scholarly journals Wheat Bran Extract Regulates Mast Cell-Mediated Allergic Responses In Vitro and In Vivo

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3997 ◽  
Author(s):  
Jae Yeon Lee ◽  
Eun-Kyung Ahn ◽  
Ju-Hyoung Park ◽  
Joa Sub Oh
Keyword(s):  
Mast Cell ◽  
Wheat Bran ◽  
Molecular Mechanisms ◽  
Immunoglobulin E ◽  
Water Extract ◽  
Allergic Diseases ◽  
Mitogen Activated Protein Kinase ◽  
Food Ingredients

In the present study the effects and molecular mechanisms of wheat bran (WB), the hard outer layer of the wheat kernel used in food ingredients, on mast cell-mediated allergic responses in vitro and in vivo were investigated. The water extract of WB inhibited degranulation and expression of allergic and inflammatory mediators such as tumor necrosis factor-α, cyclooxygenase-2 and inducible nitric oxide synthase in antigen-stimulated RBL-2H3 cells. These anti-allergic activities of WB were mediated by the inactivation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase, which play important roles in degranulation and expression of various allergic and inflammatory molecules. In agreement with its in vitro effects, WB inhibited immunoglobulin E (IgE)/antigen-induced and compound 48/80-induced anaphylactic reactions in vivo. Taken together, these findings suggest the pharmacological potential of WB in the regulation of allergic diseases, including allergic rhinitis, atopic dermatitis, asthma and anaphylaxis.

Fruiting Bodies of Antrodia cinnamomea and Its Active Triterpenoid, Antcin K, Ameliorates N-Nitrosodiethylamine-Induced Hepatic Inflammation, Fibrosis and Carcinogenesis in Rats

2017 ◽  
Vol 45 (01) ◽  
pp. 173-198 ◽  
Author(s):  
An-Jan Tien ◽  
Chen-Yen Chien ◽  
Yueh-Hsi Chen ◽  
Lung-Chin Lin ◽  
Chiang-Ting Chien
Keyword(s):  
Defense Mechanisms ◽  
Molecular Mechanisms ◽  
Water Extract ◽  
Oral Intake ◽  
In Vitro Study ◽  
Mitogen Activated Protein Kinase ◽  
Hplc Fingerprint ◽  
Antrodia Cinnamomea

Antrodia cinnamomea (A. cinnamomea), a popular medicinal mushroom in Taiwan, is widely used to prevent or treat liver diseases. Systematic studies on the anti-inflammatory effect of A. cinnamomea and its molecular mechanisms have not yet been fully investigated. HPLC fingerprint analysis identified seven ergostane-type triterpenoids from A. cinnamomea water extract (ACW), including high amounts of Antcin K (AC), Antcin C, Antcin H, Dehydrosulphurenic acid, Antcin B, Antcin A and Dehydroeburicoic acid. Here, we explored the effects and mechanisms of ACW and the highest content AC on N-nitrosodiethylamine (DEN) induced liver inflammation, fibrosis and carcinogenesis in rats. In the in vitro study, we measured how ACW and AC dose-dependently scavenged O[Formula: see text], H2O2 and HOCl by a chemiluminescence analyzer. In the in vivo experiment, oral intake ACW and AC significantly inhibited DEN-enhanced hepatocellular inflammation, fibrosis and carcinoma by pathologic observation, the elevated bile and liver reactive oxygen species (ROS) amounts, plasma [Formula: see text]-glutamyl transpeptidase, and oxidative stress including 3-nitrotyrosine, 4-hydroxynonenal and Kuppfer cell infiltration (ED-1 stains) in the inflammatory livers. DEN enhanced nuclear factor-[Formula: see text]B (NF-[Formula: see text]B) translocation, whereas ACW and AC suppressed DEN-enhanced NF-[Formula: see text]B translocation through the inhibition of its upstream signaling of p85/phosphoinositide-3-kinase, mitogen activated protein kinase and CYP2E1 expression. In conclusion, DEN can induce hepatocellular inflammation, fibrosis and carcinoma by increasing NF-[Formula: see text]B translocation to the nucleus, and oxidative injury. ACW and its active component, Antcin K, counteract DEN-induced hepatic injury and inflammation by the protective and therapeutic mechanisms of a direct scavenging ROS activity and an upregulation of anti-oxidant defense mechanisms.

scholarly journals IgE Antibodies against Cancer: Efficacy and Safety

Antibodies ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 55
Author(s):  
Jitesh Chauhan ◽  
Alex J. McCraw ◽  
Mano Nakamura ◽  
Gabriel Osborn ◽  
Heng Sheng Sow ◽  
...  
Keyword(s):  
Perceived Risk ◽  
Immunoglobulin E ◽  
Ex Vivo ◽  
Risk Mitigation ◽  
Antitumour Activity ◽  
Allergic Diseases ◽  
Type I ◽  
Ige Antibodies

Immunoglobulin E (IgE) antibodies are well known for their role in allergic diseases and for contributions to antiparasitic immune responses. Properties of this antibody class that mediate powerful effector functions may be redirected for the treatment of solid tumours. This has led to the rise of a new class of therapeutic antibodies to complement the armamentarium of approved tumour targeting antibodies, which to date are all IgG class. The perceived risk of type I hypersensitivity reactions following administration of IgE has necessitated particular consideration in the development of these therapeutic agents. Here, we bring together the properties of IgE antibodies pivotal to the hypothesis for superior antitumour activity compared to IgG, observations of in vitro and in vivo efficacy and mechanisms of action, and a focus on the safety considerations for this novel class of therapeutic agent. These include in vitro studies of potential hypersensitivity, selection of and observations from appropriate in vivo animal models and possible implications of the high degree of glycosylation of IgE. We also discuss the use of ex vivo predictive and monitoring clinical tools, as well as the risk mitigation steps employed in, and the preliminary outcomes from, the first-in-human clinical trial of a candidate anticancer IgE therapeutic.

scholarly journals IgE Enhances Mouse Mast Cell FcεRI Expression In Vitro and In Vivo: Evidence for a Novel Amplification Mechanism in IgE-dependent Reactions

1997 ◽  
Vol 185 (4) ◽  
pp. 663-672 ◽  
Author(s):  
Masao Yamaguchi ◽  
Chris S. Lantz ◽  
Hans C. Oettgen ◽  
Ildy M. Katona ◽  
Tony Fleming ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Specific Antigen ◽  
Mast Cell Activation ◽  
Proinflammatory Mediators ◽  
Mouse Mast Cell

The binding of immunoglobulin E (IgE) to high affinity IgE receptors (FcεRI) expressed on the surface of mast cells primes these cells to secrete, upon subsequent exposure to specific antigen, a panel of proinflammatory mediators, which includes cytokines that can also have immunoregulatory activities. This IgE- and antigen-specific mast cell activation and mediator production is thought to be critical to the pathogenesis of allergic disorders, such as anaphylaxis and asthma, and also contributes to host defense against parasites. We now report that exposure to IgE results in a striking (up to 32-fold) upregulation of surface expression of FcεRI on mouse mast cells in vitro or in vivo. Moreover, baseline levels of FcεRI expression on peritoneal mast cells from genetically IgE-deficient (IgE −/−) mice are dramatically reduced (by ∼83%) compared with those on cells from the corresponding normal mice. In vitro studies indicate that the IgE-dependent upregulation of mouse mast cell FcεRI expression has two components: an early cycloheximide-insensitive phase, followed by a later and more sustained component that is highly sensitive to inhibition by cycloheximide. In turn, IgE-dependent upregulation of FcεRI expression significantly enhances the ability of mouse mast cells to release serotonin, interleukin-6 (IL-6), and IL-4 in response to challenge with IgE and specific antigen. The demonstration that IgE-dependent enhancement of mast cell FcεRI expression permits mast cells to respond to antigen challenge with increased production of proinflammatory and immunoregulatory mediators provides new insights into both the pathogenesis of allergic diseases and the regulation of protective host responses to parasites.

scholarly journals Negative Regulation of FcεRI-mediated Degranulation by CD81

1997 ◽  
Vol 186 (8) ◽  
pp. 1307-1314 ◽  
Author(s):  
Tony J. Fleming ◽  
Emmanuel Donnadieu ◽  
Chang Ho Song ◽  
Francois Van Laethem ◽  
Stephen J. Galli ◽  
...  
Keyword(s):  
Mast Cell ◽  
Tyrosine Kinases ◽  
Immunoglobulin E ◽  
Allergic Diseases ◽  
Calcium Mobilization ◽  
Mast Cell Degranulation ◽  
Antigen Receptors ◽  
High Affinity Receptor ◽  
Inositol Phosphatases

Signaling through the high affinity receptor for immunoglobulin E (FcεRI) results in the coordinate activation of tyrosine kinases before calcium mobilization. Receptors capable of interfering with the signaling of antigen receptors, such as FcεRI, recruit tyrosine and inositol phosphatases that results in diminished calcium mobilization. Here, we show that antibodies recognizing CD81 inhibit FcεRI-mediated mast cell degranulation but, surprisingly, without affecting aggregation-dependent tyrosine phosphorylation, calcium mobilization, or leukotriene synthesis. Furthermore, CD81 antibodies also inhibit mast cell degranulation in vivo as measured by reduced passive cutaneous anaphylaxis responses. These results reveal an unsuspected calcium-independent pathway of antigen receptor regulation, which is accessible to engagement by membrane proteins and on which novel therapeutic approaches to allergic diseases could be based.

scholarly journals S100A4 Is Critical for a Mouse Model of Allergic Asthma by Impacting Mast Cell Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Tongqian Wu ◽  
Lan Ma ◽  
Xiaoqian Jin ◽  
Jingjing He ◽  
Ke Chen ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Calcium Binding ◽  
Cell Activation ◽  
Allergic Diseases ◽  
Lavage Fluid ◽  
Mast Cell Activation ◽  
Asthma Model

BackgroundThe calcium-binding protein S100A4 demonstrates important regulatory roles in many biological processes including tumorigenesis and inflammatory disorders such as allergy. However, the specific mechanism of the contribution of S100A4 to allergic diseases awaits further clarification.ObjectiveTo address the effect of S100A4 on the regulation of mast cell activation and its impact on allergy.MethodsBone marrow-derived cultured mast cells (BMMCs) were derived from wild-type (WT) or S100A4-/- mice for in vitro investigation. WT and S100A4-/- mice were induced to develop a passive cutaneous anaphylaxis (PCA) model, a passive systemic anaphylaxis (PSA) model, and an ovalbumin (OVA)-mediated mouse asthma model.ResultsFollowing OVA/alum-based sensitization and provocation, S100A4-/- mice demonstrated overall suppressed levels of serum anti-OVA IgE and IgG antibodies and proinflammatory cytokines in serum, bronchoalveolar lavage fluid (BALF), and lung exudates. S100A4-/- mice exhibited less severe asthma signs which included inflammatory cell infiltration in the lung tissue and BALF, and suppressed mast cell recruitment in the lungs. Reduced levels of antigen reencounter-induced splenocyte proliferation in vitro were recorded in splenocytes from OVA-sensitized and challenged mice that lacked S100A4-/-. Furthermore, deficiency in the S100A4 gene could dampen mast cell activation both in vitro and in vivo, evidenced by reduced β-hexosaminidase release and compromised PCA and PSA reaction. We also provided evidence supporting the expression of S100A4 by mast cells.ConclusionS100A4 is required for mast cell functional activation, and S100A4 may participate in the regulation of allergic responses at least partly through regulating the activation of mast cells.

scholarly journals Trigonelline, An Alkaloid From Leonurus japonicus Houtt., Suppresses Mast Cell Activation and OVA-Induced Allergic Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenhui Zhang ◽  
Yingling Zhang ◽  
Simin Chen ◽  
Hong Zhang ◽  
Man Yuan ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mast Cell Activation ◽  
Dependent Manner ◽  
Anti Inflammatory

Trigonelline, one of the active compounds from Leonurus japonicus Houtt., has been proven to have pharmacological value in diabetes, the central nervous system and cardiovascular diseases. Recent studies have shown that it may also be beneficial in controlling inflammation. However, the mechanism of the antiallergic effects of trigonelline has not been well studied. As the key effector cells participating in the development of allergies, mast cells have been linked to the pathogenesis of asthma for ages. In this study, we demonstrated the inhibitory effect of trigonelline on activated bone marrow-derived mast cells (BMMCs) and verified its anti-inflammatory properties using an ovalbumin (OVA)-induced asthma model. Trigonelline suppressed BMMC degranulation and decreased the production of the cytokines, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) in a dose-dependent manner. The potent mechanism is mainly through the suppression of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Trigonelline can alleviate pathological damage in lung tissue and reduce the levels of serum immunoglobulin E (IgE) and T helper 2 (Th2) cytokines. RNA-seq results revealed the HIF-1α to be a potential target for the allergic reaction. Taken together, our study demonstrated that trigonelline can inhibit allergic inflammation in vitro and in vivo, which may provide a basis for novel anti-inflammatory drug development.

scholarly journals Pazopanib and Trametinib as a Synergistic Strategy against Osteosarcoma: Preclinical Activity and Molecular Insights

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1519
Author(s):  
Giulia Chiabotto ◽  
Giovanni Grignani ◽  
Maja Todorovic ◽  
Valentina Martin ◽  
Maria Laura Centomo ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Mitogen Activated Protein Kinase ◽  
Osteosarcoma Cell ◽  
Antitumor Effects ◽  
Interleukin 7 ◽  
Nanostring Technology

Receptor tyrosine kinases (RTKs) inhibitors’ activity in advanced osteosarcoma is significant but short-lived. To prevent or at least delay drug resistance, we explored a vertical inhibition by combining drugs acting at different levels of the RTK pathways (pazopanib + trametinib). We studied pazopanib + trametinib antitumor activity both in vitro and in vivo (MNNG-HOS and KHOS xenografts in NOD/SCID mice) investigating the molecular mechanisms and potential escapes. The involvement of MAPK-PI3K pathways was validated by Nanostring technology, western blot and by silencing/overexpression experiments. Pazopanib targets were expressed on seven osteosarcoma cell lines and their pathways were activated. Pazopanib + trametinib exhibited synergistic antitumor activity by inducing apoptosis and inhibiting ERK1/2 and Akt. In vivo antitumor activity was shown in osteosarcoma-bearing mice. The drug combination significantly down-modulated RTK Ephrin Type-A Receptor 2 (EphA2) and Interleukin-7 Receptor (IL-7R), whereas induced mitogen-activated protein-kinase kinase (MAPKK) MEK6. EphA2 silencing significantly reduced osteosarcoma cell proliferation and migration, while impeding MEK6 up-regulation in the treated cells significantly increased the antitumor effect of the studied drugs. Moreover, the up-regulation of MEK6 reduced combination activity. Pazopanib + trametinib demonstrated synergistic antitumor effects in osteosarcoma models through ERK and Akt inhibition and EphA2 and IL-7R down-modulation. MEK6 up-regulation might evoke escaping mechanism.

scholarly journals Attenuating Effect of Peruvian Cocoa Populations on the Acute Asthmatic Response in Brown Norway Rats

Nutrients ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2301
Author(s):  
Marta Périz ◽  
Francisco J. Pérez-Cano ◽  
Trinitat Cambras ◽  
Àngels Franch ◽  
Ivan Best ◽  
...  
Keyword(s):  
Mast Cell ◽  
Allergic Asthma ◽  
Immunoglobulin E ◽  
In Vivo Study ◽  
Brown Norway ◽  
Mast Cell Protease ◽  
Norway Rats ◽  
Anaphylactic Response

Cocoa contains bioactive components, which vary according to genetic and environmental factors. The present study aimed to ascertain the anti-allergic properties of native Peruvian cocoa populations (“Blanco de Piura” or BPC, “Amazonas Peru” or APC, “Criollo de Montaña” or CMC, “Chuncho” or CCC, and an ordinary cocoa or OC). To do so, after an initial in vitro approach, an in vivo study focused on the induction of an anaphylactic response associated with allergic asthma in Brown Norway rats was carried out. Based on their polyphenol content, antioxidant activity and in vitro effects, the APC and CMC were selected to be included in the in vivo study. Cocoa diets were tested in a model of allergic asthma in which anaphylactic response was assessed by changes in body temperature, motor activity and body weight. The concentration of specific immunoglobulin E (IgE), mast cell protease and leukotrienes was also quantified in serum and/or bronchoalveolar lavage fluid. CMC and OC populations exhibited a protective effect on the allergic asthma rat model as evidenced by means of a partial protection against anaphylactic response and, above all, in the synthesis of IgE and the release of mast cell protease.

scholarly journals MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Lorenzo Stramucci ◽  
Angelina Pranteda ◽  
Arianna Stravato ◽  
Carla Azzurra Amoreo ◽  
Annarita Pennetti ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Map Kinases ◽  
Molecular Mechanisms ◽  
Malignant Tumors ◽  
Mapk Pathway ◽  
Primary Cultures ◽  
Mitogen Activated Protein Kinase ◽  
Antitumor Effects

Abstract Colorectal cancer (CRC) is one of the most common malignant tumors worldwide and understanding its underlying molecular mechanisms is crucial for the development of therapeutic strategies. The mitogen-activated protein kinase-kinase 3 (MKK3) is a specific activator of p38 MAP kinases (p38 MAPKs), which contributes to the regulation of several cellular functions, such as proliferation, differentiation, apoptosis as well as response to drugs. At present, the exact MKK3/p38 MAPK pathway contribution in cancer is heavily debated because of its pleiotropic function. In this work, we retrospectively explored the prognostic and pathobiologic relevance of MKK3 in a cohort of CRC patients and assessed MKK3 molecular functions in a panel of CRC lines and colonocytes primary cultures. We found increased MKK3 levels in late-stage CRC patients which correlated with shorter overall survival. Herein, we report that the MKK3 targeting by inducible RNA interference univocally exerts antitumor effects in CRC lines but not in primary colonocytes. While MKK3 depletion per se affects growth and survival by induction of sustained autophagy and death in some CRC lines, it potentiates response to chemotherapeutic drug 5-fluorouracil (5-FU) in all of the tested CRC lines in vitro. Here, we demonstrate for the first time that in CRC the MKK3 specifically activates p38delta MAPK isoform to sustain prosurvival signaling and that such effect is exacerbated upon 5-FU challenge. Indeed, p38delta MAPK silencing recapitulates MKK3 depletion effects in CRC cells in vitro and in vivo. Overall, our data identified a molecular mechanism through which MKK3 supports proliferation and survival signaling in CRC, further supporting MKK3 as a novel and extremely attractive therapeutic target for the development of promising strategies for the management of CRC patients.

scholarly journals Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring

2008 ◽  
Vol 205 (1) ◽  
pp. 43-51 ◽  
Author(s):  
Ryoichi Mori ◽  
Tanya J. Shaw ◽  
Paul Martin
Keyword(s):  
Mast Cell ◽  
Neutralizing Antibodies ◽  
Molecular Mechanisms ◽  
Mouse Skin ◽  
Inflammatory Cells ◽  
In Vivo Studies ◽  
Paracrine Factors ◽  
Cultured Fibroblasts

Previous studies of tissue repair have revealed osteopontin (OPN) to be up-regulated in association with the wound inflammatory response. We hypothesize that OPN may contribute to inflammation-associated fibrosis. In a series of in vitro and in vivo studies, we analyze the effects of blocking OPN expression at the wound, and determine which inflammatory cells, and which paracrine factors from these cells, may be responsible for triggering OPN expression in wound fibroblasts. Delivery of OPN antisense oligodeoxynucleotides into mouse skin wounds by release from Pluronic gel decreases OPN protein levels at the wound and results in accelerated healing and reduced granulation tissue formation and scarring. To identify which leukocytic lineages may be responsible for OPN expression, we cultured fibroblasts in macrophage-, neutrophil-, or mast cell–conditioned media (CM), and found that macrophage- and mast cell–secreted factors, specifically platelet-derived growth factor (PDGF), induced fibroblast OPN expression. Correspondingly, Gleevec, which blocks PDGF receptor signaling, and PDGF-Rβ–neutralizing antibodies, inhibited OPN induction by macrophage-CM. These studies indicate that inflammation-triggered expression of OPN both hinders the rate of repair and contributes to wound fibrosis. Thus, OPN and PDGF are potential targets for therapeutic modulation of skin repair to improve healing rate and quality.

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