scholarly journals Nicotinamide Prevents Apolipoprotein B-Containing Lipoprotein Oxidation, Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1162
Author(s):  
Karen Alejandra Méndez-Lara ◽  
Nicole Letelier ◽  
Nuria Farre ◽  
Elena M. G. Diarte-Añazco ◽  
Núria Nieto-Nicolau ◽  
...  
Keyword(s):  
Apolipoprotein B ◽  
Immunohistochemical Staining ◽  
Low Dose ◽  
Low Density Lipoproteins ◽  
High Dose ◽  
Aortic Atherosclerosis ◽  
Lipoprotein Oxidation ◽  
Apo E ◽  
Inflammatory Pattern ◽  
Deficient Mice

The potential of nicotinamide (NAM) to prevent atherosclerosis has not yet been examined. This study investigated the effect of NAM supplementation on the development of atherosclerosis in a mouse model of the disease. The development of aortic atherosclerosis was significantly reduced (NAM low dose: 45%; NAM high dose: 55%) in NAM-treated, apolipoprotein (Apo)E-deficient mice challenged with a Western diet for 4 weeks. NAM administration significantly increased (1.8-fold) the plasma concentration of proatherogenic ApoB-containing lipoproteins in NAM high-dose (HD)-treated mice compared with untreated mice. However, isolated ApoB-containing lipoproteins from NAM HD mice were less prone to oxidation than those of untreated mice. This result was consistent with the decreased (1.5-fold) concentration of oxidized low-density lipoproteins in this group. Immunohistochemical staining of aortas from NAM-treated mice showed significantly increased levels of IL-10 (NAM low-dose (LD): 1.3-fold; NAM HD: 1.2-fold), concomitant with a significant decrease in the relative expression of TNFα (NAM LD: −44%; NAM HD: −57%). An improved anti-inflammatory pattern was reproduced in macrophages cultured in the presence of NAM. Thus, dietary NAM supplementation in ApoE-deficient mice prevented the development of atherosclerosis and improved protection against ApoB-containing lipoprotein oxidation and aortic inflammation.

The neonatal Fc receptor (FcRn) is not required for IVIg or anti-CD44 monoclonal antibody–mediated amelioration of murine immune thrombocytopenia

Blood ◽  
2011 ◽  
Vol 118 (24) ◽  
pp. 6403-6406 ◽  
Author(s):  
Andrew R. Crow ◽  
Sara J. Suppa ◽  
Xi Chen ◽  
Patrick J. Mott ◽  
Alan H. Lazarus
Keyword(s):  
Immune Thrombocytopenia ◽  
Low Dose ◽  
Fc Receptor ◽  
High Dose ◽  
Neonatal Fc Receptor ◽  
Antiplatelet Antibody ◽  
Antibody Treatment ◽  
Acute Itp ◽  
Deficient Mice ◽  
Cd44 Antibody

Abstract To definitively determine whether the neonatal Fc receptor (FcRn) is required for the acute amelioration of immune thrombocytopenia (ITP) by IVIg, we used FcRn-deficient mice in a murine ITP model. Mice injected with antiplatelet antibody in the presence or absence of IVIg displayed no difference in platelet-associated IgG between FcRn deficient versus C57BL/6 mice. FcRn-deficient mice treated with high-dose (2 g/kg) IVIg or a low–dose (2 mg/kg) of an IVIg-mimetic CD44 antibody were, however, protected from thrombocytopenia to an equivalent extent as wild-type mice. To verify and substantiate the results found with FcRn-deficient mice, we used β2-microglobulin–deficient mice (which do not express functional FcRn) and found that IVIg or CD44 antibody also protected them from thrombocytopenia. These data suggest that for both high-dose IVIg as well as low-dose CD44 antibody treatment in an acute ITP model, FcRn expression is neither necessary nor required.

scholarly journals CD8+ T Cells Mediate Recovery andImmunopathology in West Nile VirusEncephalitis

2003 ◽  
Vol 77 (24) ◽  
pp. 13323-13334 ◽  
Author(s):  
Yang Wang ◽  
Mario Lobigs ◽  
Eva Lee ◽  
Arno Müllbacher
Keyword(s):  
T Cells ◽  
Dose Group ◽  
Low Dose ◽  
Neuronal Degeneration ◽  
High Dose ◽  
West Nile ◽  
Activation Markers ◽  
High Doses ◽  
The Brain ◽  
Deficient Mice

ABSTRACT C57BL/6J mice infected intravenously with the Sarafend strain of West Nile virus (WNV) develop a characteristic central nervous system (CNS) disease, including an acute inflammatory reaction. Dose response studies indicate two distinct kinetics of mortality. At high doses of infection (108 PFU), direct infection of the brain occurred within 24 h, resulting in 100% mortality with a 6-day mean survival time (MST), and there was minimal destruction of neural tissue. A low dose (103 PFU) of infection resulted in 27% mortality (MST, 11 days), and virus could be detected in the CNS 7 days postinfection (p.i.). Virus was present in the hypogastric lymph nodes and spleens at days 4 to 7 p.i. Histology of the brains revealed neuronal degeneration and inflammation within leptomeninges and brain parenchyma. Inflammatory cell infiltration was detectable in brains from day 4 p.i. onward in the high-dose group and from day 7 p.i. in the low-dose group, with the severity of infiltration increasing over time. The cellular infiltrates in brain consisted predominantly of CD8+, but not CD4+, T cells. CD8+ T cells in the brain and the spleen expressed the activation markers CD69 early and expressed CD25 at later time points. CD8+ T-cell-deficient mice infected with 103 PFU of WNV showed increased mortalities but prolonged MST and early infection of the CNS compared to wild-type mice. Using high doses of virus in CD8-deficient mice leads to increased survival. These results provide evidence that CD8+ T cells are involved in both recovery and immunopathology in WNV infection.

scholarly journals The Endogenous Estradiol Metabolite 2-Methoxyestradiol Reduces Atherosclerotic Lesion Formation in Female Apolipoprotein E-Deficient Mice

Endocrinology ◽  
2007 ◽  
Vol 148 (9) ◽  
pp. 4128-4132 ◽  
Author(s):  
Johan Bourghardt ◽  
Göran Bergström ◽  
Alexandra Krettek ◽  
Sara Sjöberg ◽  
Jan Borén ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Low Dose ◽  
Hormone Replacement ◽  
Atherosclerotic Lesion ◽  
Total Serum ◽  
High Dose ◽  
Lesion Formation ◽  
Cholesterol Levels ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Formation

Estradiol, the major endogenous estrogen, reduces experimental atherosclerosis and metabolizes to 2-methoxyestradiol in vascular cells. Currently undergoing evaluation in clinical cancer trials, 2-methoxyestradiol potently inhibits cell proliferation independently of the classical estrogen receptors. This study examined whether 2-methoxyestradiol affects atherosclerosis development in female mice. Apolipoprotein E-deficient mice, a well-established mouse model of atherosclerosis, were ovariectomized and treated through slow-release pellets with placebo, 17β-estradiol (6 μg/d), or 2-methoxyestradiol [6.66 μg/d (low-dose) or 66.6 μg/d (high-dose)]. After 90 d, body weight gain decreased and uterine weight increased in the high-dose but not low-dose 2-methoxyestradiol group. En face analysis showed that the fractional area of the aorta covered by atherosclerotic lesions decreased in the high-dose 2-methoxyestradiol (52%) but not in the low-dose 2-methoxyestradiol group. Total serum cholesterol levels decreased in the high- and low-dose 2-methoxyestradiol groups (19%, P < 0.05 and 21%, P = 0.062, respectively). Estradiol treatment reduced the fractional atherosclerotic lesion area (85%) and decreased cholesterol levels (42%). In conclusion, our study shows for the first time that 2-methoxyestradiol reduces atherosclerotic lesion formation in vivo. The antiatherogenic activity of an estradiol metabolite lacking estrogen receptor activating capacity may argue that trials on cardiovascular effects of hormone replacement therapy should use estradiol rather than other estrogens. Future research should define the role of 2-methoxyestradiol as a mediator of the antiatherosclerotic actions of estradiol. Furthermore, evaluation of the effects of 2-methoxyestradiol on cardiovascular disease endpoints in ongoing clinical trials is of great interest.

scholarly journals Protective Effect of the Immunosuppressant Sirolimus Against Aortic Atherosclerosis In Apo E-Deficient Mice

2003 ◽  
Vol 3 (5) ◽  
pp. 562-569 ◽  
Author(s):  
M. Merle Elloso ◽  
Neal Azrolan ◽  
Suren N. Sehgal ◽  
Pa-Lang Hsu ◽  
Kristen L. Phiel ◽  
...  
Keyword(s):  
Protective Effect ◽  
Aortic Atherosclerosis ◽  
Apo E ◽  
Deficient Mice

scholarly journals Interleukin-12 Therapy Reduces the Number of Immune Cells and Pathology in Lungs of Mice Infected with Mycobacterium tuberculosis

2004 ◽  
Vol 72 (5) ◽  
pp. 2976-2988 ◽  
Author(s):  
Dawn Nolt ◽  
JoAnne L. Flynn
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Cells ◽  
Low Dose ◽  
Multidrug Resistant ◽  
Interleukin 12 ◽  
High Dose ◽  
Wild Type ◽  
Early Increase ◽  
Serious Disease ◽  
Deficient Mice

ABSTRACT Alternate modalities for the treatment of Mycobacterium tuberculosis are needed due to the rise in numbers of immunosuppressed individuals at risk for serious disease and the increasing prevalence of multidrug-resistant isolates. Interleukin-12 (IL-12) has been shown to improve immune responses against M. tuberculosis infection in both humans and mice. Previous studies using high-dose IL-12 in various disease models reported a paradoxical immunosuppression. We demonstrate here that exogenous administration of IL-12 for 8 weeks after an aerosolized low dose of M. tuberculosis results in increased survival and decreased pulmonary bacterial loads for CD4-T-cell-deficient mice, most likely due to an early increase in gamma interferon. IL-12 treatment did not impair or enhance the ability of the wild-type mice to control infection, as measured by bacterial numbers. Two novel findings are reported here regarding exogenous IL-12 therapy for M. tuberculosis infections: (i) IL-12 treatment resulted in decreased numbers of immune cells and reduced frequencies of lymphocytes (CD8+, CD4+, and NK cells) in the lungs of infected mice and (ii) IL-12 therapy reduced the pathology of M. tuberculosis-infected lungs, as granulomas were smaller and less numerous. These studies support an immunoregulatory role for IL-12 in tuberculosis.

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Regulates Activated Complement C5a in Vivo.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2973-2973
Author(s):  
Toshihiko Nishimura ◽  
Timothy Myles ◽  
Mariko Nagashima ◽  
John Morser ◽  
Ronald G. Pearl ◽  
...  
Keyword(s):  
Low Dose ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Saline Control ◽  
High Dose ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Cell Counts ◽  
Fibrinolysis Inhibitor ◽  
Anti Inflammatory ◽  
Deficient Mice

Abstract The latent plasma carboxypeptidase thrombin-activatable fibrinolysis inhibitor (TAFI) is activated by thrombin/thrombomodulin on the endothelial cell surface, and functions in dampening fibrinolysis. We recently showed that TAFIa efficiently inactivates bradykinin, C5a, and thrombin-cleaved osteopontin, suggesting that it may have a broad anti-inflammatory role. In this study, we examined the pulmonary inflammatory responses in a C5a-induced alveolitis model in wild-type (WT) and TAFI deficient mice. TAFI deficient mice had been backcrossed into a pure C57/B6 background. C5a was instilled into the trachea of anesthetized mice, which were then allowed to recover. Six hours later, bronchiole alveolar lavage (BAL) was performed and the extent of pulmonary inflammation determined. C5a caused a dose-dependent increase in cell counts (WBC/ul) in the BAL fluids in WT mice (saline control, 5.3±4.1 (mean±SD); C5a at 0.05 mg/ml, 28.7±8.5, C5a at 0.1 mg/ml, 60.4±23.8; n=6 for saline and low-dose C5a, n=12 for high dose C5a; p < 0.0005 and < 0.0001 for low-dose and high-dose C5a compared to saline control respectively). Significantly increased BAL cell counts in the TAFI deficient mice in response to C5a stimulation were noted (saline control, 3.3±3.9; low-dose C5a 70±11.2; high-dose C5a 159.6±58.7; n=6 for saline and low-dose C5a, n=12 for high dose C5a; p < 0.00001 and < 5E-0.6 respectively), representing ~2.4–2.6 fold increase in BAL cell counts in the TAFI deficient mice. Determinations of the wet/dried lung weight ratios, an index of pulmonary edema, showed similarly significant results (WT mice: 4.1±0.14, 4.25±0.1, 4.52±0.15 and TAFI-deficient mice: 4.27±0.41, 5.3±0.53, 5.77±0.62 for saline control, low- and high-dose C5a respectively). Our data indicate that in the absence of TAFI, the chemotactic and inflammatory effects of C5a in pulmonary inflammation were enhanced. We are in the process of testing whether E229K thrombin, which selectively activates protein C and TAFI, will ameliorate the C5a alveolitis response in WT mice. Our results support our thesis that the function of TAFIa is not restricted to fibrinolysis. It has a broad anti-inflammatory role and may serve as a homeostatic counterbalance to thrombin’s inflammatory functions.

Plasma and lipoprotein oxidation in apo E-deficient mice with severe hypercholesterolemia and atherosclerosis

1994 ◽  
Vol 109 (1-2) ◽  
pp. 51
Author(s):  
T. Hayek ◽  
J. Oiknine ◽  
J.L. Breslow ◽  
M. Aviram ◽  
J.G. Brook
Keyword(s):  
Lipoprotein Oxidation ◽  
Apo E ◽  
Deficient Mice

scholarly journals NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes

2002 ◽  
Vol 173 (3) ◽  
pp. 457-464 ◽  
Author(s):  
JG Mabley ◽  
G Hasko ◽  
L Liaudet ◽  
F Soriano ◽  
GJ Southan ◽  
...  
Keyword(s):  
Pancreatic Beta Cells ◽  
Low Dose ◽  
Autoimmune Diabetes ◽  
Insulin Dependent Diabetes Mellitus ◽  
Interleukin 12 ◽  
Dependent Diabetes Mellitus ◽  
High Dose ◽  
Streptozotocin Induced Diabetes ◽  
Deficient Mice

Insulin-dependent diabetes mellitus (IDDM) is a disease characterized by the autoimmune destruction of the pancreatic beta-cells, which requires the expression of a number of immune-related genes including major histocompatibility complex proteins, cytokines, chemokines, and cytotoxic enzymes, many of which are regulated by the transcription factor, NFkappaB. Inhibition of the entire NFkappaB family of transcription factors may be harmful, as these factors are involved in many normal physiological processes. However, identifying and targeting specific NFkappaB subunits critical for the pathogenesis of disease may prove to be valuable in designing new therapeutic strategies. To assess the potential role of the NFkappaB subunit, p50, in the development of IDDM, mice with gene disruption for NFkappaB (p50) were investigated for susceptibility to IDDM. We found that p50-deficient mice were fully resistant against multiple low-dose streptozotocin-induced diabetes, a model of diabetes with a strong autoimmune component. The site of involvement of NFkappaB (p50) lies at an early, critical juncture of immune activation and proinflammatory mediator production, because: (1) isolated islets of Langerhans from NFkappaB (p50)-deficient mice were not protected from the islet dysfunction induced by in vitro application of proinflammatory cytokines; (2) p50-deficient mice were not resistant to diabetes induced by a single high dose of streptozotocin, a model with a large oxidant component and no autoimmune involvement; and (3) diabetes induced up-regulation of nitric oxide and interleukin-12 was blocked in the p50-deficient mice. Our data suggest that NFkappaB (p50) has an essential role in the development of autoimmune diabetes. Selective therapeutic blockade of this subunit may be beneficial in preventing IDDM.

scholarly journals Relative Importance of T-Cell Subsets in Monocytotropic Ehrlichiosis: a Novel Effector Mechanism Involved in Ehrlichia-Induced Immunopathology in Murine Ehrlichiosis

2007 ◽  
Vol 75 (9) ◽  
pp. 4608-4620 ◽  
Author(s):  
Nahed Ismail ◽  
Emily C. Crossley ◽  
Heather L. Stevenson ◽  
David H. Walker
Keyword(s):  
T Cells ◽  
T Cell ◽  
Low Dose ◽  
High Dose ◽  
Th1 Cells ◽  
Bacterial Burden ◽  
Toxic Shock ◽  
T Cell Apoptosis ◽  
Tnf Α ◽  
Deficient Mice

ABSTRACT Infection with gram-negative monocytotropic Ehrlichia strains results in a fatal toxic shock-like syndrome characterized by a decreased number of Ehrlichia-specific CD4+ Th1 cells, the expansion of tumor necrosis factor alpha (TNF-α)-producing CD8+ T cells, and the systemic overproduction of interleukin-10 (IL-10) and TNF-α. Here, we investigated the role of CD4+ and CD8+ T cells in immunity to Ehrlichia and the pathogenesis of fatal ehrlichiosis caused by infection with low- and high-dose (103 and 105 bacterial genomes/mouse, respectively) ehrlichial inocula. The CD4+ T-cell-deficient mice showed exacerbated susceptibility to a lethal high- or low-dose infection and harbored higher bacterial numbers than did wild-type (WT) mice. Interestingly, the CD8+ T-cell-deficient mice were resistant to a low dose but succumbed to a high dose of Ehrlichia. The absence of CD8+ T cells abrogated TNF-α and IL-10 production, reduced tissue injury and bacterial burden, restored splenic CD4+ T-cell numbers, and increased the frequency of Ehrlichia-specific CD4+ Th1 cells in comparison to infected WT mice. Although fatal disease is perforin independent, our data suggested that perforin played a critical role in controlling bacterial burden and mediating liver injury. Similar to WT mice, mortality of infected perforin-deficient mice was associated with CD4+ T-cell apoptosis and a high serum concentration of IL-10. Depletion of IL-10 restored the number of CD4+ and CD8+ T cells in infected WT mice. Our data demonstrate a novel mechanism of immunopathology in which CD8+ T cells mediate Ehrlichia-induced toxic shock, which is associated with IL-10 overproduction and CD4+ T-cell apoptosis.

Comparison of localization of metallothionein in tissues of metallothionein-deficient mice

1995 ◽  
Vol 53 ◽  
pp. 1042-1043
Author(s):  
H. Nishimura ◽  
R Nishimura ◽  
D.L. Adelson ◽  
A.E. Michaelska ◽  
K.H.A. Choo ◽  
...  
Keyword(s):  
Metal Binding ◽  
Immunohistochemical Staining ◽  
Squamous Epithelium ◽  
Rabbit Antiserum ◽  
Slight Modification ◽  
Positive Control ◽  
Heavy Metal Binding ◽  
Critical Organ ◽  
Metal Binding Protein ◽  
Deficient Mice

Metallothionein (MT), a cysteine-rich heavy metal binding protein, has several isoforms designated from I to IV. Its major isoforms, I and II, can be induced by heavy metals like cadmium (Cd) and, are present in various organs of man and animals. Rodent testes are a critical organ to Cd and it is still a controversial matter whether MT exists in the testis although it is clear that MT is not induced by Cd in this tissue. MT-IV mRNA was found to localize within tongue squamous epithelium. Whether MT-III is present mainly glial cells or neurons has become a debatable topic. In the present study, we have utilized MT-I and II gene targeted mice and compared MT localization in various tissues from both MT-deficient mice and C57Black/6J mice (C57BL) which were used as an MT-positive control. For MT immunostaining, we have used rabbit antiserum against rat MT-I known to cross-react with mammalian MT-I and II and human MT-III. Immunohistochemical staining was conducted by the method described in the previous paper with a slight modification after the tissues were fixed in HistoChoice and embedded in paraffin.

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