scholarly journals D-Mannose Slows Glioma Growth by Modulating Myeloperoxidase Activity

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6360
Author(s):  
Negin Jalali Motlagh ◽  
Cuihua Wang ◽  
Enrico Giovanni Kuellenberg ◽  
Gregory R. Wojtkiewicz ◽  
Stephan Schmidt ◽  
...  
Keyword(s):  
Immune Response ◽  
Cell Model ◽  
Host Immune Response ◽  
H2o2 Production ◽  
Myeloperoxidase Activity ◽  
Stem Cell Model ◽  
Glioma Growth ◽  
Immunocompetent Mice ◽  
Glioma Progression

Host immune response in the tumor microenvironment plays key roles in tumorigenesis. We hypothesized that D-mannose, a simple sugar with anti-inflammatory properties, could decrease oxidative stress and slow glioma progression. Using a glioma stem cell model in immunocompetent mice, we induced gliomas in the brain and tracked MPO activity in vivo with and without D-mannose treatment. As expected, we found that D-mannose treatment decreased the number of MPO+ cells and slowed glioma progression compared to PBS-treated control animals with gliomas. Unexpectedly, instead of decreasing MPO activity, D-mannose increased MPO activity in vivo, revealing that D-mannose boosted the MPO activity per MPO+ cell. On the other hand, D-glucose had no effect on MPO activity. To better understand this effect, we examined the effect of D-mannose on bone marrow-derived myeloid cells. We found that D-mannose modulated MPO activity via two mechanisms: directly via N-glycosylation of MPO, which boosted the MPO activity of each molecule, and indirectly by increasing H2O2 production, the main substrate for MPO. This increased host immune response acted to reduce tumor size, suggesting that increasing MPO activity such as through D-mannose administration may be a potential new therapeutic direction for glioma treatment.

scholarly journals Optimal control of acute myeloid leukaemia

2018 ◽  
Author(s):  
Jesse A Sharp ◽  
Alexander P Browning ◽  
Tarunendu Mapder ◽  
Kevin Burrage ◽  
Matthew J Simpson
Keyword(s):  
Optimal Control ◽  
Immune Response ◽  
Acute Myeloid Leukaemia ◽  
Myeloid Leukaemia ◽  
Cell Model ◽  
Control Strategies ◽  
Treatment Strategies ◽  
Numerical Convergence ◽  
Stem Cell Model ◽  
Acute Myeloid

AbstractAcute myeloid leukaemia (AML) is a blood cancer affecting haematopoietic stem cells. AML is routinely treated with chemotherapy, and so it is of great interest to develop optimal chemotherapy treatment strategies. In this work, we incorporate an immune response into a stem cell model of AML, since we find that previous models lacking an immune response are inappropriate for deriving optimal control strategies. Using optimal control theory, we produce continuous controls and bang-bang controls, corresponding to a range of objectives and parameter choices. Through example calculations, we provide a practical approach to applying optimal control using Pontryagin’s Maximum Principle. In particular, we describe and explore factors that have a profound influence on numerical convergence. We find that the convergence behaviour is sensitive to the method of control updating, the nature of the control, and to the relative weighting of terms in the objective function. All codes we use to implement optimal control are made available.

Factors modifying protective effect of anti-CD18 antibodies on myocardial reperfusion injury in dogs

1996 ◽  
Vol 270 (1) ◽  
pp. H53-H64 ◽  
Author(s):  
R. G. Perez ◽  
M. Arai ◽  
C. Richardson ◽  
A. DiPaula ◽  
C. Siu ◽  
...  
Keyword(s):  
Infarct Size ◽  
Reperfusion Injury ◽  
Myocardial Reperfusion ◽  
Myocardial Reperfusion Injury ◽  
H2o2 Production ◽  
Myeloperoxidase Activity ◽  
Collateral Flow ◽  
Severe Ischemia

Anti-CD18 monoclonal antibodies (MAb) have demonstrated variable protection against neutrophil (PMN)-mediated myocardial reperfusion injury. To identify factors contributing to this variability, open-chest dogs underwent coronary artery occlusion for 90 min followed by reperfusion for 3.5 h. Ten minutes before reperfusion the dogs received saline (n = 18) or one of three anti-CD18 MAb: MHM.23, R15.7, or PLM-2 (2, 1, and 1 mg/kg and n = 19, 8, and 4, respectively). Collateral flow was measured with radioactive microspheres, area at risk was assessed with monastral blue dye, and infarct size was measured postmortem by triphenyltetrazolium chloride. In vitro, all three MAb bound to canine PMNs, but only MHM.23 and R15.7 inhibited their adherence to keyhole limpet hemocyanin-coated plastic. In vivo, only MHM.23 and R15.7 significantly reduced infarct size after adjusting for the effect of collateral flow. MHM.23 afforded protection in dogs with moderate ischemia (epicardial collateral flow > 0.1 ml.min-1.g-1, infarct size reduced 46%) but not in dogs with more severe ischemia. Only R15.7 was effective in dogs with severe ischemia. Although MHM.23 and R15.7 produced similar inhibition of tissue PMN accumulation, as reflected by myeloperoxidase activity. R15.7 markedly inhibited H2O2 production by PMNs after exposure to platelet-activating factor, whereas MHM.23 had only a minimal effect. The effectiveness of different anti-CD18 MAb in preventing reperfusion injury appears to be 1) highly dependent on the specific anti-CD18 MAb employed, 2) predicted only partially by in vitro binding to PMNs, static in vitro tests of PMN adherence, or the extent of inhibition of PMN accumulation in vivo, 3) related more to their ability to inhibit oxidant release from activated PMNs, and 4) strongly influenced by the severity of myocardial ischemia before reperfusion.

Unravelling some mysteries of porcine respiratory and reproductive syndrome virus (PRRSV) infections: new insights from modelling studies

2009 ◽  
Vol 2009 ◽  
pp. 30-30
Author(s):  
A Doeschl-Wilson ◽  
I Kyriazakis ◽  
L Galina-Pantoja
Keyword(s):  
Immune Response ◽  
Host Immune Response ◽  
Growing Pigs ◽  
Modelling Studies ◽  
Porcine Respiratory ◽  
Insight Into

Porcine reproductive and respiratory syndrome (PRRS) is an endemic pig disease in most European countries, causing respiratory distress, fever and growth reductions in growing pigs and increased litter mortality in sows. The disease is characterised by exceptionally long-term viral persistence within the host, a weak innate host immune response and delayed adaptive host immune response, and large between animal variation in the immune response (Murtaugh et al., 2004). Although numerous in-vitro and in-vivo studies produced valid insight into the fine details of the virus dynamics and its interaction with the host’s immune response, several fundamental questions concerning the role of diverse immune components and host genetics remain unanswered. In this study mathematical models were developed to investigate the role of diverse processes caused by the virus or the immune response on the infection characteristics.

scholarly journals Lack of Interleukin-6 Affects IFN-γ and TNF-α Production and Early In Vivo Control of Brucella abortus Infection

Pathogens ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 1040
Author(s):  
Erika S. Guimarães ◽  
Jéssica M. Martins ◽  
Marco Túlio R. Gomes ◽  
Daiane M. Cerqueira ◽  
Sergio C. Oliveira
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Brucella Abortus ◽  
Interleukin 6 ◽  
Early Phase ◽  
Protective Role ◽  
Myeloperoxidase Activity ◽  
Tnf Α ◽  
Ifn Γ

Interleukin-6 (IL-6) is a pleiotropic cytokine promptly produced in response to infections, which contributes to host defense through the stimulation of acute phase immune responses. Brucella abortus is an intracellular bacterium that causes chronic disease in humans and domestic animals and triggers a robust immune response, characterized by the production of inflammatory cytokines. However, the mechanisms of IL-6-related immune responses in the context of Brucella infections are not completely understood. In this report, we describe an increased susceptibility of IL-6 knockout (KO) mice in the early phase of Brucella infection. Furthermore, we demonstrate that IL-6 is required for interferon (IFN)-γ and tumor necrosis factor (TNF)-α induction by infected splenocytes, indicating a protective role for IL-6 against B. abortus that parallels with Th1 type of immune response. Additionally, IL-6 KO mice exhibited reduced splenomegaly during the early phase of the infection. Corroborating this result, IL-6 KO mice displayed reduced numbers of macrophages, dendritic cells, and neutrophils in the spleen and reduced myeloperoxidase activity in the liver compared to wild-type infected mice. However, we demonstrate that IL-6 is not involved in B. abortus intracellular restriction in mouse macrophages. Taken together, our findings demonstrate that IL-6 contributes to host resistance during the early phase of B. abortus infection in vivo, and suggest that its protective role maybe partially mediated by proinflammatory immune responses and immune cell recruitment.

scholarly journals Opticalin vivoandex vivoimaging of glioma cells migration via the cerebral vessels: Prospective clinical application of the beta2-adrenoreceptors blockade for glioma treatment

2018 ◽  
Vol 11 (04) ◽  
pp. 1850025 ◽  
Author(s):  
Olga Pavlova ◽  
Alexander Shirokov ◽  
Alexander Fomin ◽  
Nikita Navolokin ◽  
Andrey Terskov ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Malignant Gliomas ◽  
Glioma Cells ◽  
Cerebral Vessels ◽  
Limited Information ◽  
Glioma Growth ◽  
Slow Progress ◽  
Pharmacological Blockade ◽  
Glioma Progression

Malignant gliomas are highly invasive tumors that use the cerebral vessels for invasion due to high vascular fragility of the blood–brain barrier (BBB). On one hand, glioma is characterized by the BBB disruption, on the other hand, drug brain delivery via the BBB is a big challenge in glioma therapy. The limited information about vascular changes associated with glioma growth is a reason of slow progress in prevention of glioma development.Here, we present in vivo and ex vivo study of the BBB disruption and glioma cells (GCs) migration in rats using fluorescence and confocal microscopy. We uncovered a local breach in the BBB in the main tumor mass but not within the border of normal and malignant cells, where the BBB was impermeable for high weight molecules. The migration of GCs were observed via the cerebral vessels with the intact BBB that was associated with macrophages infiltration.The mechanisms underlying glioma progression remain unknown but there is an evidence that the sympathetic nervous system (SNS) via activation of vascular beta2-adrenoreceptors (B2-ADRs) can play an important role in tumor metastasis. Our results clearly show an increase in the expression of vascular B2-ADRs and production of the beta-arrestin-1 — co-factor of B2-ADRs signaling pathway in rats with glioma. Pharmacological blockade of B2-ADRs reduces the BBB disruption, macrophages infiltration, GCs migration and increases survival rate.These data suggest that the blockade of B2-ADRs may be a novel adjuvant therapeutic strategy to reduce glioma progression and prevent metastasis.

Comparative in vivo infection models yield insights on early host immune response to Campylobacter in chickens

2008 ◽  
Vol 61 (2) ◽  
pp. 101-110 ◽  
Author(s):  
Kieran G. Meade ◽  
Fernando Narciandi ◽  
Sarah Cahalane ◽  
Carla Reiman ◽  
Brenda Allan ◽  
...  
Keyword(s):  
Immune Response ◽  
Host Immune Response ◽  
Infection Models

Invincible, but Not Invisible: Imaging Approaches Toward In Vivo Detection of Cancer Stem Cells

2008 ◽  
Vol 26 (17) ◽  
pp. 2901-2910 ◽  
Author(s):  
Lori S. Hart ◽  
Wafik S. El-Deiry
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cancer Stem Cells ◽  
Cancer Stem Cell ◽  
Natural Environment ◽  
Cell Model ◽  
Advanced Imaging ◽  
Stem Cell Model ◽  
Cancer Stem Cell Model

With evidence emerging in support of a cancer stem-cell model of carcinogenesis, it is of paramount importance to identify and image these elusive cells in their natural environment. The cancer stem-cell hypothesis has the potential to explain unresolved questions of tumorigenesis, tumor heterogeneity, chemotherapeutic and radiation resistance, and even the metastatic phenotype. Intravital imaging of cancer stem cells could be of great value for determining prognosis, as well as monitoring therapeutic efficacy and influencing therapeutic protocols. Cancer stem cells represent a rare population of cells, as low as 0.1% of cells within a human tumor, and the phenotype of isolated cancer stem cells is easily altered when placed under in vitro conditions. This represents a challenge in studying cancer stem cells without manipulation or extraction from their natural environment. Advanced imaging techniques allow for the in vivo observation of physiological events at cellular resolution. Cancer stem-cell studies must take advantage of such technology to promote a better understanding of the cancer stem-cell model in relation to tumor growth and metastasis, as well as to potentially improve on the principles by which cancers are treated. This review examines the opportunities for in vivo imaging of putative cancer stem cells with regard to currently accepted cancer stem-cell characteristics and advanced imaging technologies.

scholarly journals The Bacterial Second Messenger Cyclic di-GMP Regulates Brucella Pathogenesis and Leads to Altered Host Immune Response

2016 ◽  
Vol 84 (12) ◽  
pp. 3458-3470 ◽  
Author(s):  
Mike Khan ◽  
Jerome S. Harms ◽  
Fernanda M. Marim ◽  
Leah Armon ◽  
Cherisse L. Hall ◽  
...  
Keyword(s):  
Immune Response ◽  
Second Messenger ◽  
Host Immune Response ◽  
Vital Role ◽  
Host Cells ◽  
Content Type ◽  
Type Iv

Brucella species are facultative intracellular bacteria that cause brucellosis, a chronic debilitating disease significantly impacting global health and prosperity. Much remains to be learned about how Brucella spp. succeed in sabotaging immune host cells and how Brucella spp. respond to environmental challenges. Multiple types of bacteria employ the prokaryotic second messenger cyclic di-GMP (c-di-GMP) to coordinate responses to shifting environments. To determine the role of c-di-GMP in Brucella physiology and in shaping host- Brucella interactions, we utilized c-di-GMP regulatory enzyme deletion mutants. Our results show that a Δ bpdA phosphodiesterase mutant producing excess c-di-GMP displays marked attenuation in vitro and in vivo during later infections. Although c-di-GMP is known to stimulate the innate sensor STING, surprisingly, the Δ bpdA mutant induced a weaker host immune response than did wild-type Brucella or the low-c-di-GMP guanylate cyclase Δ cgsB mutant. Proteomics analysis revealed that c-di-GMP regulates several processes critical for virulence, including cell wall and biofilm formation, nutrient acquisition, and the type IV secretion system. Finally, Δ bpdA mutants exhibited altered morphology and were hypersensitive to nutrient-limiting conditions. In summary, our results indicate a vital role for c-di-GMP in allowing Brucella to successfully navigate stressful and shifting environments to establish intracellular infection.

scholarly journals Exposure of Immunocompetent Adult Mice to Pneumocystis carinii f. sp. muris by Cohousing: Growth of P. carinii f. sp. muris and Host Immune Response

2003 ◽  
Vol 71 (4) ◽  
pp. 2065-2070 ◽  
Author(s):  
Chun Li An ◽  
Francis Gigliotti ◽  
Allen G. Harmsen
Keyword(s):  
Immune Response ◽  
Pneumocystis Carinii ◽  
Clinical Signs ◽  
Host Immune Response ◽  
Immunocompetent Adult ◽  
Adult Mice ◽  
Specific Immunoglobulin ◽  
Immunocompetent Mice ◽  
Kinetics Of ◽  
Microscopic Techniques

ABSTRACT There has been emerging evidence that immunocompetent hosts can harbor Pneumocystis in their lungs. The purpose of this study was to determine the kinetics of Pneumocystis carinii f. sp. muris infection in adult immunocompetent mice and the host immune response to the organisms. To accomplish this, we exposed adult immunocompetent mice to SCID mice infected with P. carinii f. sp. muris by cohousing. We found that P. carinii f. sp. muris was detectable in the lungs of cohoused immunocompetent mice by PCR by 3 weeks after the beginning of cohousing. At about 4 weeks of cohousing, P. carinii f. sp. muris was readily detectable in the lungs of mice by microscopic techniques. Also at this time, P. carinii f. sp. muris-specific immunoglobulin G was found in the sera of the mice, and CD62low CD4- and CD8-positve T cells accumulated in the lungs. Shortly after this immune response, the P. carinii f. sp. muris organisms were cleared from the lungs. Adult mice cohoused for only 1 week also contained P. carinii f. sp. muris cysts detectable by silver staining at 5 and 6 weeks after the beginning of cohousing. We also found that the P. carinii f. sp. muris organisms grew to greater numbers in the lungs of BALB/c mice than in those of C57BL6 mice. This indicates that immunocompetent hosts develop a mild infection with P. carinii f. sp. muris which resolves in 5 to 6 weeks when there is a detectable immune response to the organism. Once an acquired immune response was initiated, the P. carinii f. sp. muris organisms were quickly eliminated without clinical signs of disease.

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