Over the past century, the prevailing view of macrophage origin states that all macrophage populations resided in tissues are terminally differentiated and replenished by monocytes from bone-marrow progenitors. Nonetheless, this theory has been reformed by ground-breaking discoveries from the past decades. It is now believed that tissue-resident macrophages (TRMs) are originated from the embryonic precursors and seeded in tissue prenatally. They can replenish via self-renewal throughout the lifespan. Indeed, recent studies have demonstrated that tissue-resident macrophages should not be classified by the over-simplified macrophage polarization (M1/M2) dogma during inflammation. Moreover, multiple lines of evidence have indicated that tissue-resident macrophages play critical roles in maintaining tissue homeostasis and facilitating tissue repair through controlling infection and resolving inflammation. In this review, we summarize the properties of resident macrophages in the lung, spleen, and heart, and further highlight the impact of TRM populations on inflammation control and tissue repair. We also discuss the potential role of local proliferation in maintaining a physiologically stable TRM pool in response to acute inflammation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)
- Published
- 2021
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6. GDF3 Protects Mice against Sepsis-Induced Cardiac Dysfunction and Mortality by Suppression of Macrophage Pro-Inflammatory Phenotype.
- Author
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Wang L, Li Y, Wang X, Wang P, Essandoh K, Cui S, Huang W, Mu X, Liu Z, Wang Y, Peng T, and Fan GC
- Subjects
- Adult, Animals, Case-Control Studies, Cell Polarity drug effects, Cytokines biosynthesis, Endotoxins, Growth Differentiation Factor 3 blood, Growth Differentiation Factor 3 genetics, Humans, Inflammation blood, Mice, Inbred C57BL, Models, Biological, Phenotype, RNA, Messenger genetics, RNA, Messenger metabolism, Recombinant Proteins administration & dosage, Recombinant Proteins pharmacology, Sepsis blood, Smad Proteins metabolism, Spleen pathology, Survival Analysis, Treatment Outcome, Growth Differentiation Factor 3 metabolism, Heart physiopathology, Inflammation pathology, Macrophages pathology, Sepsis physiopathology, Sepsis prevention & control
- Abstract
Macrophages are critical for regulation of inflammatory response during endotoxemia and septic shock. However, the mediators underlying their regulatory function remain obscure. Growth differentiation factor 3 (GDF3), a member of transforming growth factor beta (TGF-β) superfamily, has been implicated in inflammatory response. Nonetheless, the role of GDF3 in macrophage-regulated endotoxemia/sepsis is unknown. Here, we show that serum GDF3 levels in septic patients are elevated and strongly correlate with severity of sepsis and 28-day mortality. Interestingly, macrophages treated with recombinant GDF3 protein (rGDF3) exhibit greatly reduced production of pro-inflammatory cytokines, comparing to controls upon endotoxin challenge. Moreover, acute administration of rGDF3 to endotoxin-treated mice suppresses macrophage infiltration to the heart, attenuates systemic and cardiac inflammation with less pro-inflammatory macrophages (M1) and more anti-inflammatory macrophages (M2), as well as prolongs mouse survival. Mechanistically, GDF3 is able to activate Smad2/Smad3 phosphorylation, and consequently inhibits the expression of nod-like receptor protein-3 (NLRP3) in macrophages. Accordingly, blockade of Smad2/Smad3 phosphorylation with SB431542 significantly offsets rGDF3-mediated anti-inflammatory effects. Taken together, this study uncovers that GDF3, as a novel sepsis-associated factor, may have a dual role in the pathophysiology of sepsis. Acute administration of rGDF3 into endotoxic shock mice could increase survival outcome and improve cardiac function through anti-inflammatory response by suppression of M1 macrophage phenotype. However, constitutive high levels of GDF3 in human sepsis patients are associated with lethality, suggesting that GDF3 may promote macrophage polarization toward M2 phenotype which could lead to immunosuppression.
- Published
- 2020
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7. Versatile effects of bacterium-released membrane vesicles on mammalian cells and infectious/inflammatory diseases.
- Author
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Yu YJ, Wang XH, and Fan GC
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- Animals, Communicable Diseases therapy, Extracellular Vesicles chemistry, Extracellular Vesicles immunology, Extracellular Vesicles microbiology, Humans, Vaccines, Acellular therapeutic use, Bacteria metabolism, Communicable Diseases physiopathology, Dendritic Cells metabolism, Extracellular Vesicles metabolism, Inflammation physiopathology, Phagocytes metabolism
- Abstract
Gram-negative bacterium-released outer-membrane vesicles (OMVs) and Gram-positive bacterium-released membrane vesicles (MVs) share significant similarities with mammalian cell-derived MVs (eg, microvesicles and exosomes) in terms of structure and their biological activities. Recent studies have revealed that bacterial OMVs/MVs could (1) interact with immune cells to regulate inflammatory responses, (2) transport virulence factors (eg, enzymes, DNA and small RNAs) to host cells and result in cell injury, (3) enhance barrier function by stimulating the expression of tight junction proteins in intestinal epithelial cells, (4) upregulate the expression of endothelial cell adhesion molecules, and (5) serve as natural nanocarriers for immunogenic antigens, enzyme support and drug delivery. In addition, OMVs/MVs can enter the systemic circulation and induce a variety of immunological and metabolic responses. This review highlights the recent advances in the understanding of OMV/MV biogenesis and their compositional remodeling. In addition, interactions between OMVs/MVs and various types of mammalian cells (ie, immune cells, epithelial cells, and endothelial cells) and their pathological/preventive effects on infectious/inflammatory diseases are summarized. Finally, methods for engineering OMVs/MVs and their therapeutic potential are discussed.
- Published
- 2018
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8. Inhibition of cerebral vascular inflammation by brain endothelium-targeted oligodeoxynucleotide complex.
- Author
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Hu J, Al-Waili D, Hassan A, Fan GC, Xin M, and Hao J
- Subjects
- Animals, Anti-Inflammatory Agents blood, Anti-Inflammatory Agents pharmacokinetics, Aptamers, Nucleotide blood, Aptamers, Nucleotide pharmacokinetics, Brain blood supply, Brain immunology, Cell Hypoxia drug effects, Cell Line, Disease Models, Animal, Drug Design, Drug Evaluation, Preclinical, Endothelial Cells immunology, Glucose deficiency, Goats, Inflammation metabolism, Lipopolysaccharides, Male, Mice, Neuroprotective Agents blood, Neuroprotective Agents pharmacokinetics, Neuroprotective Agents pharmacology, Oligodeoxyribonucleotides blood, Oligodeoxyribonucleotides pharmacokinetics, Tumor Necrosis Factor-alpha, Vasculitis, Central Nervous System metabolism, Anti-Inflammatory Agents pharmacology, Aptamers, Nucleotide pharmacology, Brain drug effects, Endothelial Cells drug effects, Inflammation drug therapy, Oligodeoxyribonucleotides pharmacology, Vasculitis, Central Nervous System drug therapy
- Abstract
The present study generated a novel DNA complex to specifically target endothelial NF-κB to inhibit cerebral vascular inflammation. This DNA complex (GS24-NFκB) contains a DNA decoy which inhibits NF-κB activity, and a DNA aptamer (GS-24), a ligand of transferrin receptor (TfR), which allows for targeted delivery of the DNA decoy into cells. The results indicate that GS24-NFκB was successfully delivered into a murine brain-derived endothelial cell line, bEND5, and inhibited inflammatory responses induced by tumor necrosis factor α (TNF-α) or oxygen-glucose deprivation/re-oxygenation (OGD/R) via down-regulation of the nuclear NF-κB subunit, p65, as well as its downstream inflammatory cytokines, inter-cellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1). The inhibitory effect of the GS24-NFκB was demonstrated by a significant reduction in TNF-α or OGD/R induced monocyte adhesion to the bEND5 cells after GS24-NFκB treatment. Intravenous (i.v.) injection of GS24-'NFκB (15mg/kg) was able to inhibit the levels of phoseph-p65 and VCAM-1 in brain endothelial cells in a mouse lipopolysaccharide (LPS)-induced inflammatory model in vivo. In conclusion, our approach using DNA nanotechnology for DNA decoy delivery could potentially be utilized for inhibition of inflammation in ischemic stroke and other neuro-inflammatory diseases affecting cerebral vasculature., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2016
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9. MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response.
- Author
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Essandoh K, Li Y, Huo J, and Fan GC
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- Animals, Cell Polarity, Humans, Inflammation metabolism, Macrophages cytology, Macrophages immunology, Macrophages physiology, Mice, MicroRNAs genetics, Inflammation immunology, Macrophage Activation immunology, Macrophages metabolism, MicroRNAs metabolism
- Abstract
Monocytes and macrophages are important components of the immune system, specialized in either removing pathogens as part of innate immunity or contributing to adaptive immunity through antigen presentation. Essential to such functions is classical activation (M1) and alternative activation (M2) of macrophages. M1 polarization of macrophages is characterized by production of pro-inflammatory cytokines, antimicrobial and tumoricidal activity, whereas M2 polarization of macrophages is linked to immunosuppression, tumorigenesis, wound repair, and elimination of parasites. MiRNAs are small non-coding RNAs with the ability to regulate gene expression and network of cellular processes. A number of studies have determined miRNA expression profiles in M1 and M2 polarized human and murine macrophages using microarray and RT-qPCR arrays techniques. More specifically, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M1 polarization while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p induce M2 polarization in macrophages by targeting various transcription factors and adaptor proteins. Further, M1 and M2 phenotypes play distinctive roles in cell growth and progression of inflammation-related diseases such as sepsis, obesity, cancer, and multiple sclerosis. Hence, miRNAs that modulate macrophage polarization may have therapeutic potential in the treatment of inflammation-related diseases. This review highlights recent findings in miRNA expression profiles in polarized macrophages from murine and human sources, and summarizes how these miRNAs regulate macrophage polarization. Last, therapeutic potential of miRNAs in inflammation-related diseases through modulation of macrophage polarization is also discussed.
- Published
- 2016
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10. [Analysis of influence of inflammatory factor in patients with ovarian endometriosis follicular fluid on the outcome of in vitro fertilization].
- Author
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Ning Y, Liu B, Han B, Guo J, Liu X, Fan G, Guo C, Wang F, Zhou J, and Yin L
- Subjects
- Case-Control Studies, Embryo Transfer, Female, Humans, Interleukin-6 chemistry, Pregnancy, Pregnancy Rate, Retrospective Studies, Sperm Injections, Intracytoplasmic, Tumor Necrosis Factor-alpha chemistry, Endometriosis pathology, Fertilization in Vitro, Follicular Fluid chemistry, Infertility, Female pathology, Inflammation pathology
- Abstract
Objective: To observe the effect of follicular fluid IL-6, TNF-α on the clinical outcome of in vitro fertilization and embryo transfer (IVF-ET) in patients with ovarian endometriosis., Method: From June 2013 to June 2014, the data of 64 (from Tangshan Maternal and Child Health Hospital IVF center) ovarian endometriosis patients was analyzed retrospectively. 58 infertility cases caused by male side were used as control group. Oocyte retrieval rate, M II oocytes rate, fertilization rate, recovery-intracytoplasmic sperm injection (R-ICSI) rate, good quality embryo rate, biochemical pregnancy rate and clinical pregnancy rate were analyzed and compared between two groups. Changes in the expression of follicular fluid IL-6, TNF-α were detected., Results: Oocyte retrieval rate, M II oocytes rate, fertilization rate, good quality embryo rate, biochemical pregnancy rate and clinical pregnancy rate in ovarian endometriosis group were significantly lower than those in the control group (all P < 0.05), while R-ICSI rate increased in ovarian endometriosis group compared with control group (P < 0.05). IL-6, TNF-α expressions of follicular fluid were higher in affected side of ovarian endometriosis patients than those in the unaffected side and those in control group., Conclusion: Inflammation microenvironment of the follicular fluid may influence IVF-ET outcomes in ovarian endometriosis patients.
- Published
- 2015
11. CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance.
- Author
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Guo CA, Kogan S, Amano SU, Wang M, Dagdeviren S, Friedline RH, Aouadi M, Kim JK, and Czech MP
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- Adipocytes metabolism, Animals, Blotting, Western, Diet, Disease Progression, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Glucose Clamp Technique, Glucose Tolerance Test, Lipid Metabolism genetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA biosynthesis, RNA genetics, Real-Time Polymerase Chain Reaction, Adipose Tissue pathology, CD40 Antigens deficiency, Fatty Liver genetics, Fatty Liver pathology, Inflammation genetics, Inflammation pathology, Insulin Resistance genetics, Obesity genetics, Obesity pathology
- Abstract
The pathophysiology of obesity and type 2 diabetes in rodents and humans is characterized by low-grade inflammation in adipose tissue and liver. The CD40 receptor and its ligand CD40L initiate immune cell signaling promoting inflammation, but conflicting data on CD40L-null mice confound its role in obesity-associated insulin resistance. Here, we demonstrate that CD40 receptor-deficient mice on a high-fat diet display the expected decrease in hepatic cytokine levels but paradoxically exhibit liver steatosis, insulin resistance, and glucose intolerance compared with their age-matched wild-type controls. Hyperinsulinemic-euglycemic clamp studies also demonstrated insulin resistance in glucose utilization by the CD40-null mice compared with wild-type mice. In contrast to liver, adipose tissue in CD40-deficient animals harbors elevated cytokine levels and infiltration of inflammatory cells, particularly macrophages and CD8(+) effector T cells. In addition, ex vivo explants of epididymal adipose tissue from CD40(-/-) mice display elevated basal and isoproterenol-stimulated lipolysis, suggesting a potential increase of lipid efflux from visceral fat to the liver. These findings reveal that 1) CD40-null mice represent an unusual model of hepatic steatosis with reduced hepatic inflammation, and 2) CD40 unexpectedly functions in adipose tissue to attenuate its inflammation in obesity, thereby protecting against hepatic steatosis.
- Published
- 2013
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12. S-nitrosylation of surfactant protein-D controls inflammatory function.
- Author
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Guo CJ, Atochina-Vasserman EN, Abramova E, Foley JP, Zaman A, Crouch E, Beers MF, Savani RC, and Gow AJ
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- Animals, Cysteine chemistry, Cysteine metabolism, Dimerization, Gene Expression Regulation, Humans, Immunity, Innate, Inflammation metabolism, Lung immunology, Lung metabolism, Macrophages, Male, Mice, Pulmonary Surfactant-Associated Protein D chemistry, Pulmonary Surfactant-Associated Protein D genetics, Pulmonary Surfactant-Associated Protein D immunology, Rats, Rats, Sprague-Dawley, Respiratory Mucosa immunology, Acute Lung Injury immunology, Inflammation immunology, Nitric Oxide metabolism, Pulmonary Surfactant-Associated Protein D metabolism, S-Nitrosothiols metabolism, Signal Transduction
- Abstract
The pulmonary collectins, surfactant proteins A and D (SP-A and SP-D) have been implicated in the regulation of the innate immune system within the lung. In particular, SP-D appears to have both pro- and anti-inflammatory signaling functions. At present, the molecular mechanisms involved in switching between these functions remain unclear. SP-D differs in its quaternary structure from SP-A and the other members of the collectin family, such as C1q, in that it forms large multimers held together by the N-terminal domain, rather than aligning the triple helix domains in the traditional "bunch of flowers" arrangement. There are two cysteine residues within the hydrophobic N terminus of SP-D that are critical for multimer assembly and have been proposed to be involved in stabilizing disulfide bonds. Here we show that these cysteines exist within the reduced state in dodecameric SP-D and form a specific target for S-nitrosylation both in vitro and by endogenous, pulmonary derived nitric oxide (NO) within a rodent acute lung injury model. S-nitrosylation is becoming increasingly recognized as an important post-translational modification with signaling consequences. The formation of S-nitrosothiol (SNO)-SP-D both in vivo and in vitro results in a disruption of SP-D multimers such that trimers become evident. SNO-SP-D but not SP-D, either dodecameric or trimeric, is chemoattractive for macrophages and induces p38 MAPK phosphorylation. The signaling capacity of SNO-SP-D appears to be mediated by binding to calreticulin/CD91. We propose that NO controls the dichotomous nature of this pulmonary collectin and that posttranslational modification by S-nitrosylation causes quaternary structural alterations in SP-D, causing it to switch its inflammatory signaling role. This represents new insight into both the regulation of protein function by S-nitrosylation and NO's role in innate immunity.
- Published
- 2008
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13. Editorial: Hypoxia and inflammation: A two-way street
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Philippe Saas and Guo-Chang Fan
- Subjects
hypoxia ,HIF ,inflammation ,macrophages ,hematopoietic progenitor and stem cells ,inflammatory diseases ,Immunologic diseases. Allergy ,RC581-607 - Published
- 2023
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14. Deficient chaperone‐mediated autophagy in macrophage aggravates inflammation of nonalcoholic steatohepatitis by targeting Nup85.
- Author
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Zhang, Miao, Tian, Si Y, Ma, Shuo Y, Zhou, Xia, Zheng, Xiao H, Li, Bo, Guo, Guan Y, Yu, Jia H, Su, Rui, Yang, Fang F, Hu, Yi N, Ma, Gang, Yang, Hui, Zheng, Lin H, Guo, Chang C, Shang, Yu L, Wang, Jing B, and Han, Ying
- Subjects
NON-alcoholic fatty liver disease ,HEPATIC fibrosis ,HEPATITIS ,MACROPHAGES ,AUTOPHAGY - Abstract
Background & Aims: Nonalcoholic steatohepatitis (NASH), a more severe subtype of nonalcoholic fatty liver disease, can cause cirrhosis and hepatocellular carcinoma. Macrophages play critical roles in initiating and maintaining NASH‐induced liver inflammation and fibrosis. However, the underlying molecular mechanism of macrophage chaperone‐mediated autophagy (CMA) in NASH remains unclear. We aimed to investigate the effects of macrophage‐specific CMA on liver inflammation and identify a potential therapeutic target for NASH treatment. Methods: The CMA function of liver macrophages was detected using Western blot, quantitative reverse transcription‐polymerase chain reaction (RT‐qPCR) and flow cytometry. By constructing myeloid‐specific CMA deficiency mice, we evaluated the effects of deficient CMA of macrophages on monocyte recruitment, liver injury, steatosis and fibrosis in NASH mice. A label‐free mass spectrometry was utilized to screen the substrates of CMA in macrophages and their mutual interactions. The association between CMA and its substrate was further examined by immunoprecipitation, Western blot and RT‐qPCR. Results: A typical hallmark in murine NASH models was impaired CMA function in hepatic macrophages. Monocyte‐derived macrophages (MDM) were the dominant macrophage population in NASH, and CMA function was impaired in MDM. CMA dysfunction aggravated liver‐targeted recruitment of monocyte and promoted steatosis and fibrosis. Mechanistically, Nup85 functions as a substrate for CMA and its degradation was inhibited in CMA‐deficient macrophages. Inhibition of Nup85 attenuated the steatosis and monocyte recruitment caused by CMA deficiency in NASH mice. Conclusions: We proposed that the impaired CMA‐induced Nup85 degradation aggravated monocyte recruitment, promoting liver inflammation and disease progression of NASH. [ABSTRACT FROM AUTHOR]
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- 2023
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15. Loss of Lipocalin 10 Exacerbates Diabetes-Induced Cardiomyopathy
- Author
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Qianqian, Li, Yutian, Li, Wei, Huang, Xiaohong, Wang, Zhenling, Liu, Jing, Chen, Yanbo, Fan, Tianqing, Peng, Sakthivel, Sadayappan, Yigang, Wang, and Guo-Chang, Fan
- Subjects
Heart Failure ,Inflammation ,Mice, Knockout ,Mice ,Diabetes Mellitus, Type 2 ,Macrophages ,Nuclear Receptor Subfamily 4, Group A, Member 1 ,Animals ,Humans ,Lipocalins ,Diabetes Mellitus, Experimental - Abstract
Metabolic disorders (i.e., hyperglycemia, hyperlipidemia, and hyperinsulinemia) cause increased secretion of inflammatory cytokines/chemokines, leading to gradual loss of cardiac resident macrophage population and increased accumulation of inflammatory monocytes/macrophages in the heart. Such self-perpetuating effect may contribute to the development of cardiomyopathy during diabetes. Recent meta-analysis data reveal that lipocalin 10 (Lcn10) is significantly downregulated in cardiac tissue of patients with heart failure but is increased in the blood of septic patients. However, the functional role of Lcn10 in cardiac inflammation triggered by metabolic disorders has never been investigated. In this study, we demonstrate that the expression of Lcn10 in macrophages was significantly decreased under multiple metabolic stress conditions. Furthermore, Lcn10-null macrophages exhibited pro-inflammatory phenotype in response to inflammation stimuli. Next, using a global Lcn10-knockout (KO) mouse model to induce type-2 diabetes (T2D), we observed that loss of Lcn10 promoted more pro-inflammatory macrophage infiltration into the heart, compared to controls, leading to aggravated insulin resistance and impaired cardiac function. Similarly, adoptive transfer of Lcn10-KO bone marrow cells into X-ray irradiated mice displayed higher ratio of pro-/anti-inflammatory macrophages in the heart and worsened cardiac function than those mice received wild-type (WT) bone marrows upon T2D conditions. Mechanistically, RNA-sequencing analysis showed that Nr4a1, a nuclear receptor known to have potent anti-inflammatory effects, is involved in Lcn10-mediated macrophage activation. Indeed, we found that nuclear translocation of Nr4a1 was disrupted in Lcn10-KO macrophages upon stimulation with LPS + IFNγ. Accordingly, treatment with Cytosporone B (CsnB), an agonist of Nr4a1, attenuated the pro-inflammatory response in Lcn10-null macrophages and partially improved cardiac function in Lcn10-KO diabetic mice. Together, these findings indicate that loss of Lcn10 skews macrophage polarization to pro-inflammatory phenotype and aggravates cardiac dysfunction during type-2 diabetes through the disruption of Nr4a1-mediated anti-inflammatory signaling pathway in macrophages. Therefore, reduction of Lcn10 expression observed in diabetic macrophages may be responsible for the pathogenesis of diabetes-induced cardiac dysfunction. It suggests that Lcn10 might be a potential therapeutic factor for diabetic heart failure.
- Published
- 2022
16. Sectm1a deficiency aggravates inflammation-triggered cardiac dysfunction through disruption of LXRα signalling in macrophages
- Author
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Anil G. Jegga, Shan Deng, Kobina Essandoh, Tianqing Peng, Xingjiang Mu, Yigang Wang, David E. Adams, Jack Rubinstein, Guo-Chang Fan, Jiangtong Peng, Nathan Robbins, Xiaohong Wang, Yutian Li, Wei Huang, and Jing Chen
- Subjects
Lipopolysaccharides ,Male ,0301 basic medicine ,Cardiac function curve ,medicine.medical_specialty ,Heart Diseases ,Physiology ,medicine.medical_treatment ,Inflammation ,030204 cardiovascular system & hematology ,Diet, High-Fat ,Ventricular Function, Left ,Proinflammatory cytokine ,Rats, Sprague-Dawley ,Sepsis ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Animals ,Liver X receptor ,Liver X Receptors ,Mice, Knockout ,business.industry ,Macrophages ,Membrane Proteins ,Original Articles ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Phenotype ,RAW 264.7 Cells ,030104 developmental biology ,Endocrinology ,Cytokine ,Gene Expression Regulation ,Heart failure ,Knockout mouse ,Cytokines ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Signal Transduction - Abstract
Aim Cardiac dysfunction is a prevalent comorbidity of disrupted inflammatory homeostasis observed in conditions such as sepsis (acute) or obesity (chronic). Secreted and transmembrane protein 1a (Sectm1a) has previously been implicated to regulate inflammatory responses, yet its role in inflammation-associated cardiac dysfunction is virtually unknown. Methods and results Using the CRISPR/Cas9 system, we generated a global Sectm1a-knockout (KO) mouse model and observed significantly increased mortality and cardiac injury after LPS injection, when compared to wild-type (WT) control. Further analysis revealed significantly increased accumulation of inflammatory macrophages in hearts of LPS-treated KO mice. Accordingly, ablation of Sectm1a remarkably increased inflammatory cytokines levels both in vitro [from bone marrow-derived macrophages (BMDMs)] and in vivo (in serum and myocardium) after LPS challenge. RNA-sequencing results and bioinformatics analyses showed that the most significantly downregulated genes in KO-BMDMs were modulated by LXRα, a nuclear receptor with robust anti-inflammatory activity in macrophages. Indeed, we identified that the nuclear translocation of LXRα was disrupted in KO-BMDMs when treated with GW3965 (LXR agonist), resulting in higher levels of inflammatory cytokines, compared to GW3965-treated WT-cells. Furthermore, using chronic inflammation model of high-fat diet (HFD) feeding, we observed that infiltration of inflammatory monocytes/macrophages into KO-hearts were greatly increased and accordingly, worsened cardiac function, compared to WT-HFD controls. Conclusion This study defines Sectm1a as a new regulator of inflammatory-induced cardiac dysfunction through modulation of LXRα signaling in macrophages. Our data suggest that augmenting Sectm1a activity may be a potential therapeutic approach to resolve inflammation and associated cardiac dysfunction. Translational perspective Better understanding on the interaction between inflammatory responses and cardiac health is prominent for the development of safer and more efficacious therapies for heart failure patients. The present study, using both acute (LPS) and chronic (high-fat diet) inflammation models, reiterated the adverse effects of abnormal macrophages activation on cardiac function. Our Sectm1a knockout mouse model showed exacerbated cardiac and systemic inflammatory responses, resulting in further aggravation of contractile dysfunction on the heart after endotoxin challenge. We also demonstrated Sectm1a as a new regulator of macrophage function through LXRα pathway. These data suggest a novel approach to regulate macrophage-elicited inflammation.
- Published
- 2020
17. Sectm1a Facilitates Protection against Inflammation-Induced Organ Damage through Promoting TRM Self-Renewal
- Author
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Xiaohong Wang, Qianqian Li, Kobina Essandoh, Tianqing Peng, Hongkuan Fan, Peng Wang, Guo-Chang Fan, Yutian Li, Xingjiang Mu, Jing Chen, and Karen Domenico
- Subjects
Lipopolysaccharide ,medicine.medical_treatment ,Multiple Organ Failure ,Inflammation ,Monocytes ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Immune system ,Downregulation and upregulation ,Glucocorticoid-Induced TNFR-Related Protein ,Drug Discovery ,Genetics ,Medicine ,Animals ,Homeostasis ,Molecular Biology ,Tissue homeostasis ,Interleukin 4 ,030304 developmental biology ,Pharmacology ,0303 health sciences ,business.industry ,Macrophages ,Membrane Proteins ,T helper cell ,T-Lymphocytes, Helper-Inducer ,medicine.anatomical_structure ,Cytokine ,chemistry ,030220 oncology & carcinogenesis ,Immunology ,Molecular Medicine ,Original Article ,medicine.symptom ,business ,Immunologic Memory - Abstract
Tissue-resident macrophages (TRMs) are sentinel cells for maintaining tissue homeostasis and organ function. In this study, we discovered that lipopolysaccharide (LPS) administration dramatically reduced TRM populations and suppressed their self-renewal capacities in multiple organs. Using loss- and gain-of-function approaches, we define Sectm1a as a novel regulator of TRM self-renewal. Specifically, at the earlier stage of endotoxemia, Sectm1a deficiency exaggerated acute inflammation-induced reduction of TRM numbers in multiple organs by suppressing their proliferation, which was associated with more infiltrations of inflammatory monocytes/neutrophils and more serious organ damage. By contrast, administration of recombinant Sectm1a enhanced TRM populations and improved animal survival upon endotoxin challenge. Mechanistically, we identified that Sectm1a-induced upregulation in the self-renewal capacity of TRM is dependent on GITR-activated T helper cell expansion and cytokine production. Meanwhile, we found that TRMs may play an important role in protecting local vascular integrity during endotoxemia. Our study demonstrates that Sectm1a contributes to stabling TRM populations through maintaining their self-renewal capacities, which benefits the host immune response to acute inflammation. Therefore, Sectm1a may serve as a new therapeutic agent for the treatment of inflammatory diseases.
- Published
- 2020
18. Macrophage Efferocytosis in Cardiac Pathophysiology and Repair
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Qianqian Li, Guo-Chang Fan, and Yutian Li
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Cardiac function curve ,Inflammation ,Apoptosis ,030204 cardiovascular system & hematology ,Critical Care and Intensive Care Medicine ,Article ,03 medical and health sciences ,Necrosis ,0302 clinical medicine ,Phagocytosis ,medicine ,Macrophage ,Humans ,Efferocytosis ,business.industry ,Macrophages ,030208 emergency & critical care medicine ,Heart ,medicine.disease ,Pathophysiology ,Heart failure ,Emergency Medicine ,Cancer research ,medicine.symptom ,business ,Homeostasis - Abstract
As an integral component of cardiac tissue, macrophages are critical for cardiac development, adult heart homeostasis, as well as cardiac healing. One fundamental function of macrophages involves the clearance of dying cells or debris, a process termed efferocytosis. Current literature primarily pays attention to the impact of efferocytosis on apoptotic cells. However, emerging evidence suggests that necrotic cells and their released cellular debris can also be removed by cardiac macrophages through efferocytosis. Importantly, recent studies have demonstrated that macrophage efferocytosis plays an essential role in cardiac pathophysiology and repair. Therefore, understanding macrophage efferocytosis would provide valuable insights on cardiac health, and may offer new therapeutic strategies for the treatment of patients with heart failure. In this review, we first summarize the molecular signals that are associated with macrophage efferocytosis of apoptotic and necrotic cells, and then discuss how the linkage of efferocytosis to the resolution of inflammation affects cardiac function and recovery under normal and diseased conditions. Lastly, we highlight new discoveries related to the effects of macrophage efferocytosis on cardiac injury and repair.
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- 2020
19. Tissue-Resident Macrophages in the Control of Infection and Resolution of Inflammation
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Guo-Chang Fan, Yutian Li, and Xingjiang Mu
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Inflammation ,Macrophages ,Macrophage polarization ,030208 emergency & critical care medicine ,Spleen ,030204 cardiovascular system & hematology ,Biology ,Critical Care and Intensive Care Medicine ,Embryonic stem cell ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Immune system ,Immunology ,Emergency Medicine ,medicine ,Macrophage ,Homeostasis ,Humans ,medicine.symptom ,Progenitor cell ,Tissue homeostasis - Abstract
Macrophage, as an integral component of the immune system and the first responder to local damage, is on the front line of defense against infection. Over the past century, the prevailing view of macrophage origin states that all macrophage populations resided in tissues are terminally differentiated and replenished by monocytes from bone-marrow progenitors. Nonetheless, this theory has been reformed by ground-breaking discoveries from the past decades. It is now believed that tissue-resident macrophages (TRMs) are originated from the embryonic precursors and seeded in tissue prenatally. They can replenish via self-renewal throughout the lifespan. Indeed, recent studies have demonstrated that tissue-resident macrophages should not be classified by the over-simplified macrophage polarization (M1/M2) dogma during inflammation. Moreover, multiple lines of evidence have indicated that tissue-resident macrophages play critical roles in maintaining tissue homeostasis and facilitating tissue repair through controlling infection and resolving inflammation. In this review, we summarize the properties of resident macrophages in the lung, spleen, and heart, and further highlight the impact of TRM populations on inflammation control and tissue repair. We also discuss the potential role of local proliferation in maintaining a physiologically stable TRM pool in response to acute inflammation.
- Published
- 2020
20. GDF3 Protects Mice against Sepsis-Induced Cardiac Dysfunction and Mortality by Suppression of Macrophage Pro-Inflammatory Phenotype
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Xiaohong Wang, Tianqing Peng, Yutian Li, Wei Huang, Lu Wang, Shu-Nan Cui, Guo-Chang Fan, Kobina Essandoh, Xingjiang Mu, Peng Wang, Zhenling Liu, and Yigang Wang
- Subjects
endotoxin ,Smad Proteins ,SMAD ,0302 clinical medicine ,cardiac inflammation ,Macrophage ,Receptor ,lcsh:QH301-705.5 ,0303 health sciences ,biology ,cardiac dysfunction ,Cell Polarity ,Heart ,General Medicine ,Recombinant Proteins ,3. Good health ,Phenotype ,Treatment Outcome ,030220 oncology & carcinogenesis ,Cytokines ,medicine.symptom ,Adult ,smad ,macrophage polarization ,Macrophage polarization ,Inflammation ,Models, Biological ,Article ,Sepsis ,03 medical and health sciences ,medicine ,Animals ,Humans ,RNA, Messenger ,030304 developmental biology ,nlrp3 ,Septic shock ,business.industry ,Macrophages ,growth differentiation factor 3 ,Transforming growth factor beta ,medicine.disease ,Survival Analysis ,sepsis biomarker ,Endotoxins ,Mice, Inbred C57BL ,lcsh:Biology (General) ,Case-Control Studies ,Immunology ,biology.protein ,business ,Spleen - Abstract
Macrophages are critical for regulation of inflammatory response during endotoxemia and septic shock. However, the mediators underlying their regulatory function remain obscure. Growth differentiation factor 3 (GDF3), a member of transforming growth factor beta (TGF-&beta, ) superfamily, has been implicated in inflammatory response. Nonetheless, the role of GDF3 in macrophage-regulated endotoxemia/sepsis is unknown. Here, we show that serum GDF3 levels in septic patients are elevated and strongly correlate with severity of sepsis and 28-day mortality. Interestingly, macrophages treated with recombinant GDF3 protein (rGDF3) exhibit greatly reduced production of pro-inflammatory cytokines, comparing to controls upon endotoxin challenge. Moreover, acute administration of rGDF3 to endotoxin-treated mice suppresses macrophage infiltration to the heart, attenuates systemic and cardiac inflammation with less pro-inflammatory macrophages (M1) and more anti-inflammatory macrophages (M2), as well as prolongs mouse survival. Mechanistically, GDF3 is able to activate Smad2/Smad3 phosphorylation, and consequently inhibits the expression of nod-like receptor protein-3 (NLRP3) in macrophages. Accordingly, blockade of Smad2/Smad3 phosphorylation with SB431542 significantly offsets rGDF3-mediated anti-inflammatory effects. Taken together, this study uncovers that GDF3, as a novel sepsis-associated factor, may have a dual role in the pathophysiology of sepsis. Acute administration of rGDF3 into endotoxic shock mice could increase survival outcome and improve cardiac function through anti-inflammatory response by suppression of M1 macrophage phenotype. However, constitutive high levels of GDF3 in human sepsis patients are associated with lethality, suggesting that GDF3 may promote macrophage polarization toward M2 phenotype which could lead to immunosuppression.
- Published
- 2020
21. Administration of nicotinamide riboside prevents oxidative stress and organ injury in sepsis
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Lulu Zhang, Zhongqiu Lu, Tianqing Peng, Grace Wang, Rui Ni, Guangliang Hong, Guo-Chang Fan, and Dong Zheng
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Lipopolysaccharides ,Male ,Niacinamide ,0301 basic medicine ,Multiple Organ Failure ,Apoptosis ,Pyridinium Compounds ,Vascular permeability ,Inflammation ,030204 cardiovascular system & hematology ,Pharmacology ,HMGB1 ,medicine.disease_cause ,Biochemistry ,Article ,Sepsis ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,Intensive care ,Animals ,Medicine ,HMGB1 Protein ,biology ,business.industry ,Macrophages ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,chemistry ,Nicotinamide riboside ,biology.protein ,NAD+ kinase ,medicine.symptom ,business ,Oxidative stress - Abstract
Aims Sepsis-caused multiple organ failure remains the major cause of morbidity and mortality in intensive care units. Nicotinamide riboside (NR) is a precursor of nicotinamide adenine dinucleotide (NAD+), which is important in regulating oxidative stress. This study investigated whether administration of NR prevented oxidative stress and organ injury in sepsis. Methods Mouse sepsis models were induced by injection of lipopolysaccharides (LPS) or feces-injection-in-peritoneum. NR was given before sepsis onset. Cultured macrophages and endothelial cells were incubated with various agents. Results Administration of NR elevated the NAD+ levels, and elicited a reduction of oxidative stress, inflammation and caspase-3 activity in lung and heart tissues, which correlated with attenuation of pulmonary microvascular permeability and myocardial dysfunction, leading to less mortality in sepsis models. These protective effects of NR were associated with decreased levels of plasma high mobility group box-1 (HMGB1) in septic mice. Consistently, pre-treatment of macrophages with NR increased NAD+ content and reduced HMGB1 release upon LPS stimulation. NR also prevented reactive oxygen species (ROS) production and apoptosis in endothelial cells induced by a conditioned-medium collected from LPS-treated macrophages. Furthermore, inhibition of SIRT1 by EX527 offset the negative effects of NR on HMGB1 release in macrophages, and ROS and apoptosis in endothelial cells. Conclusions Administration of NR prevents lung and heart injury, and improves the survival in sepsis, likely by inhibiting HMGB1 release and oxidative stress via the NAD+/SIRT1 signaling. Given NR has been used as a health supplement, it may be a useful agent to prevent organ injury in sepsis.
- Published
- 2018
22. Versatile effects of bacterium-released membrane vesicles on mammalian cells and infectious/inflammatory diseases
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You-jiang Yu, Xiaohong Wang, and Guo-Chang Fan
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0301 basic medicine ,030106 microbiology ,Review Article ,Communicable Diseases ,Extracellular Vesicles ,03 medical and health sciences ,Vaccines, Acellular ,Immune system ,Downregulation and upregulation ,Antigen ,Animals ,Humans ,Pharmacology (medical) ,Inflammation ,Pharmacology ,Phagocytes ,Bacteria ,Tight junction ,Chemistry ,Vesicle ,Dendritic Cells ,General Medicine ,Microvesicles ,Cell biology ,Nanocarriers ,Biogenesis - Abstract
Gram-negative bacterium-released outer-membrane vesicles (OMVs) and Gram-positive bacterium-released membrane vesicles (MVs) share significant similarities with mammalian cell-derived MVs (eg, microvesicles and exosomes) in terms of structure and their biological activities. Recent studies have revealed that bacterial OMVs/MVs could (1) interact with immune cells to regulate inflammatory responses, (2) transport virulence factors (eg, enzymes, DNA and small RNAs) to host cells and result in cell injury, (3) enhance barrier function by stimulating the expression of tight junction proteins in intestinal epithelial cells, (4) upregulate the expression of endothelial cell adhesion molecules, and (5) serve as natural nanocarriers for immunogenic antigens, enzyme support and drug delivery. In addition, OMVs/MVs can enter the systemic circulation and induce a variety of immunological and metabolic responses. This review highlights the recent advances in the understanding of OMV/MV biogenesis and their compositional remodeling. In addition, interactions between OMVs/MVs and various types of mammalian cells (ie, immune cells, epithelial cells, and endothelial cells) and their pathological/preventive effects on infectious/inflammatory diseases are summarized. Finally, methods for engineering OMVs/MVs and their therapeutic potential are discussed.
- Published
- 2017
23. Tumor susceptibility gene 101 ameliorates endotoxin-induced cardiac dysfunction by enhancing Parkin-mediated mitophagy
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Evangelia G. Kranias, Yigang Wang, Kobina Essandoh, Wei Huang, Xiaohong Wang, Yutian Li, Shan Deng, Guo-Chang Fan, Xingjiang Mu, and George Gardner
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0301 basic medicine ,Lipopolysaccharides ,Male ,Heart Diseases ,Transgene ,Ubiquitin-Protein Ligases ,Inflammation ,PINK1 ,macromolecular substances ,Mitochondrion ,Biochemistry ,Parkin ,Mitochondria, Heart ,03 medical and health sciences ,Mice ,Mitophagy ,medicine ,Animals ,Molecular Biology ,Mice, Knockout ,Gene knockdown ,030102 biochemistry & molecular biology ,Endosomal Sorting Complexes Required for Transport ,Chemistry ,Autophagy ,Molecular Bases of Disease ,Cell Biology ,Myocardial Contraction ,Cell biology ,DNA-Binding Proteins ,030104 developmental biology ,medicine.symptom ,Protein Kinases ,Transcription Factors - Abstract
Cardiac mitochondrial damage and subsequent inflammation are hallmarks of endotoxin-induced myocardial depression. Activation of the Parkin/PTEN-induced kinase 1 (PINK1) pathway has been shown to promote autophagy of damaged mitochondria (mitophagy) and to protect from endotoxin-induced cardiac dysfunction. Tumor susceptibility gene 101 (TSG101) is a key member of the endosomal recycling complexes required for transport, which may affect autophagic flux. In this study, we investigated whether TSG101 regulates mitophagy and influences the outcomes of endotoxin-induced myocardial dysfunction. TSG101 transgenic and knockdown mice underwent endotoxin/lipopolysaccharide treatment (10 μg/g) and were assessed for survival, cardiac function, systemic/local inflammation, and activity of mitophagy mediators in the heart. Upon endotoxin challenge and compared with WT mice, TSG101 transgenic mice exhibited increased survival, preserved cardiac contractile function, reduced inflammation, and enhanced mitophagy activation in the heart. By contrast, TSG101 knockdown mice displayed opposite phenotypes during endotoxemia. Mechanistically, both coimmunoprecipitation assays and coimmunofluorescence staining revealed that TSG101 directly binds to Parkin in the cytosol of myocytes and facilitates translocation of Parkin from the cytosol to the mitochondria. Our results indicate that TSG101 elevation could protect against endotoxin-triggered myocardial injury by promoting Parkin-induced mitophagy.
- Published
- 2019
24. Inhibition of cerebral vascular inflammation by brain endothelium-targeted oligodeoxynucleotide complex
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Daniah I Al-Waili, Jiukuan Hao, Mei Xin, Aishlin Hassan, Jing Hu, and Guo-Chang Fan
- Subjects
Lipopolysaccharides ,Male ,0301 basic medicine ,Anti-Inflammatory Agents ,Drug Evaluation, Preclinical ,Inflammation ,Biology ,Vascular endothelial growth inhibitor ,Article ,Cell Line ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Animals ,VCAM-1 ,Vasculitis, Central Nervous System ,ICAM-1 ,Tumor Necrosis Factor-alpha ,Cell adhesion molecule ,Goats ,General Neuroscience ,Brain ,Endothelial Cells ,Aptamers, Nucleotide ,Molecular biology ,Cell Hypoxia ,Endothelial stem cell ,Disease Models, Animal ,Glucose ,Neuroprotective Agents ,030104 developmental biology ,Oligodeoxyribonucleotides ,chemistry ,Drug Design ,Cancer research ,Tumor necrosis factor alpha ,medicine.symptom - Abstract
The present study generated a novel DNA complex to specifically target endothelial NF-κB to inhibit cerebral vascular inflammation. This DNA complex (GS24-NFκB) contains a DNA decoy which inhibits NF-κB activity, and a DNA aptamer (GS-24), a ligand of transferrin receptor (TfR), which allows for targeted delivery of the DNA decoy into cells. The results indicate that GS24-NFκB was successfully delivered into a murine brain-derived endothelial cell line, bEND5, and inhibited inflammatory responses induced by tumor necrosis factor α (TNF-α) or oxygen-glucose deprivation/re-oxygenation (OGD/R) via down-regulation of the nuclear NF-κB subunit, p65, as well as its downstream inflammatory cytokines, inter-cellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule (VCAM-1). The inhibitory effect of the GS24-NFκB was demonstrated by a significant reduction in TNF-α or OGD/R induced monocyte adhesion to the bEND5 cells after GS24-NFκB treatment. Intravenous (i.v.) injection of GS24-'NFκB (15mg/kg) was able to inhibit the levels of phoseph-p65 and VCAM-1 in brain endothelial cells in a mouse lipopolysaccharide (LPS)-induced inflammatory model in vivo. In conclusion, our approach using DNA nanotechnology for DNA decoy delivery could potentially be utilized for inhibition of inflammation in ischemic stroke and other neuro-inflammatory diseases affecting cerebral vasculature.
- Published
- 2016
25. MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response
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Kobina Essandoh, Jiuzhou Huo, Guo-Chang Fan, and Yutian Li
- Subjects
0301 basic medicine ,Antigen presentation ,Macrophage polarization ,Biology ,Critical Care and Intensive Care Medicine ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,microRNA ,Gene expression ,Animals ,Humans ,Transcription factor ,Inflammation ,Innate immune system ,Macrophages ,Cell Polarity ,Macrophage Activation ,Acquired immune system ,Cell biology ,MicroRNAs ,030104 developmental biology ,030220 oncology & carcinogenesis ,Emergency Medicine - Abstract
Monocytes and macrophages are important components of the immune system, specialized in either removing pathogens as part of innate immunity or contributing to adaptive immunity through antigen presentation. Essential to such functions is classical activation (M1) and alternative activation (M2) of macrophages. M1 polarization of macrophages is characterized by production of pro-inflammatory cytokines, antimicrobial and tumoricidal activity, whereas M2 polarization of macrophages is linked to immunosuppression, tumorigenesis, wound repair, and elimination of parasites. MiRNAs are small non-coding RNAs with the ability to regulate gene expression and network of cellular processes. A number of studies have determined miRNA expression profiles in M1 and M2 polarized human and murine macrophages using microarray and RT-qPCR arrays techniques. More specifically, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M1 polarization while miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p induce M2 polarization in macrophages by targeting various transcription factors and adaptor proteins. Further, M1 and M2 phenotypes play distinctive roles in cell growth and progression of inflammation-related diseases such as sepsis, obesity, cancer, and multiple sclerosis. Hence, miRNAs that modulate macrophage polarization may have therapeutic potential in the treatment of inflammation-related diseases. This review highlights recent findings in miRNA expression profiles in polarized macrophages from murine and human sources, and summarizes how these miRNAs regulate macrophage polarization. Last, therapeutic potential of miRNAs in inflammation-related diseases through modulation of macrophage polarization is also discussed.
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- 2016
26. An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination
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Shan Deng, Diego Perez-Tilve, Tiemin Liu, Jiangtong Peng, Robert K. McNamara, Yutian Li, Tianqing Peng, Emily Yates, Kobina Essandoh, Guo-Chang Fan, Xiaohong Wang, Xingjiang Mu, Jenna Holland, Jing Chen, Takahisa Nakamura, Boyu Wang, Anil G. Jegga, Haitao Gu, and Kai Huang
- Subjects
0301 basic medicine ,Adipose Tissue, White ,Peroxisome Proliferation ,General Biochemistry, Genetics and Molecular Biology ,Article ,Rosiglitazone ,03 medical and health sciences ,chemistry.chemical_compound ,Downregulation and upregulation ,Ubiquitin ,Adipocyte ,Heat shock protein ,Brown adipose tissue ,medicine ,Adipocytes ,Animals ,HSP20 Heat-Shock Proteins ,Obesity ,RNA, Messenger ,Adiposity ,Inflammation ,Mice, Knockout ,biology ,Protein Stability ,F-Box Proteins ,fungi ,Ubiquitination ,Lipid metabolism ,Lipid Metabolism ,Cell biology ,Cold Temperature ,Mice, Inbred C57BL ,PPAR gamma ,030104 developmental biology ,medicine.anatomical_structure ,Glucose ,chemistry ,Ubiquitin ligase complex ,biology.protein ,Insulin Resistance ,Energy Metabolism - Abstract
Exposure to cold temperature is well known to upregulate heat shock protein (Hsp) expression and recruit and/or activate brown adipose tissue and beige adipocytes in humans and animals. However, whether and how Hsps regulate adipocyte function for energy homeostatic responses is poorly understood. Here, we demonstrate a critical role of Hsp20 as a negative regulator of adipocyte function. Deletion of Hsp20 enhances non-shivering thermogenesis and suppresses inflammatory responses, leading to improvement of glucose and lipid metabolism under both chow diet and high-fat diet conditions. Mechanistically, Hsp20 controls adipocyte function by interacting with the subunit of the ubiquitin ligase complex, F-box only protein 4 (FBXO4), and regulating the ubiquitin-dependent degradation of peroxisome proliferation activated receptor gamma (PPARγ). Indeed, Hsp20 deficiency mimics and enhances the pharmacological effects of the PPARγ agonist rosiglitazone. Together, our findings suggest a role of Hsp20 in mediating adipocyte function by linking β-adrenergic signaling to PPARγ activity.
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- 2018
27. Pathological Effects of Exosomes in Mediating Diabetic Cardiomyopathy
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Esam S. B. Salem and Guo-Chang Fan
- Subjects
0301 basic medicine ,Cell type ,Diabetic Cardiomyopathies ,Cardiomyopathy ,Inflammation ,030204 cardiovascular system & hematology ,Exosomes ,Article ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Diabetic cardiomyopathy ,Diabetes mellitus ,microRNA ,medicine ,Animals ,Humans ,business.industry ,Myocardium ,medicine.disease ,Microvesicles ,030104 developmental biology ,Cancer research ,medicine.symptom ,business ,Signal Transduction - Abstract
Diabetic subjects are at risk of developing cardiovascular disease, which accounts for 60–80% of diabetes-related mortality. Atherosclerosis is still considered as a leading cause of heart failure in diabetic patients, but it could also be an intrinsic and long-term effect of contractile cardiac cells malfunction, known as diabetic cardiomyopathy (DCM). Pathologically, this cardiac dysfunction is manifested by inflammation, apoptosis, fibrosis, hypertrophy and altered cardiomyocytes metabolism. However, the underlying molecular mechanisms of DCM pathophysiology are not clearly understood. Recent and several studies have suggested that exosomes are contributed to the regulation of cell-to-cell communication. Therefore, their in-depth investigation can interpret the complex pathophysiology of DCM. Structurally, exosomes are membrane-bounded vesicles (10–200 nm in diameter), which are actively released from all types of cells and detected in all biological fluids. They carry a wide array of bioactive molecules, including mRNAs, none-coding RNAs (e.g., microRNAs, lncRNAs, circRNAs, etc), proteins and lipids. Importantly, the abundance and nature of loaded molecules inside exosomes fluctuate with cell types and pathological conditions. This chapter summarizes currently available studies on the exosomes’ role in the regulation of diabetic cardiomyopathy. Specifically, the advances on the pathological effects of exosomes in diabetic cardiomyopathy as well as the therapeutic potentials and perspectives are also discussed.
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- 2017
28. Loss of duplexmiR-223 (5p and 3p) aggravates myocardial depression and mortality in polymicrobial sepsis
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Xiaohong Wang, Wei Huang, Guo-Chang Fan, Basilia Zingarelli, Jiang Chang, Tianqing Peng, Yigang Wang, Charles C. Caldwell, and Yang Yang
- Subjects
Male ,Exacerbation ,Sema3A ,Myocardial depression ,Inflammation ,030204 cardiovascular system & hematology ,Biology ,Real-Time Polymerase Chain Reaction ,Article ,Sepsis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Molecular Biology ,030304 developmental biology ,Cause of death ,DNA Primers ,Mice, Knockout ,0303 health sciences ,Base Sequence ,Activator (genetics) ,Coinfection ,MicroRNA ,SEMA3A ,Heart ,medicine.disease ,3. Good health ,Mice, Inbred C57BL ,MicroRNAs ,Real-time polymerase chain reaction ,Immunology ,Molecular Medicine ,Female ,medicine.symptom ,Cytokine storm - Abstract
Sepsis is the leading cause of death in critically ill patients. While myocardial dysfunction has been recognized as a major manifestation in severe sepsis, the underlying molecular mechanisms associated with septic cardiomyopathy remain unclear. In this study, we performed a miRNA array analysis in hearts collected from a severe septic mouse model induced by cecal ligation and puncture (CLP). Among the 19 miRNAs that were dys-regulated in CLP-mouse hearts, miR-223(3p) and miR-223*(5p) were most significantly downregulated, compared with sham-operated mouse hearts. To test whether a drop of miR-223 duplex plays any roles in sepsis-induced cardiac dysfunction and inflammation, a knockout (KO) mouse model with a deletion of the miR-223 gene locus and wild-type (WT) mice were subjected to CLP or sham surgery. We observed that sepsis-induced cardiac dysfunction, inflammatory response and mortality were remarkably aggravated in CLP-treated KO mice, compared with control WTs. Using Western-blotting and luciferase reporter assays, we identified Sema3A, an activator of cytokine storm and a neural chemorepellent for sympathetic axons, as an authentic target of miR-223* in the myocardium. In addition, we validated that miR-223 negatively regulated the expression of STAT-3 and IL-6 in mouse hearts. Furthermore, injection of Sema3A protein into WT mice revealed an exacerbation of sepsis-triggered inflammatory response and myocardial depression, compared with control IgG1 protein-treated WT mice following CLP surgery. Taken together, these data indicate that loss of miR-223/-223* causes an aggravation of sepsis-induced inflammation, myocardial dysfunction and mortality. Our study uncovers a previously unrecognized mechanism underlying septic cardiomyopathy and thereby, may provide a new strategy to treat sepsis.
- Published
- 2014
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29. Pulmonary effects of inhalation of spark-generated silver nanoparticles in Brown-Norway and Sprague–Dawley rats
- Author
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Seiffert, Joanna, Buckley, Alison, Leo, Bey, Martin, Nicholas G., Zhu, Jie, Dai, Ranran, Hussain, Farhana, Guo, Chang, Warren, James, Hodgson, Alan, Gong, Jicheng, Ryan, Mary P., Zhang, Junfeng (Jim), Porter, Alexandra, Tetley, Terry D., Gow, Andrew, Smith, Rachel, Chung, Kian Fan, Natural Environment Research Council (NERC), and National Institutes of Health
- Subjects
Pulmonary and Respiratory Medicine ,Male ,Silver ,Time Factors ,Respiratory System ,Metal Nanoparticles ,1102 Cardiovascular Medicine And Haematology ,Rats, Sprague-Dawley ,Rats, Inbred BN ,Macrophages, Alveolar ,Animals ,Pulmonary Eosinophilia ,Lung ,Phospholipids ,Inflammation ,Inhalation Exposure ,Dose-Response Relationship, Drug ,Research ,1103 Clinical Sciences ,Pneumonia ,respiratory system ,Pulmonary Surfactant-Associated Protein D ,Silver nanospheres ,respiratory tract diseases ,Inhalation ,Respiratory Mechanics ,Cytokines ,Lungs ,Inflammation Mediators ,Bronchoalveolar Lavage Fluid - Abstract
Background The increasing use of silver nanoparticles (AgNPs) in consumer products is concerning. We examined the potential toxic effects when inhaled in Brown-Norway (BN) rats with a pre-inflammatory state compared to Sprague–Dawley (SD) rats. Methods We determined the effect of AgNPs generated from a spark generator (mass concentration: 600–800 μg/mm3; mean diameter: 13–16 nm; total lung doses: 8 [Low] and 26–28 [High] μg) inhaled by the nasal route in both rat strains. Rats were sacrificed at day 1 and day 7 after exposure and measurement of lung function. Results In both strains, there was an increase in neutrophils in bronchoalveolar lavage (BAL) fluid at 24 h at the high dose, with concomitant eosinophilia in BN rats. While BAL inflammatory cells were mostly normalised by Day 7, lung inflammation scores remained increased although not the tissue eosinophil scores. Total protein levels were elevated at both lung doses in both strains. There was an increase in BAL IL-1β, KC, IL-17, CCL2 and CCL3 levels in both strains at Day 1, mostly at high dose. Phospholipid levels were increased at the high dose in SD rats at Day 1 and 7, while in BN rats, this was only seen at Day 1; surfactant protein D levels decreased at day 7 at the high dose in SD rats, but was increased at Day 1 at the low dose in BN rats. There was a transient increase in central airway resistance and in tissue elastance in BN rats at Day 1 but not in SD rats. Positive silver-staining was seen particularly in lung tissue macrophages in a dose and time-dependent response in both strains, maximal by day 7. Lung silver levels were relatively higher in BN rat and present at day 7 in both strains. Conclusions Presence of cellular inflammation and increasing silver-positive macrophages in lungs at day 7, associated with significant levels of lung silver indicate that lung toxicity is persistent even with the absence of airway luminal inflammation at that time-point. The higher levels and persistence of lung silver in BN rats may be due to the pre-existing inflammatory state of the lungs.
- Published
- 2016
30. Deficiency of Capn4 Gene Inhibits Nuclear Factor-κB (NF-κB) Protein Signaling/Inflammation and Reduces Remodeling after Myocardial Infarction
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Morris Karmazyn, James C. Lacefield, Hao Wang, Meng Wei, Qiang Wang, Tianqing Peng, Jianmin Li, Weihua Liu, Jian Ma, Peter A. Greer, and Guo-Chang Fan
- Subjects
medicine.medical_specialty ,Time Factors ,Endomyocardial fibrosis ,Myocardial Infarction ,Apoptosis ,Inflammation ,Biochemistry ,Proinflammatory cytokine ,Mice ,chemistry.chemical_compound ,Internal medicine ,medicine ,Animals ,Myocytes, Cardiac ,cardiovascular diseases ,Myocardial infarction ,Molecular Biology ,Cells, Cultured ,Mice, Knockout ,biology ,Calpain ,business.industry ,Myocardium ,NF-kappa B ,Molecular Bases of Disease ,NF-κB ,Cell Biology ,Endomyocardial Fibrosis ,NFKB1 ,medicine.disease ,Disease Models, Animal ,Endocrinology ,Gene Expression Regulation ,chemistry ,Heart failure ,Immunology ,cardiovascular system ,biology.protein ,Cytokines ,I-kappa B Proteins ,medicine.symptom ,business ,Gene Deletion ,Signal Transduction - Abstract
Calpain has been implicated in acute myocardial injury after myocardial infarction (MI). However, the causal relationship between calpain and post-MI myocardial remodeling has not been fully understood. This study examined whether deletion of Capn4, essential for calpain-1 and calpain-2 activities, reduces myocardial remodeling and dysfunction following MI, and if yes, whether these effects of Capn4 deletion are associated with NF-κB signaling and inflammatory responses in the MI heart. A novel mouse model with cardiomyocyte-specific deletion of Capn4 (Capn4-ko) was employed. MI was induced by left coronary artery ligation. Deficiency of Capn4 dramatically reduced the protein levels and activities of calpain-1 and calpain-2 in the Capn4-ko heart. In vivo cardiac function was relatively improved in Capn4-ko mice at 7 and 30 days after MI when compared with their wild-type littermates. Deletion of Capn4 reduced apoptosis, limited infarct expansion, prevented left ventricle dilation, and reduced mortality in Capn4-ko mice. Furthermore, cardiomyocyte cross-sectional areas and myocardial collagen deposition were significantly attenuated in Capn4-ko mice, which were accompanied by down-regulation of hypertrophic genes and profibrotic genes. These effects of Capn4 knock-out correlated with restoration of IκB protein and inhibition of NF-κB activation, leading to suppression of proinflammatory cytokine expression and inflammatory cell infiltration in the Capn4-ko heart after MI. In conclusion, deficiency of Capn4 reduces adverse myocardial remodeling and myocardial dysfunction after MI. These effects of Capn4 deletion may be mediated through prevention of IκB degradation and NF-κB activation, resulting in inhibition of inflammatory responses.
- Published
- 2012
31. Exosomal miR-223 Contributes to Mesenchymal Stem Cell-Elicited Cardioprotection in Polymicrobial Sepsis
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Basilia Zingarelli, Yigang Wang, Dongze Qin, Guo-Chang Fan, Kobina Essandoh, Haitao Gu, Wei Huang, Charles C. Caldwell, Xiaohong Wang, Tianqing Peng, and Liwang Yang
- Subjects
Lipopolysaccharides ,STAT3 Transcription Factor ,Programmed cell death ,Heart Diseases ,Inflammation ,Biology ,Exosomes ,Mesenchymal Stem Cell Transplantation ,Exosome ,Article ,Sepsis ,03 medical and health sciences ,Mice ,0302 clinical medicine ,mir-223 ,medicine ,Animals ,Myocytes, Cardiac ,030304 developmental biology ,Cardioprotection ,Mice, Knockout ,0303 health sciences ,Multidisciplinary ,Cell Death ,Macrophages ,Mesenchymal stem cell ,Mesenchymal Stem Cells ,Semaphorin-3A ,medicine.disease ,Microvesicles ,Disease Models, Animal ,MicroRNAs ,030220 oncology & carcinogenesis ,Immunology ,Cancer research ,Cytokines ,Female ,medicine.symptom ,Inflammation Mediators - Abstract
Mesenchymal stem cells (MSCs) have been shown to elicit cardio-protective effects in sepsis. However, the underlying mechanism remains obscure. While recent studies have indicated that miR-223 is highly enriched in MSC-derived exosomes, whether exosomal miR-223 contributes to MSC-mediated cardio-protection in sepsis is unknown. In this study, loss-of-function approach was utilized and sepsis was induced by cecal ligation and puncture (CLP). We observed that injection of miR-223-KO MSCs at 1 h post-CLP did not confer protection against CLP-triggered cardiac dysfunction, apoptosis and inflammatory response. However, WT-MSCs were able to provide protection which was associated with exosome release. Next, treatment of CLP mice with exosomes released from miR-223-KO MSCs significantly exaggerated sepsis-induced injury. Conversely, WT-MSC-derived-exosomes displayed protective effects. Mechanistically, we identified that miR-223-KO exosomes contained higher levels of Sema3A and Stat3, two known targets of miR-223 (5p & 3p), than WT-exosomes. Accordingly, these exosomal proteins were transferred to cardiomyocytes, leading to increased inflammation and cell death. By contrast, WT-exosomes encased higher levels of miR-223, which could be delivered to cardiomyocytes, resulting in down-regulation of Sema3A and Stat3. These data for the first time indicate that exosomal miR-223 plays an essential role for MSC-induced cardio-protection in sepsis.
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- 2015
32. Abstract 12624: Blockade of Exosome Secretion Attenuates Inflammatory Cytokines, Mitigates Cardiac Dysfunction, and Reduces Mortality in Polymicrobial Sepsis
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Yigang Wang, Xiaohong Wang, Haitao Gu, Wei Huang, Dongze Qin, Guo-Chang Fan, Ronald W. Millard, Liwang Yang, and Kobina Essandoh
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Cardioprotection ,medicine.medical_specialty ,Ejection fraction ,biology ,business.industry ,Inflammation ,medicine.disease ,Exosome ,Blockade ,Proinflammatory cytokine ,Sepsis ,Endocrinology ,Physiology (medical) ,Myeloperoxidase ,Internal medicine ,Immunology ,biology.protein ,medicine ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business - Abstract
Introduction: Exosomes, a group of nano-vesicles secreted from living cells, are documented to increase in the circulation and are believed to promote cardiac dysfunction in sepsis patients and animal models. However, whether inhibition of exosome release could exert a cardio-protective effect in polymicrobial sepsis remains unexplored. Methods and Results: C57BL/6 mice (male, 8-week old) were pre-treated with GW4869 (dissolved in DMSO, injection i.p. at a dose of 2.5μg/g body weight), a known inhibitor of exosome secretion. Same volume of DMSO was used as controls. One hour later, cecal ligation and puncture (CLP) surgery was performed to induce polymicrobial sepsis. We found that the concentration of serum exosomes, measured by membrane markers CD63 and CD81with detection ELISA kits, was increased by 3.5-fold in DMSO-CLP mice, but no increase was detected in GW4869-CLP mice or in sham operated mice (n=4-6, p Conclusions: Together, this study indicates that blockade of exosome secretion could attenuate the inflammatory cytokine response as well as the consequent cardiac dysfunction and mortality in polymicrobial sepsis. Thus, our study may provide a new approach to the treatment of sepsis.
- Published
- 2014
33. Exosomes Function in Pro- and Anti-Angiogenesis
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Guo-Chang Fan, Ronald W. Millard, Mara Fernandes Ribeiro, and Hongyan Zhu
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Cancer Research ,education.field_of_study ,Angiogenesis ,business.industry ,Population ,Inflammation ,Bioinformatics ,Microvesicles ,Article ,Cell biology ,Endothelial stem cell ,Oncology ,microRNA ,Medicine ,Stem cell ,Progenitor cell ,medicine.symptom ,education ,business - Abstract
Exosomes, a group of small vesicles (30-100 nm), originate when the inward budding of the endosomal membrane forms multivesicular bodies (MVBs). Exosomes are released into the extracellular space when the MVBs fuse with the plasma membrane. Numerous studies have indicated that exosomes play critical roles in mediating cell-to-cell communication. Also, exosomes are believed to possess a powerful capacity in regulating cell survival/death, inflammation and tumor metastasis, depending on the particular array of molecules contained within a particular population of exosomes. This mini-review will summarize dual roles of exosomes derived from different types of cells (i.e. endothelial cells, tumor cells, platelets, bone-marrow stem cells, cardiomyocytes, myocardial progenitor cells and among others) in endothelial cell proliferation, migration and tube-like formation. In particular, this review will focus on the therapeutic potential of exosomes as a natural nano-particle for delivering pro-/anti-angiogenic factors (proteins, mRNAs and microRNAs) into endothelial cells.
- Published
- 2014
34. Endothelial progenitor cells attenuate the lung ischemia/reperfusion injury following lung transplantation via the endothelial nitric oxide synthase pathway.
- Author
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Gao, Wei, Jiang, Tao, Liu, Yan-hong, Ding, Wen-gang, Guo, Chang-chun, and Cui, Xiao-guang
- Abstract
Abstract Objective Endothelial progenitor cells (EPCs) can improve endothelial integrity. This study aimed to examine the effects and the mechanism of EPCs on lung ischemia-reperfusion injury (LIRI). Methods Wistar rats were randomized into the sham or the left lung transplantation group. The recipients were randomized and treated with vehicle as the LIRI group, with EPC as the EPC group, or with N5-(1-iminoethyl)-l-ornithine-pretreated EPC as the EPC/L group (n = 8 per group). The ratios of arterial oxygen partial pressure to fractional inspiratory oxygen were measured. The lung wet-to-dry weight ratios, protein levels, and injury, as well as the levels of plasma cytokines, were examined. The levels of endothelin (ET)-1, endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, inducible NOS, phosphorylated myosin light chain, nuclear factor-κBp65, Bax, Bcl-2, cleaved caspase-3, and myeloperoxidase in the graft lungs were detected. Results Compared with the LIRI group, EPC treatment significantly increased the ratios of arterial oxygen partial pressure to fractional inspiratory oxygen and decreased the lung wet-to-dry weight ratios and protein levels in the grafts, accompanied by increasing eNOS expression and phosphorylation, but decreasing endothelin-1, inducible NOS, phosphorylated nuclear factor-kBp65, phosphorylated myosin light chain expression, and myeloperoxidase activity. EPCs reduced lung tissue damage and apoptosis associated with decreased levels of Bax and cleaved caspase-3 expression, but increased Bcl-2 expression. EPC treatment significantly reduced the levels of serum proinflammatory factors, but elevated levels of interleukin-10. In contrast, the protective effect of EPCs were mitigated and abrogated by N5-(1-iminoethyl)-l-ornithine pretreatment. Conclusions Data indicated that EPC ameliorated LIRI by increasing eNOS expression. Graphical abstract [ABSTRACT FROM AUTHOR]
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- 2019
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35. Interleukin-6 derived from cutaneous deficiency of stearoyl-CoA desaturase- 1 may mediate metabolic organ crosstalk among skin, adipose tissue and liver.
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Dumas, Sabrina N., Guo, Chang-an, Kim, Jason K., Friedline, Randall H., and Ntambi, James M.
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LIPOLYSIS , *INTERLEUKIN-6 , *COENZYME A , *SKIN diseases , *OBESITY treatment , *DESATURASES , *LABORATORY mice - Abstract
Abstract Stearoyl-CoA desaturase 1 (SCD1), a lipogenic enzyme that adds a double bond at the delta 9 position of stearate (C18: 0) and palmitate (C16: 0), has been proven to be important in the development of obesity. Mice with skin-specific deficiency of SCD1 (SKO) display increased whole-body energy expenditure, which is protective against adiposity from a high-fat diet because it improves glucose clearance, insulin sensitivity, and hepatic steatosis. Of note, these mice also display elevated levels of the "pro-inflammatory" plasma interleukin-6 (IL-6). In whole skin of SKO mice, IL-6 mRNA levels are increased, and protein expression is evident in hair follicle cells and in keratinocytes. Recently, the well-known role of IL-6 in causing white adipose tissue lipolysis has been linked to indirectly activating the gluconeogenic enzyme pyruvate carboxylase 1 in the liver, thereby increasing hepatic glucose production. In this study, we suggest that skin-derived IL-6 leads to white adipose tissue lipolysis, which contributes to the lean phenotype of SKO mice without the incidence of meta-inflammation that is associated with IL-6 signaling. Highlights • IL-6 expression is significantly increased in the skin of SKO mice and is also dramatically elevated in blood. • White adipose tissue lipolysis, a well-known effect of IL-6, is evident in SKO mice. • Hepatic PC1 is activated by WAT-derived fatty acids and leads to increased gluconeogenesis in SKO mice. [ABSTRACT FROM AUTHOR]
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- 2019
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36. The small airway epithelium as a target for the adverse pulmonary effects of silver nanoparticle inhalation.
- Author
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Guo, Chang, Buckley, Alison, Marczylo, Tim, Seiffert, Joanna, Römer, Isabella, Warren, James, Hodgson, Alan, Chung, Kian Fan, Gant, Timothy W., Smith, Rachel, and Leonard, Martin O.
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- *
SILVER nanoparticles , *INHALATION injuries , *INFLAMMATION , *GENOMICS , *EPITHELIAL cells , *LUNG diseases , *GENE expression - Abstract
Experimental modeling to identify specific inhalation hazards for nanomaterials has in the main focused on in vivo approaches. However, these models suffer from uncertainties surrounding species-specific differences and cellular targets for biologic response. In terms of pulmonary exposure, approaches which combine ‘inhalation-like’ nanoparticulate aerosol deposition with relevant human cell and tissue air-liquid interface cultures are considered an important complement to in vivo work. In this study, we utilized such a model system to build on previous results from in vivo exposures, which highlighted the small airway epithelium as a target for silver nanoparticle (AgNP) deposition. RNA-SEQ was used to characterize alterations in mRNA and miRNA within the lung. Organotypic-reconstituted 3D human primary small airway epithelial cell cultures (SmallAir) were exposed to the same spark-generated AgNP and at the same dose used in vivo, in an aerosol-exposure air-liquid interface (AE-ALI) system. Adverse effects were characterized using lactate, LDH release and alterations in mRNA and miRNA. Modest toxicological effects were paralleled by significant regulation in gene expression, reflective mainly of specific inflammatory events. Importantly, there was a level of concordance between gene expression changes observed in vitro and in vivo. We also observed a significant correlation between AgNP and mass equivalent silver ion (Ag+) induced transcriptional changes in SmallAir cultures. In addition to key mechanistic information relevant for our understanding of the potential health risks associated with AgNP inhalation exposure, this work further highlights the small airway epithelium as an important target for adverse effects. [ABSTRACT FROM AUTHOR]
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- 2018
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37. Copper disrupts S-nitrosothiol signaling in activated BV2 microglia.
- Author
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Rossi-George, Alba and Guo, Chang-Jiang
- Subjects
- *
CENTRAL nervous system diseases , *CELLULAR signal transduction , *THIOL derivatives , *PHYSIOLOGICAL effects of copper , *MICROGLIA - Abstract
Microglia, the primary resident immune cells of the central nervous system (CNS), responds rapidly to pathogens and injury by secreting immune mediators including nitric oxide (NO). The reaction of NO with the anti-oxidant glutathione forms S-nitrosoglutathione (GSNO), the major pool of biologic NO in the body. GSNO is degraded by GSNO reductase (GSNOR). Recently, we have shown that copper (Cu(I)) inhibits the release of NO in lipopolysaccharide (LPS)-stimulated BV2 microglia and induces BV2 microglia to acquire a mixed a profile with both pro- and anti-inflammatory characteristics. Since GSNOR is the critical enzyme in GSNO metabolism, we sought to determine whether Cu(I) affects GSNOR activity and S-nitrosothiol (SNO) accumulation in activated BV2 microglia. Our results show that GSNOR protein expression is reduced by Cu(I) treatment in LPS-stimulated BV2 microglia. Our results also show a decrease in S-nitrosothiol content despite a reduced GSNOR expression. This effect is most likely due to Cu(I) reacting with the central thiol of the S NO bond resulting in the degradation of SNO. A dose of 1 μM Cu(I) did not affect SNO protein accumulation in LPS-stimulated BV2 microglia, however, a dose of 100 μM Cu(I) inhibited SNO protein in accordance with inhibition of S-nitrosothiols. These data provide direct evidence that Cu(I) disrupts S-nitrosothiol homeostasis and NO metabolism, and, thus, provide new insights into the mechanisms involved in microglia-mediated-CNS disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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38. Study on the Anti-Gout Activity of Chlorogenic Acid: Improvement on Hyperuricemia and Gouty Inflammation.
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Meng, Zhao-Qing, Tang, Zhao-Hui, Yan, Yun-Xia, Guo, Chang-Run, Cao, Liang, Ding, Gang, Huang, Wen-Zhe, Wang, Zhen-Zhong, Wang, Kelvin D.G., Xiao, Wei, and Yang, Zhong-Lin
- Subjects
ANALYSIS of variance ,ANIMAL experimentation ,ENZYME-linked immunosorbent assay ,GOUT ,HYPERURICEMIA ,INFLAMMATION ,INTERLEUKINS ,MICE ,OXIDOREDUCTASES ,POLYPHENOLS ,RATS ,RESEARCH funding ,STATISTICS ,TUMOR necrosis factors ,DATA analysis ,CARBOCYCLIC acids ,DATA analysis software ,DESCRIPTIVE statistics - Abstract
Gout is a metabolic disorder associated with hyperuricemia resulting in the deposition of monosodium urate (MSU) crystals in joints and tissues. Lowering serum uric acid (Sur) levels and anti-inflammation are highly essential in treating gout. Chlorogenic acid (CA), as one of the most abundant polyphenols in the Chinese medicines, has been rarely reported to have an anti-gout effect. The model of potassium oxonate (PO)-induced hyperuricemia in mice and MSU crystal-induced inflammation in rats has been established in this study. The potential beneficial effects and mechanisms of CA on hyperuricemia and gouty arthritis were elucidated. The results demonstrated that CA significantly decreased the Sur level by inhibiting the xanthine oxidase (XOD) activity but not increasing the urinary uric acid (Uur) level. In addition, CA also exhibited the effect of suppressing paw swelling. Further investigation indicated that CA improved the symptoms of inflammation induced by MSU crystals by inhibiting the production of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). The present study suggests that CA may have a considerable potential for development as an anti-gouty arthritis agent for clinical application. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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39. Role of extracellular and intracellular microRNAs in sepsis.
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Essandoh, Kobina and Fan, Guo-Chang
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SEPSIS , *MICRORNA genetics , *BIOMARKERS , *CAUSES of death , *SEVERITY of illness index , *INFLAMMATION , *INTENSIVE care units - Abstract
Sepsis is the major cause of death in the intensive care unit (ICU). Numerous biomarkers have been studied to identify the cause and severity of sepsis but these factors cannot differentiate between infectious and non-infectious inflammatory response. MicroRNAs (miRNAs) are non-coding RNA transcripts that regulate the expression of genes by repressing translation or degrading mRNA. Importantly, miRNAs can be released outside cells and easily detectable in bodily fluids such as blood, sweat, urine and breast milk. Numerous studies have explored the idea of utilizing extracellular miRNAs as biomarkers for sepsis by profiling the dysregulation of miRNAs in blood samples of sepsis patients. So far, miR-223, miR-146a and miR-150 have been identified to have promising prognostic and diagnostic value to sepsis. In addition, various intracellular miRNAs have been implicated to play critical roles in regulating the TLR-NF-κB pathway, which is a well-known inflammatory signaling pathway involved in the process of sepsis. Here, we summarize the recent progress on the role of extracellular and intracellular miRNAs in sepsis. Specifically, we discuss the possible role of circulating miRNA biomarkers for the diagnosis of sepsis and how intracellular miRNAs regulate the inflammatory responses in sepsis. [ABSTRACT FROM AUTHOR]
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- 2014
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40. Molecular cloning of IKKβ from the mandarin fish Siniperca chuatsi and its up-regulation in cells by ISKNV infection
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Chen, Wei-Jian, Guo, Chang-Jun, Zhou, Zhi-Cheng, Yuan, Li-Qun, Xiang, Zhi-Ming, Weng, Shao-Ping, Zhang, Ying-Fen, Yu, Xiao-Qing, and He, Jian-Guo
- Subjects
- *
MOLECULAR cloning , *CELLULAR control mechanisms , *AMINO acids , *CYTOLOGY , *INFLAMMATION , *HELIX-loop-helix motifs , *GENE expression , *NF-kappa B , *VIRUS diseases in fishes - Abstract
Abstract: The IκB kinase β (IKKβ) plays crucial roles in regulating activation of nuclear factor-kappa B (NF-κB) in response to proinflammatory factors and microbial and viral infections. Here, we report the cloning of an IKKβ cDNA (named SicIKKβ) from the mandarin fish Siniperca chuatsi. The full-length cDNA is 4052bp and contains an ORF that encodes a predicted protein of 743-amino acid residues. The deduced amino acid sequence of SicIKKβ has the same domain organization as human IKKβ, which consists of a serine/threonine kinase domain, a leucine zipper motif and a putative helix-loop-helix motif. Quantitative RT-PCR showed that SicIKKβ was ubiquitously expressed in tissues of mandarin fish, and its expression in mandarin fish fry (MFF-1) cells was up-regulated during the course of ISKNV infection. [Copyright &y& Elsevier]
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- 2011
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41. Inflammatory Chemokines in Atherosclerosis.
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Gencer, Selin, Evans, Bryce R., van der Vorst, Emiel P.C., Döring, Yvonne, Weber, Christian, and Fan, Guo-Chang
- Subjects
CHEMOKINES ,PHENOTYPIC plasticity ,ATHEROSCLEROSIS ,CARDIOVASCULAR diseases ,CHEMOKINE receptors ,INTERLEUKIN-8 - Abstract
Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, chemokines and their receptors earned great attention in the research of atherosclerosis as they play a key role in development and progression of atherosclerotic lesions. They orchestrate activation, recruitment, and infiltration of immune cells and subsequent phenotypic changes, e.g., increased uptake of oxidized low-density lipoprotein (oxLDL) by macrophages, promoting the development of foam cells, a key feature developing plaques. In addition, chemokines and their receptors maintain homing of adaptive immune cells but also drive pro-atherosclerotic leukocyte responses. Recently, specific targeting, e.g., by applying cell specific knock out models have shed new light on their functions in chronic vascular inflammation. This article reviews recent findings on the role of immunomodulatory chemokines in the development of atherosclerosis and their potential for targeting. [ABSTRACT FROM AUTHOR]
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- 2021
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42. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction
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Xiaohong Wang, Jiukuan Hao, Tianqing Peng, Kobina Essandoh, Yigang Wang, Guo-Chang Fan, Dongze Qin, Liwang Yang, Wei Huang, and Basilia Zingarelli
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Cardiac function curve ,business.industry ,Macrophages ,Inflammatory response ,Inflammation ,medicine.disease ,Exosomes ,Exosome ,Microvesicles ,Article ,Blockade ,Cardiac dysfunction ,Sepsis ,In vivo ,Immunology ,Medicine ,Molecular Medicine ,medicine.symptom ,business ,Molecular Biology - Abstract
Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12h after LPS treatment or CLP surgery, WT mice pre-treated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival.
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43. Puerarin alleviates streptozotocin (STZ)-induced osteoporosis in rats through suppressing inflammation and apoptosis via HDAC1/HDAC3 signaling.
- Author
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Guo, Chang-Jun, Xie, Jing-Jing, Hong, Rong-Hua, Pan, Han-Song, Zhang, Fu-Guo, and Liang, Yi-Min
- Subjects
- *
RUNX proteins , *BONE density , *ACID phosphatase , *COLLAGEN , *OSTEOPOROSIS , *RATS , *HISTONE deacetylase - Abstract
Diabetic osteoporosis is a severe public health concern in the world. Puerarin (PU) is extensively attractive due to its superior bioactivities. In the study, we found that PU protected against streptozotocin (STZ)-induced osteoporotic changes in rats. PU treatment improved STZ-induced diabetes in rats, as evidenced by the reduced serum glucose and insulin levels. PU administration markedly attenuated bone loss and tartarate-resistant acid phosphatase (TRAP) activity in STZ-induced rats. Bone mineral density (BMD) was significantly decreased in diabetic rats, while being prevented by PU. STZ-induced impairments in microarchitecture of femoral tissues were markedly alleviated by PU treatment. In addition, bone-specific alkaline phosphatase (BALP), osteoprotegerin (OPG) and Runt-related transcription factor 2 (Runx2) levels in serum or tibia were improved by PU in STZ-injected rats; however, TRACP isoform 5b (TRACP-5b), carboxy-terminal collagen cross-links (β-CTX) and receptor activator of nuclear factor-κB ligand (RANKL) levels were decreased. Further, PU treatment inhibited inflammation and apoptosis in STZ-treated rats. Additionally, STZ injection increased histone deacetylase (HDAC)-1 and -3 expressions in femoral heads of rats, which were relieved by PU treatment. Notably, both HDAC1 and HDAC3 could enhance osteoporosis in vitro, as proved by the decreased ALP and Runx2 levels and the increased TRAP expression. Inflammation and apoptosis were exacerbated by HDAC1/3 over-expression, which were markedly diminished by PU treatment. In contrast, suppressing HDAC1/3 significantly abrogated fructose (Fru)-elicited inflammation and apoptosis in cells. Collectively, our data illustrated that PU is a potential therapeutic option to prevent diabetic osteoporosis by inhibiting HDAC1/HDAC3 signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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44. MicroRNA-223-5p and -3p Cooperatively Suppress Necroptosis in Ischemic/Reperfused Hearts.
- Author
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Dongze Qin, Xiaohong Wang, Yutian Li, Liwang Yang, Ruitao Wang, Jiangtong Peng, Kobina Essandoh, Xingjiang Mu, Tianqing Peng, Qinghua Han, Kai-Jiang Yu, and Guo-Chang Fan
- Subjects
- *
MICRORNA , *HEART diseases , *THERAPEUTICS , *INFLAMMATION , *GENE expression , *IN vivo studies - Abstract
Recent studies have shown that myocardial ischemia/reperfusion (I/R)-induced necrosis can be controlled by multiple genes. In this study, we observed that both strands (5p and 3p) of miR- 223 were remarkably dysregulated in mouse hearts upon I/R. Precursor miR-223 (pre-miR-223) transgenic mouse hearts exhibited better recovery of contractile performance over reperfusion period and lesser degree of myocardial necrosis than wild type hearts upon ex vivo and in vivo myocardial ischemia. Conversely, pre-miR-223 knock-out (KO) mouse hearts displayed opposite effects. Furthermore, we found that the RIP1/ RIP3/MLKL necroptotic pathway and inflammatory response were suppressed in transgenic hearts, whereas they were activated in pre-miR-223 KO hearts upon I/R compared with wild type controls. Accordingly, treatment of pre-miR-223 KO mice with necrostatin-1s, a potent necroptosis inhibitor, significantly decreased I/R-triggered cardiac necroptosis, infarction size, and dysfunction. Mechanistically, we identified two critical cell death receptors, TNFR1 and DR6, as direct targets of miR-223- 5p, whereas miR-223-3p directly suppressed the expression of NLRP3 and IκB kinaseα, two important mediators known to be involved in I/R-induced inflammation and cell necroptosis. Our findings indicate that miR-223-5p/-3p duplex works together and cooperatively inhibits I/R-induced cardiac necroptosis at multiple layers. Thus, pre-miR-223 may constitute a new therapeutic agent for the treatment of ischemic heart disease. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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45. Blockade of exosome generation with GW4869 dampens the sepsis-induced inflammation and cardiac dysfunction.
- Author
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Essandoh, Kobina, Yang, Liwang, Wang, Xiaohong, Huang, Wei, Qin, Dongze, Hao, Jiukuan, Wang, Yigang, Zingarelli, Basilia, Peng, Tianqing, and Fan, Guo-Chang
- Subjects
- *
HEART disease genetics , *SEPSIS , *INFLAMMATION , *MULTIPLE organ failure , *EXOSOMES , *CYTOKINES , *MACROPHAGES - Abstract
Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo , we injected wild-type (WT) mice with GW4869 for 1 h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12 h after LPS treatment or CLP surgery, WT mice pre-treated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
46. Loss of duplexmiR-223 (5p and 3p) aggravates myocardial depression and mortality in polymicrobial sepsis.
- Author
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Wang, Xiaohong, Huang, Wei, Yang, Yang, Wang, Yigang, Peng, Tianqing, Chang, Jiang, Caldwell, Charles C., Zingarelli, Basilia, and Fan, Guo-Chang
- Subjects
- *
MICRORNA , *MYOCARDIAL depressants , *CARDIOMYOPATHIES , *MORTALITY , *SEPSIS , *CRITICALLY ill , *MOLECULAR biology - Abstract
Abstract: Sepsis is the leading cause of death in critically ill patients. While myocardial dysfunction has been recognized as a major manifestation in severe sepsis, the underlying molecular mechanisms associated with septic cardiomyopathy remain unclear. In this study, we performed a miRNA array analysis in hearts collected from a severe septic mouse model induced by cecal ligation and puncture (CLP). Among the 19 miRNAs that were dys-regulated in CLP-mouse hearts, miR-223(3p) and miR-223*(5p) were most significantly downregulated, compared with sham-operated mouse hearts. To test whether a drop of miR-223 duplex plays any roles in sepsis-induced cardiac dysfunction and inflammation, a knockout (KO) mouse model with a deletion of the miR-223 gene locus and wild-type (WT) mice were subjected to CLP or sham surgery. We observed that sepsis-induced cardiac dysfunction, inflammatory response and mortality were remarkably aggravated in CLP-treated KO mice, compared with control WTs. Using Western-blotting and luciferase reporter assays, we identified Sema3A, an activator of cytokine storm and a neural chemorepellent for sympathetic axons, as an authentic target of miR-223* in the myocardium. In addition, we validated that miR-223 negatively regulated the expression of STAT-3 and IL-6 in mouse hearts. Furthermore, injection of Sema3A protein into WT mice revealed an exacerbation of sepsis-triggered inflammatory response and myocardial depression, compared with control IgG1 protein-treated WT mice following CLP surgery. Taken together, these data indicate that loss of miR-223/-223* causes an aggravation of sepsis-induced inflammation, myocardial dysfunction and mortality. Our study uncovers a previously unrecognized mechanism underlying septic cardiomyopathy and thereby, may provide a new strategy to treat sepsis. [Copyright &y& Elsevier]
- Published
- 2014
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47. Abstract 15694: Tsg101 Ameliorates Endotoxin-Induced Cardiac Dysfunction Through Enhancing p62/Parkin-Mediated Mitophagy.
- Author
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Essandoh, Kobina, Deng, Shan, Wang, Xiaohong, Mu, Xingjiang, Li, Yutian, and Fan, Guo-Chang
- Subjects
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MITOCHONDRIAL DNA , *PARKIN (Protein) , *INTRAPERITONEAL injections , *MITOCHONDRIA , *REACTIVE oxygen species , *CONTRACTILE proteins - Abstract
Introduction: Cardiac mitochondria l dysfunction and subsequent inflammation are hallmarks of sepsis-induced cardiomyopathy. The p62/Parkin pathway has recently been identified to activate autophagy of damaged mitochondria (mitophagy), regeneration of mitochondria and protection from LPS-induced cardiac dysfunction. Our latest data indicate that p62/Parkin interacted with tumor susceptibility gene 101 (Tsg101) in myocytes, and all three proteins were dysregulated in mouse hearts at 24 h post-injection of LPS. Hypothesis: Overexpression of Tsg101 may protect against endotoxin-induced cardiac injury by promoting of p62/Parkin-induced autophagic removal of damaged mitochondria. Methods and Results: We generated a transgenic (TG) mouse model with cardiac-specific overexpression of Tsg101. TG and wild-type (WT) hearts were subjected to intraperitoneal injection of LPS (10μg/g) to induce endotoxemia. TG hearts exhibited preserved cardiac contractile function and decreased mortality compared to WT mice (n=8, p <0.05). These beneficial effects were accompanied by decreased cardiomyocyte apoptosis (DNA fragmentation and TUNEL-positive nuclei) (n=6, p<0.05) in TG hearts compared with WT. In addition, myocardial inflammation was greatly reduced in endotoxemic-TG hearts compared with WTs, evidenced by lower levels of cytokines, TNF-α, IL-1β and IL-6 (n=6, p<0.05). Mechanistically, co-immunoprecipitation analysis showed that Tsg101 was directly bound to p62 and Parkin in myocytes and protein levels of p62 and Parkin were increased in TG hearts, compared to WTs. Hence, TG hearts showed an enhanced mitophagy, reduced mitochondria damage and lower levels of mitochondria DNA (mtDNA) and reactive oxygen species (mtROS) upon LPS treatment, compared to WTs. Consequently, the use of mitophagy inhibitor, bafilomycin, abrogated the Tsg101-mediated cardioprotection against LPS-induced cardiac damage. In vitro , overexpression of Tsg101 in cardiomyocytes led to increased cell survival upon LPS challenge, which was blocked by either siRNA-mediated knockdown of p62 or Parkin. Conclusion: Our data indicate that elevation of Tsg101 could protect against endotoxin-triggered myocardial injury by promoting p62/Parkin-induced mitophagy. [ABSTRACT FROM AUTHOR]
- Published
- 2018
48. Inflammatory and apoptotic remodeling in autonomic nervous system following myocardial infarction
- Author
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Christoph Rau, Kalyanam Shivkumar, Tatsuo Takamiya, Aman Mahajan, Chen Gao, Yibin Wang, Yang Song, Kimberly Howard-Quijano, and Fan, Guo-Chang
- Subjects
Male ,0301 basic medicine ,Nervous system ,Pathology ,Swine ,Stellate Ganglion ,Myocardial Infarction ,lcsh:Medicine ,Gene Expression ,Apoptosis ,030204 cardiovascular system & hematology ,Cardiovascular ,Regenerative Medicine ,Pathology and Laboratory Medicine ,Vascular Medicine ,0302 clinical medicine ,Ischemia ,Ganglia, Spinal ,Medicine and Health Sciences ,2.1 Biological and endogenous factors ,Myocardial infarction ,Aetiology ,lcsh:Science ,Immune Response ,Multidisciplinary ,Cell Death ,Genomics ,Heart Disease ,medicine.anatomical_structure ,Cell Processes ,Cardiology ,Anatomy ,medicine.symptom ,Transcriptome Analysis ,Arrhythmia ,Biotechnology ,Research Article ,medicine.medical_specialty ,Spinal ,General Science & Technology ,Immunology ,Inflammation ,03 medical and health sciences ,Signs and Symptoms ,Diagnostic Medicine ,Internal medicine ,Genetics ,medicine ,Animals ,Heart Disease - Coronary Heart Disease ,business.industry ,Gene Expression Profiling ,lcsh:R ,Neurosciences ,Biology and Life Sciences ,Computational Biology ,Cardiac arrhythmia ,Cell Biology ,Genome Analysis ,medicine.disease ,Gene expression profiling ,Autonomic nervous system ,Good Health and Well Being ,Biological Tissue ,030104 developmental biology ,Myocardial infarction complications ,lcsh:Q ,Ganglia ,business - Abstract
Author(s): Gao, Chen; Howard-Quijano, Kimberly; Rau, Christoph; Takamiya, Tatsuo; Song, Yang; Shivkumar, Kalyanam; Wang, Yibin; Mahajan, Aman | Abstract: BackgroundChronic myocardial infarction (MI) triggers pathological remodeling in the heart and cardiac nervous system. Abnormal function of the autonomic nervous system (ANS), including stellate ganglia (SG) and dorsal root ganglia (DRG) contribute to increased sympathoexcitation, cardiac dysfunction and arrythmogenesis. ANS modulation is a therapeutic target for arrhythmia associated with cardiac injury. However, the molecular mechanism involved in the pathological remodeling in ANS following cardiac injury remains to be established.Methods and resultsIn this study, we performed transcriptome analysis by RNA-sequencing in thoracic SG and (T1-T4) DRG obtained from Yorkshire pigs following either acute (3 to 5 hours) or chronic (8 weeks) myocardial infarction. By differential expression and weighted gene co-expression network analysis (WGCNA), we identified significant transcriptome changes and specific gene modules in the ANS tissues in response to myocardial infarction at either acute or chronic phases. Both differential expressed genes and the member genes of the WGCNA gene module associated with post-infarct condition were significantly enriched for inflammatory signaling and apoptotic cell death. Targeted validation analysis supported a significant induction of inflammatory and apoptotic signal in both SG and DRG following myocardial infarction, along with cellular evidence of apoptosis induction based on TUNEL analysis. Importantly, these molecular changes were observed specifically in the thoracic segments but not in their counterparts obtained from lumbar sections.ConclusionMyocardial injury leads to time-dependent global changes in gene expression in the innervating ANS. Induction of inflammatory gene expression and loss of neuron cell viability in SG and DRG are potential novel mechanisms contributing to abnormal ANS function which can promote cardiac arrhythmia and pathological remodeling in myocardium.
- Published
- 2017
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