scholarly journals Upregulation of Cardiac IL-10 and Downregulation of IFN-γin Balb/c IL-4−/−in Acute Chagasic Myocarditis due to Colombian Strain ofTrypanosoma cruzi

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Marcos Vinicius da Silva ◽  
Vera Lúcia de Almeida ◽  
Wendyson Duarte de Oliveira ◽  
Natália Carasek Matos Cascudo ◽  
Pollyana Guimarães de Oliveira ◽  
...  
Keyword(s):  
Acute Phase ◽  
Experimental Infection ◽  
Cardiac Tissue ◽  
Histopathological Analysis ◽  
Nest Density ◽  
Cytokine Levels ◽  
Splenic Cells ◽  
Immune System Regulation ◽  
Deficient Mice

Inflammatory response in Chagas disease is related to parasite and host factors. However, immune system regulation has not been fully elucidated. Thus, this study is aimed at evaluating IL-4 influence on acute phase ofTrypanosoma cruziexperimental infection through dosage of cytokine levels in cardiac homogenate of infected Balb/c WT and Balb/c IL-4−/−as well as its histopathological repercussions. For such purpose, mice were divided into two groups: an infected group with 100 forms of the Colombian strain and an uninfected group. After 21 days of infection, animals were euthanized and the blood, spleen, and heart were collected. The spleen was used to culture splenic cells in 48 h. Subsequently, cytokines TNF-α, IL-12p70, IL-10, IFN-γ, and IL-17 were measured in the blood, culture supernatant, and heart apex by ELISA. The base of the heart was used for histopathological analysis. From these analysis, infected Balb/c IL-4−/−mice showed milder inflammatory infiltrate compared to Balb/c WT, but without changes in nest density and collagen deposition. IL-4 absence culminated in lower cardiac tissue IFN-γproduction, although it did not affect TNF-αexpression in situ. It also decreased TNF-αsystemic production and increased IL-10, both systemically andin situ. In addition, IL-4 absence did not influence IL-17 expression. Splenocytes of IL-4-deficient mice produced higher amounts of IFN-γ, TNF-α, and IL-17 and lower amounts of IL-10. Thus, IL-4 absence in acute phase of experimental infection withT. cruziColombian strain reduces myocarditis due to lower IFN-γproduction and greater IL-10 productionin situand this pattern is not influenced by splenocyte general repertoire.

Hepatoprotective Role of Berberine on Doxorubicin Induced Hepatotoxicity - Involvement of Cyp

2020 ◽  
Vol 21 (7) ◽  
pp. 541-547
Author(s):  
Bao Sun ◽  
Yue Yang ◽  
Mengzi He ◽  
Yanan Jin ◽  
Xiaoyu Cao ◽  
...  
Keyword(s):  
Drug Metabolism ◽  
Cardiac Tissue ◽  
Liver Toxicity ◽  
Elevated Serum ◽  
Similar Response ◽  
Wide Range ◽  
Cytokine Levels ◽  
Major Organ ◽  
Anti Oxidant

Background: The liver is one of the major organ involved in drug metabolism. Cytochrome P450s are predominantly involved in drug metabolism. A wide range of CYPs have been reported in the liver which have been involved in its normal as well as in diseased conditions. Doxorubicin, one of the most potent chemotherapeutic drugs, although highly efficacious, also has adverse side effects, with its targets being liver and cardiac tissue. Objective: The study aims to evaluate the reversal potentials of berberine on Doxorubicin induced cyp conversion. Methodology: In the present study, the interplay between anti-oxidants, cytochrome and inflammatory markers in DOX induced liver toxicity and its possible reversal by berberine was ascertained. Results: DOX administration significantly elevated serum as well as tissue stress, which was reverted by berberine treatment. A similar response was observed in tissue inflammatory mediators as well as in serum cytokine levels. Most profound reduction in the cytochrome expression was found in Cyp 2B1, 2B2, and 2E1. However, 2C1, 2C6, and 3A1 although showed a decline, but it did not revert the expression back to control levels. Conclusion: It could be concluded that berberine may be an efficient anti-oxidant and immune modulator. It possesses low to moderate cytochrome modulatory potentials.

scholarly journals Construction of a mammalian embryo model from stem cells organized by a morphogen signalling centre

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Peng-Fei Xu ◽  
Ricardo Moraes Borges ◽  
Jonathan Fillatre ◽  
Maraysa de Oliveira-Melo ◽  
Tao Cheng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Tracking ◽  
Cardiac Tissue ◽  
Embryonic Stem ◽  
Mammalian Embryo ◽  
Wide Range ◽  
Vitro Model ◽  
Neurula Stage

AbstractGenerating properly differentiated embryonic structures in vitro from pluripotent stem cells remains a challenge. Here we show that instruction of aggregates of mouse embryonic stem cells with an experimentally engineered morphogen signalling centre, that functions as an organizer, results in the development of embryo-like entities (embryoids). In situ hybridization, immunolabelling, cell tracking and transcriptomic analyses show that these embryoids form the three germ layers through a gastrulation process and that they exhibit a wide range of developmental structures, highly similar to neurula-stage mouse embryos. Embryoids are organized around an axial chordamesoderm, with a dorsal neural plate that displays histological properties similar to the murine embryo neuroepithelium and that folds into a neural tube patterned antero-posteriorly from the posterior midbrain to the tip of the tail. Lateral to the chordamesoderm, embryoids display somitic and intermediate mesoderm, with beating cardiac tissue anteriorly and formation of a vasculature network. Ventrally, embryoids differentiate a primitive gut tube, which is patterned both antero-posteriorly and dorso-ventrally. Altogether, embryoids provide an in vitro model of mammalian embryo that displays extensive development of germ layer derivatives and that promises to be a powerful tool for in vitro studies and disease modelling.

Experimental infection with Rangelia vitalii in dogs: Acute phase, parasitemia, biological cycle, clinical-pathological aspects and treatment

2011 ◽  
Vol 128 (4) ◽  
pp. 347-352 ◽  
Author(s):  
Aleksandro S. Da Silva ◽  
Raqueli T. França ◽  
Marcio M. Costa ◽  
Carlos B. Paim ◽  
Francine C. Paim ◽  
...  
Keyword(s):  
Acute Phase ◽  
Experimental Infection ◽  
Biological Cycle

Abstract 116: Detrimental Role of Toll-Like Receptor 4 in Cardiovirus-Induced Myocarditis

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Fumitaka Sato ◽  
Seiichi Omura ◽  
Nicholas E Martinez ◽  
Eiichiro Kawai ◽  
Ganta V Chaitanya ◽  
...  
Keyword(s):  
Immune Responses ◽  
Acute Phase ◽  
Viral Entry ◽  
Viral Myocarditis ◽  
Chronic Phase ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tlr4 Ligand ◽  
Ifn Γ ◽  
Deficient Mice

Picornavirus infections have been known as a leading cause of viral myocarditis in humans. Theiler’s murine encephalomyelitis virus (TMEV) belongs to the genus Cardiovirus, the family Picornaviridae and was reported to cause inflammation in the heart in one manuscript, while its pathomechanism is unclear. In viral myocarditis, viral replication in the heart and/or immune responses against virus as well as heart-antigen (autoimmunity) can contribute to the pathogenesis. Toll-like receptors (TLRs) are pattern recognition receptors (PRRs) that are important for recognizing pathogens as well as triggering innate immunity. Among TLRs, TLR4 has been demonstrated to play important roles in virus-mediated pathology: 1) TLR4 can contribute to viral entry in some viruses, 2) TLR4 may mediate tissue damage by anti-virus immune responses (immunopathology), 3) high levels of TLR4 expression were observed in the heart of patients with dilated cardiomyopathy following acute viral myocarditis, and 4) some viruses can bind to lipopolysaccharide (LPS), which is a TLR4 ligand. To determine the role of TLR4 in TMEV-induced myocarditis, we infected male C3H/HeJ (TLR4-deficient) and C3H/HeNtac (control TLR4+) mice with the DA strain of TMEV. We harvested the hearts and spleens on days 6 and 7 (acute phase) or days 63 and 64 (chronic phase) post-infection. Cardiac pathology was evaluated by hematoxylin and eosin staining and production of pro-inflammatory cytokines, interleukin (IL)-17A and interferon (IFN)-γ, from spleen cells was measured by an enzyme-linked immunosorbent assay (ELISA). In both mice, mild myocarditis was observed during the acute phase of TMEV infection. During the chronic phase, both mice developed severe pathology in the heart, including basophilic degeneration and calcification. However, the incidence of myocarditis was higher in control mice than TLR4-deficient mice. IL-17A and IFN-γ production was higher in control mice than in TLR4-deficient mice (control vs. TLR4-deficient mice, acute phase: IL-17A, 196 vs. 146 pg/ml; IFN-γ, 72 vs. 39 ng/ml; chronic phase: IL-17A, 290 vs. 229 pg/ml; IFN- γ, 142 vs. 88 ng/ml). These results suggest that TLR4 may be detrimental in TMEV-induced myocarditis by increasing pro-inflammatory cytokine production.

Increased muscle fatigability in GLUT-4-deficient mice

2002 ◽  
Vol 282 (2) ◽  
pp. E348-E354 ◽  
Author(s):  
M. Gorselink ◽  
M. R. Drost ◽  
K. F. J. de Brouwer ◽  
G. Schaart ◽  
G. P. J. van Kranenburg ◽  
...  
Keyword(s):  
Peak Power ◽  
Fiber Type ◽  
Flexor Muscle ◽  
Glut 4 ◽  
Muscle Complex ◽  
Alternative Routes ◽  
Deficient Mice ◽  
Shortening Contractions ◽  
Contractile Performance

GLUT-4 plays a predominant role in glucose uptake during muscle contraction. In the present study, we have investigated in mice whether disruption of the GLUT-4 gene affects isometric and shortening contractile performance of the dorsal flexor muscle complex in situ. Moreover, we have explored the hypothesis that lack of GLUT-4 enhances muscle fatigability. Isometric performance normalized to muscle mass during a single tetanic contraction did not differ between wild-type (WT) and GLUT-4-deficient [GLUT-4(−/−)] mice. Shortening contractions, however, revealed a significant 1.4-fold decrease in peak power per unit mass, most likely caused by the fiber-type transition from fast-glycolytic fibers (IIB) to fast-oxidative fibers (IIA) in GLUT-4(−/−) dorsal flexors. In addition, the resting glycogen content was significantly lower (34%) in the dorsal flexor complex of GLUT-4(−/−) mice than in WT mice. Moreover, the muscle complex of GLUT-4(−/−) mice showed enhanced susceptibility to fatigue, which may be related to the decline in the muscle carbohydrate store. The significant decrease in relative work output during the steady-state phase of the fatigue protocol suggests that energy supply via alternative routes is not capable to compensate fully for the lack of GLUT-4.

scholarly journals Ehrlichia canis (Jaboticabal strain) induces the expression of TNF-α in leukocytes and splenocytes of experimentally infected dogs

2011 ◽  
Vol 20 (1) ◽  
pp. 71-74 ◽  
Author(s):  
Joice Lara Maia Faria ◽  
Thiago Demarchi Munhoz ◽  
Carolina Franchi João ◽  
Giovanny Vargas-Hernández ◽  
Marcos Rogério André ◽  
...  
Keyword(s):  
Acute Phase ◽  
Ehrlichia Canis ◽  
Post Inoculation ◽  
Doxycycline Hyclate ◽  
Blood Leukocytes ◽  
Canine Ehrlichiosis ◽  
Tnf Α ◽  
Study Results ◽  
Splenic Cells ◽  
Ifn Γ

Canine ehrlichiosis is caused by the bacterium Ehrlichia canis and is characterized by a systemic febrile disease of unknown pathogenesis. This study evaluated the expression of cytokines TNF-α, IL-10, IFN-γ, in splenic cells and blood leukocytes during the acute phase of ehrlichiosis and after treatment with doxycycline hyclate in dogs experimentally infected with the E. canis Jaboticabal strain. The study results showed a significant expression of TNF-α 18 days post-inoculation, reducing by approximately 70% after treatment. There was a unique peak of expression of IL-10 and IFN-γ 18 and 30 days post-inoculation, respectively. This study suggests that TNF-α plays a role in the pathogenesis of the acute phase of canine ehrlichiosis and that treatment with doxycycline hyclate reduces the systemic effects of this cytokine, possibly by reducing or eliminating parasitemia.

scholarly journals Metformin Reverses the Enhanced Myocardial SR/ER–Mitochondria Interaction and Impaired Complex I-Driven Respiration in Dystrophin-Deficient Mice

2021 ◽  
Vol 8 ◽  
Author(s):  
Claire Angebault ◽  
Mathieu Panel ◽  
Mathilde Lacôte ◽  
Jennifer Rieusset ◽  
Alain Lacampagne ◽  
...  
Keyword(s):  
Complex I ◽  
Early Stage ◽  
Intrinsic Activity ◽  
Proximity Ligation Assay ◽  
Proximity Ligation ◽  
Skeletal Muscle Dysfunction ◽  
Species Production ◽  
Therapeutic Perspective ◽  
Deficient Mice

Besides skeletal muscle dysfunction, Duchenne muscular dystrophy (DMD) exhibits a progressive cardiomyopathy characterized by an impaired calcium (Ca2+) homeostasis and a mitochondrial dysfunction. Here we aimed to determine whether sarco-endoplasmic reticulum (SR/ER)–mitochondria interactions and mitochondrial function were impaired in dystrophic heart at the early stage of the pathology. For this purpose, ventricular cardiomyocytes and mitochondria were isolated from 3-month-old dystrophin-deficient mice (mdx mice). The number of contacts points between the SR/ER Ca2+ release channels (IP3R1) and the porine of the outer membrane of the mitochondria, VDAC1, measured using in situ proximity ligation assay, was greater in mdx cardiomyocytes. Expression levels of IP3R1 as well as the mitochondrial Ca2+ uniporter (MCU) and its regulated subunit, MICU1, were also increased in mdx heart. MICU2 expression was however unchanged. Furthermore, the mitochondrial Ca2+ uptake kinetics and the mitochondrial Ca2+ content were significantly increased. Meanwhile, the Ca2+-dependent pyruvate dehydrogenase phosphorylation was reduced, and its activity significantly increased. In Ca2+-free conditions, pyruvate-driven complex I respiration was decreased whereas in the presence of Ca2+, complex I-mediated respiration was boosted. Further, impaired complex I-mediated respiration was independent of its intrinsic activity or expression, which remains unchanged but is accompanied by an increase in mitochondrial reactive oxygen species production. Finally, mdx mice were treated with the complex I modulator metformin for 1 month. Metformin normalized the SR/ER-mitochondria interaction, decreased MICU1 expression and mitochondrial Ca2+ content, and enhanced complex I-driven respiration. In summary, before any sign of dilated cardiomyopathy, the DMD heart displays an aberrant SR/ER-mitochondria coupling with an increase mitochondrial Ca2+ homeostasis and a complex I dysfunction. Such remodeling could be reversed by metformin providing a novel therapeutic perspective in DMD.

Abstract 380: SAA Lipidation and Delipidation by Hepatocytes

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Ailing Ji ◽  
Akinwunmi Akinmusire ◽  
Maria C de Beer ◽  
Frederick C de Beer ◽  
Nancy R Webb ◽  
...  
Keyword(s):  
Acute Phase ◽  
Serum Amyloid A ◽  
Free Form ◽  
Primary Hepatocytes ◽  
Binding Studies ◽  
Acute Phase Reactants ◽  
Amyloid A ◽  
Large Particles ◽  
And Function ◽  
Deficient Mice

Serum amyloid A (SAA) is one of the most striking acute phase reactants that can rapidly increase 1000-fold in plasma concentration in response to inflammatory cytokines. SAA in lipid-free form exhibits pro-inflammatory activities, but its putative physiological function(s) are poorly understood. SAA is produced and secreted largely by the liver and is present in plasma mainly as an HDL apolipoprotein. The pathways by which SAA is lipidated and incorporated into HDL are poorly understood. Plasma SAA is cleared more rapidly than the other major HDL apolipoproteins, but pathways involved in its delipidation and plasma clearance have also not been defined. In this study we examined how SAA is lipidated in primary hepatocytes and how such lipidation relates to the formation of nascent HDL particles. Endogenous hepatocyte SAA was lipidated and released from cells as large particles that were distinct from apoA-I-containing nascent HDL’s. Unlike apoA-I, formation of these SAA-containing particles was independent of ABCA-I. Similarly, when SAA was exogenously added to cells, SAA was lipidated to form nascent particles that were distinct from apoA-I-containing particles. We further studied the interaction of lipid-free and HDL-bound SAA with hepatocytes. Both in lipid-free form and as part of HDL, SAA exhibited significantly greater binding to cells than apoA-I or apoA-II. Binding studies were also carried out with normal and acute phase HDL’s isolated from control and SAA-deficient mice. Together, the results suggested that SAA, unlike apoA-I, is selectively removed from HDL by binding to hepatocytes. These findings may provide new insights into SAA metabolism and function.

Suppression of fibrin(ogen)-driven pathologies through controlled knockdown by lipid nanoparticle delivery of siRNA

Blood ◽  
2021 ◽  
Author(s):  
Lih Jiin Juang ◽  
Woosuk Steve Hur ◽  
Lakmali Munasinghage Silva ◽  
Amy W Strilchuk ◽  
Brenton Francisco ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Metastatic Potential ◽  
Plasma Fibrinogen ◽  
Fibrinogen Concentration ◽  
Nanoparticle Delivery ◽  
Lipid Nanoparticle ◽  
Cytokine Levels ◽  
Endotoxemia Model ◽  
Peritonitis Model ◽  
Deficient Mice

Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice expressing fibrinogen variants with altered function or with a germline fibrinogen deficiency. However, therapeutic strategies to safely and effectively tailor plasma fibrinogen concentration are lacking. Here, we developed a strategy to tune fibrinogen expression by administering lipid nanoparticle (LNP)-encapsulated siRNA targeting the fibrinogen α chain (siFga). Three distinct LNP-siFga reagents reduced both hepatic Fga mRNA and fibrinogen levels in platelets and plasma, with plasma levels decreased to 42%, 16% and 4% of normal within one-week of administration. Using the most potent siFga, circulating fibrinogen was controllably decreased to 32%, 14%, and 5% of baseline with a 0.5, 1, and 2 mg/kg dose, respectively. Whole blood from mice treated with siFga formed clots with significantly decreased clot strength ex vivo, but siFga treatment did not compromise hemostasis following saphenous vein puncture or tail transection. In an endotoxemia model, siFga suppressed the acute phase response and decreased plasma fibrinogen, D-dimer, and proinflammatory cytokine levels. In a sterile peritonitis model, siFga restored normal macrophage migration in plasminogen-deficient mice. Finally, treatment of mice with siFga decreased the metastatic potential of tumour cells in a manner comparable to that observed in fibrinogen-deficient mice. The results indicate that siFga causes robust and controllable depletion of fibrinogen and provide the proof-of-concept that this strategy can modulate the pleiotropic effects of fibrinogen in relevant disease models.

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