Interleukin-3 is required for thoracic aneurysm and dissection in a mouse model

2018 ◽  
Vol 132 (12) ◽  
pp. 1253-1256 ◽  
Author(s):  
Clinton S. Robbins ◽  
John S. Byrne
Keyword(s):  
Aortic Aneurysm ◽  
Mouse Model ◽  
Inflammatory Cell ◽  
Elastic Fiber ◽  
Disease Process ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 3 ◽  
Mitogen Activated Protein ◽  
Aortic Aneurysm And Dissection ◽  
Matrix Metalloproteinase 12

The pathogenesis of thoracic aortic aneurysm and dissection (TAAD) is complex and incompletely understood. The hallmarks of the disease process are aortic inflammatory cell infiltration and protease mediated elastic fiber disruption. In a study recently published in Clinical Science (2018) 132 (6), 655–668), Liu et al. explore the mechanism through which aortic vascular smooth cells and macrophages participate in TAAD using a mouse model. The authors propose that interleukin-3 (IL-3) released from aortic vascular smooth cells is central to the disease process. IL-3 stimulated matrix metalloproteinase 12 (MMP12) release from macrophages via mitogen activated protein kinase pathways. MMP12 is a protease known to be involved in both aortic aneurysm and dissection. IL-3 knockout mice had significantly reduced aortic wall MMP12, and reduced protease activity. This was associated with protection against TAAD.

scholarly journals A Review of Genetic Abnormalities in Unicentric and Multicentric Castleman Disease

Biology ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 251
Author(s):  
Alexandra Butzmann ◽  
Jyoti Kumar ◽  
Kaushik Sridhar ◽  
Sumanth Gollapudi ◽  
Robert S. Ohgami
Keyword(s):  
Plasma Cells ◽  
Treatment Options ◽  
Disease Process ◽  
Castleman Disease ◽  
Mitogen Activated Protein Kinase ◽  
Human Herpes Virus 8 ◽  
Multicentric Castleman Disease ◽  
Molecular Abnormalities ◽  
Genetic Abnormalities ◽  
Mitogen Activated Protein

Castleman disease (CD) is a rare lymphoproliferative disorder known to represent at least four distinct clinicopathologic subtypes. Large advancements in our clinical and histopathologic description of these diverse diseases have been made, resulting in subtyping based on number of enlarged lymph nodes (unicentric versus multicentric), according to viral infection by human herpes virus 8 (HHV-8) and human immunodeficiency virus (HIV), and with relation to clonal plasma cells (POEMS). In recent years, significant molecular and genetic abnormalities associated with CD have been described. However, we continue to lack a foundational understanding of the biological mechanisms driving this disease process. Here, we review all cases of CD with molecular abnormalities described in the literature to date, and correlate cytogenetic, molecular, and genetic abnormalities with disease subtypes and phenotypes. Our review notes complex karyotypes in subsets of cases, specific mutations in PDGFRB N666S in 10% of unicentric CD (UCD) and NCOA4 L261F in 23% of idiopathic multicentric CD (iMCD) cases. Genes affecting chromatin organization and abnormalities in methylation are seen more commonly in iMCD while abnormalities within the mitogen-activated protein kinase (MAPK) and interleukin signaling pathways are more frequent in UCD. Interestingly, there is a paucity of genetic studies evaluating HHV-8 positive multicentric CD (HHV-8+ MCD) and POEMS-associated CD. Our comprehensive review of genetic and molecular abnormalities in CD identifies subtype-specific and novel pathways which may allow for more targeted treatment options and unique biologic therapies.

Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes

2012 ◽  
Vol 124 (3) ◽  
pp. 191-202 ◽  
Author(s):  
Mona Sedeek ◽  
Alex Gutsol ◽  
Augusto C. Montezano ◽  
Dylan Burger ◽  
Aurelie Nguyen Dinh Cat ◽  
...  
Keyword(s):  
Body Weight ◽  
Low Dose ◽  
Transforming Growth Factor ◽  
Disease Process ◽  
Thiobarbituric Acid ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
High Dose ◽  
Diabetic Mice ◽  
Mitogen Activated Protein

Nox (NADPH oxidase)-derived ROS (reactive oxygen species) have been implicated in the development of diabetic nephropathy. Of the Nox isoforms in the kidney, Nox4 is important because of its renal abundance. In the present study, we tested the hypothesis that GKT136901, a Nox1/4 inhibitor, prevents the development of nephropathy in db/db (diabetic) mice. Six groups of male mice (8-week-old) were studied: (i) untreated control db/m, (ii) low-dose GKT136901-treated db/m (30 mg/kg of body weight per day), (iii) high-dose GKT136901-treated db/m (90 mg/kg of body weight per day), (iv) untreated db/db; (v) low dose GKT136901-treated db/db; and (vi) high-dose GKT136901-treated db/db. GKT136901, in chow, was administered for 16 weeks. db/db mice developed diabetes and nephropathy as evidenced by hyperglycaemia, albuminuria and renal injury (mesangial expansion, tubular dystrophy and glomerulosclerosis). GKT136901 treatment had no effect on plasma glucose or BP (blood pressure) in any of the groups. Plasma and urine TBARSs (thiobarbituric acid-reacting substances) levels, markers of systemic and renal oxidative stress, respectively, were increased in diabetic mice. Renal mRNA expression of Nox4, but not of Nox2, increased, Nox1 was barely detectable in db/db. Expression of the antioxidant enzyme SOD-1 (superoxide dismutase 1) decreased in db/db mice. Renal content of fibronectin, pro-collagen, TGFβ (transforming growth factor β) and VCAM-1 (vascular cell adhesion molecule 1) and phosphorylation of ERK1/2 (extracellular-signal-regulated kinase 1/2) were augmented in db/db kidneys, with no change in p38 MAPK (mitogen-activated protein kinase) and JNK (c-Jun N-terminal kinase). Treatment reduced albuminuria, TBARS and renal ERK1/2 phosphorylation and preserved renal structure in diabetic mice. Our findings suggest a renoprotective effect of the Nox1/4 inhibitor, possibly through reduced oxidative damage and decreased ERK1/2 activation. These phenomena occur independently of improved glucose control, suggesting GKT136901-sensitive targets are involved in complications of diabetes rather than in the disease process.

scholarly journals Phloretin alleviates dinitrochlorobenzene-induced dermatitis in BALB/c mice

2020 ◽  
Vol 34 ◽  
pp. 205873842092944
Author(s):  
Chieh-Shan Wu ◽  
Shih-Chao Lin ◽  
Shiming Li ◽  
Yu-Chih Chiang ◽  
Nicole Bracci ◽  
...  
Keyword(s):  
Mouse Model ◽  
Serum Levels ◽  
Interferon Γ ◽  
Chronic Inflammatory Disease ◽  
Mitogen Activated Protein Kinase ◽  
Normal Ranges ◽  
Mitogen Activated Protein ◽  
Ifn Γ ◽  
Allergic Contact

Atopic dermatitis (AD) is a chronic inflammatory disease of the skin that substantially affects a patient’s quality of life. While steroids are the most common therapy used to temporally alleviate the symptoms of AD, effective and nontoxic alternatives are urgently needed. In this study, we utilized a natural, plant-derived phenolic compound, phloretin, to treat allergic contact dermatitis (ACD) on the dorsal skin of mice. In addition, the effectiveness of phloretin was evaluated using a mouse model of ACD triggered by 2,4-dinitrochlorobenzene (DNCB). In our experimental setting, phloretin was orally administered to BALB/c mice for 21 consecutive days, and then, the lesions were examined histologically. Our data revealed that phloretin reduced the process of epidermal thickening and decreased the infiltration of mast cells into the lesion regions, subsequently reducing the levels of histamine and the pro-inflammatory cytokines interleukin (IL)-6, IL-4, thymic stromal lymphopoietin (TSLP), interferon-γ (IFN-γ) and IL-17A in the serum. These changes were associated with lower serum levels after phloretin treatment. In addition, we observed that the mitogen-activated protein kinase (MAPK) and NF-κB pathways in the dermal tissues of the phloretin-treated rodents were suppressed compared to those in the AD-like skin regions. Furthermore, phloretin appeared to limit the overproliferation of splenocytes in response to DNCB stimulation, reducing the number of IFN-γ-, IL-4-, and IL-17A-producing CD4+ T cells in the spleen back to their normal ranges. Taken together, we discovered a new therapeutic role of phloretin using a mouse model of DNCB-induced ACD, as shown by the alleviated AD-like symptoms and the reversed immunopathological effects. Therefore, we believe that phloretin has the potential to be utilized as an alternative therapeutic agent for treating AD.

scholarly journals Adipose-derived Stem Cell Conditioned Media Extends Survival time of a mouse model of Amyotrophic Lateral Sclerosis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Christine V. Fontanilla ◽  
Huiying Gu ◽  
Qingpeng Liu ◽  
Timothy Z. Zhu ◽  
Changwei Zhou ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Survival Time ◽  
Neuronal Death ◽  
Immunohistochemical Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Trophic Factors ◽  
Mitogen Activated Protein ◽  
Adipose Derived Stem Cell ◽  
Lateral Sclerosis

Abstract Adipose stromal cells (ASC) secrete various trophic factors that assist in the protection of neurons in a variety of neuronal death models. In this study, we tested the effects of human ASC conditional medium (ASC-CM) in human amyotrophic lateral sclerosis (ALS) transgenic mouse model expressing mutant superoxide dismutase (SOD1G93A). Treating symptomatic SOD1G93A mice with ASC-CM significantly increased post-onset survival time and lifespan. Moreover, SOD1G93A mice given ASC-CM treatment showed high motor neuron counts, less activation of microglia and astrocytes at an early symptomatic stage in the spinal cords under immunohistochemical analysis. SOD1G93A mice treated with ASC-CM for 7 days showed reduced levels of phosphorylated p38 (pp38) in the spinal cord, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death. Additionally, the levels of α-II spectrin in spinal cords were also inhibited in SOD1G93A mice treated with ASC-CM for 3 days. Interestingly, nerve growth factor (NGF), a neurotrophic factor found in ASC-CM, played a significant role in the protection of neurodegeneration inSOD1G93A mouse. These results indicate that ASC-CM has the potential to develop into a novel and effective therapeutic treatment for ALS.

Modulation of signal-transduction pathways by chemopreventive agents

2000 ◽  
Vol 28 (2) ◽  
pp. 7-12 ◽  
Author(s):  
M. M. Manson ◽  
K. A. Holloway ◽  
L. M. Howells ◽  
E. A. Hudson ◽  
S. M. Plummer ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Function ◽  
Cell Signalling ◽  
Growth Factor Receptor ◽  
Disease Process ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Chemopreventive Agents ◽  
Mitogen Activated Protein

For a disease such as cancer, where a number of alterations to normal cell function accumulate over time, there are several opportunities to inhibit, slow down or even reverse the process. Many of the changes which drive the disease process occur in cell-signalling pathways that regulate proliferation and apoptosis. As our knowledge of these complicated signalling networks improves, it is becoming clear that many molecules, both drugs and naturally occurring dietary constituents, can interact beneficially with deregulated pathways. Aspirin and other non-steroidal anti-inflammatory drugs, as well as natural compounds present in plants such as green vegetables and tea, can modulate signalling by affecting kinase activity and therefore phosphorylation of key molecules. Examples of pathways which can be modulated by these agents include activation of the transcription factor nuclear factor κB by tumour promoters or cytokines, signalling by growth factors through the growth-factor receptor/extracellular-regulated protein kinase pathways and by a number of other molecules through the stress-activated c-Jun N-terminal kinase and p38 pathways. These mitogen-activated protein kinase pathways regulate a number of transcription factors including c-Fos and c-Jun. Evidence exists, at least from in vitro experiments, that by targeting such pathways, certain dietary compounds may be able to restore abnormal rates of apoptosis and proliferation to more normal levels.

scholarly journals MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

2021 ◽  
Author(s):  
William E. Tidyman ◽  
Alice F. Goodwin ◽  
Yoshiko Maeda ◽  
Ophir D. Klein ◽  
Katherine A. Rauen
Keyword(s):  
Mouse Model ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Skeletal Myopathy ◽  
Mitogen Activated Protein

Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes due to mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due in part to an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction of p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.

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