scholarly journals Modulation of immune cell reactivity with cis-binding Siglec agonists

2021 ◽  
Vol 118 (3) ◽  
pp. e2012408118
Author(s):  
Corleone S. Delaveris ◽  
Shannon H. Chiu ◽  
Nicholas M. Riley ◽  
Carolyn R. Bertozzi
Keyword(s):  
Cell Lines ◽  
Immune Cell ◽  
Mapk Signaling ◽  
Age Related Macular Degeneration ◽  
Mitogen Activated Protein Kinase ◽  
Cell Reactivity ◽  
Antiinflammatory Therapy ◽  
Age Related ◽  
Mitogen Activated Protein ◽  
Inhibitory Signaling

Inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, including chronic pain and blindness due to age-related macular degeneration. Many members of the sialic acid-binding immunoglobulin-like lectin (Siglec) family are immunoinhibitory receptors whose agonism is an attractive approach for antiinflammatory therapy. Here, we show that synthetic lipid-conjugated glycopolypeptides can insert into cell membranes and engage Siglec receptors in cis, leading to inhibitory signaling. Specifically, we construct a cis-binding agonist of Siglec-9 and show that it modulates mitogen-activated protein kinase (MAPK) signaling in reporter cell lines, immortalized macrophage and microglial cell lines, and primary human macrophages. Thus, these cis-binding agonists of Siglecs present a method for therapeutic suppression of immune cell reactivity.

scholarly journals Modulation of Immune Cell Reactivity with Cis-Binding Siglec Agonist

2020 ◽  
Author(s):  
Corleone Delaveris ◽  
Shannon Chiu ◽  
Nicholas Riley ◽  
Carolyn Bertozzi
Keyword(s):  
Cell Lines ◽  
Microglial Cell ◽  
Immune Cell ◽  
Mapk Signaling ◽  
Age Related Macular Degeneration ◽  
Cell Reactivity ◽  
Age Related ◽  
Sialic Acid Binding ◽  
Inhibitory Signaling ◽  
In Cis

Primary inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, including chronic pain and blindness due to age-related macular degeneration. Many members of the sialic acid-binding immunoglobulin-like lectin (Siglec) family are immunoinhibitory receptors whose agonism is an attractive approach to for anti-inflammatory therapy. Here, we show that synthetic lipid-conjugated glycopolypeptides can insert into cell membranes and engage Siglec receptors in cis, leading to inhibitory signaling. Specifically, we construct a cis-binding agonist of Siglec-9 and show that it modulates MAPK signaling in reporter cell lines, immortalized macrophage and microglial cell lines, and primary human macrophages. These cis-binding agonists of Siglecs present a new modality for therapeutic suppression of immune cell reactivity.

scholarly journals Modulation of Immune Cell Reactivity with Cis-Binding Siglec Agonist

2020 ◽  
Author(s):  
Corleone Delaveris ◽  
Shannon Chiu ◽  
Nicholas Riley ◽  
Carolyn Bertozzi
Keyword(s):  
Cell Lines ◽  
Microglial Cell ◽  
Immune Cell ◽  
Mapk Signaling ◽  
Age Related Macular Degeneration ◽  
Cell Reactivity ◽  
Age Related ◽  
Sialic Acid Binding ◽  
Inhibitory Signaling ◽  
In Cis

Primary inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, including chronic pain and blindness due to age-related macular degeneration. Many members of the sialic acid-binding immunoglobulin-like lectin (Siglec) family are immunoinhibitory receptors whose agonism is an attractive approach to for anti-inflammatory therapy. Here, we show that synthetic lipid-conjugated glycopolypeptides can insert into cell membranes and engage Siglec receptors in cis, leading to inhibitory signaling. Specifically, we construct a cis-binding agonist of Siglec-9 and show that it modulates MAPK signaling in reporter cell lines, immortalized macrophage and microglial cell lines, and primary human macrophages. These cis-binding agonists of Siglecs present a new modality for therapeutic suppression of immune cell reactivity.

scholarly journals Targeting MAPK Signaling in Age-Related Macular Degeneration

2016 ◽  
Vol 8 ◽  
pp. OED.S32200 ◽  
Author(s):  
Svetlana V. Kyosseva
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Animal Studies ◽  
Mapk Signaling ◽  
Age Related Macular Degeneration ◽  
Mitogen Activated Protein Kinase ◽  
Age Related ◽  
Mitogen Activated Protein ◽  
Extracellular Stimuli ◽  
Mapk Inhibitors

Age-related macular degeneration (AMD) is a major cause of irreversible blindness affecting elderly people in the world. AMD is a complex multifactorial disease associated with demographic, genetics, and environmental risk factors. It is well established that oxidative stress, inflammation, and apoptosis play critical roles in the pathogenesis of AMD. The mitogen-activated protein kinase (MAPK) signaling pathways are activated by diverse extracellular stimuli, including growth factors, mitogens, hormones, cytokines, and different cellular stressors such as oxidative stress. They regulate cell proliferation, differentiation, survival, and apoptosis. This review addresses the novel findings from human and animal studies on the relationship of MAPK signaling with AMD. The use of specific MAPK inhibitors may represent a potential therapeutic target for the treatment of this debilitating eye disease.

scholarly journals TRIM25 promotes Capicua degradation independently of ERK in the absence of ATXN1L

BMC Biology ◽  
2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Derek Wong ◽  
Lisa Sogerer ◽  
Samantha S. Lee ◽  
Victor Wong ◽  
Amy Lum ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Prognostic Factor ◽  
Cell Lines ◽  
Target Genes ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Cancer Types ◽  
And Function ◽  
Erk Activity

Abstract Background Aberrations in Capicua (CIC) have recently been implicated as a negative prognostic factor in a multitude of cancer types through the derepression of targets downstream of the mitogen-activated protein kinase (MAPK) signaling cascade, such as oncogenic E26 transformation-specific (ETS) transcription factors. The Ataxin-family protein ATXN1L has previously been reported to interact with CIC in both developmental and disease contexts to facilitate the repression of CIC target genes and promote the post-translational stability of CIC. However, little is known about the mechanisms at the base of ATXN1L-mediated CIC post-translational stability. Results Functional in vitro studies utilizing ATXN1LKO human cell lines revealed that loss of ATXN1L leads to the accumulation of polyubiquitinated CIC protein, promoting its degradation through the proteasome. Although transcriptomic signatures of ATXN1LKO cell lines indicated upregulation of the mitogen-activated protein kinase pathway, ERK activity was found to contribute to CIC function but not stability. Degradation of CIC protein following loss of ATXN1L was instead observed to be mediated by the E3 ubiquitin ligase TRIM25 which was further validated using glioma-derived cell lines and the TCGA breast carcinoma and liver hepatocellular carcinoma cohorts. Conclusions The post-translational regulation of CIC through ATXN1L and TRIM25 independent of ERK activity suggests that the regulation of CIC stability and function is more intricate than previously appreciated and involves several independent pathways. As CIC status has become a prognostic factor in several cancer types, further knowledge into the mechanisms which govern CIC stability and function may prove useful for future therapeutic approaches.

scholarly journals GADD45B induced the enhancing of cell viability and proliferation in radiotherapy and increased the radioresistance of HONE1 cells

2021 ◽  
Vol 19 (1) ◽  
pp. 1233-1243
Author(s):  
Yanning Ma ◽  
Dongheng Huang ◽  
Xingtong Li ◽  
Wanqin Cheng ◽  
Xiaomin Huang ◽  
...  
Keyword(s):  
Cell Viability ◽  
Cell Line ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Cyclin B1 ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
The Core ◽  
Differential Signaling ◽  
Mitogen Activated Protein

Abstract This study aimed to investigate the key role and mechanism of GADD45B in the radiation resistance of nasopharyngeal carcinoma (NPC) cell lines. Radiotherapy-resistant HONE1 (HONE1-R) cells with stable genetic radioresistance were cultured under continuous radiation stimulation. CCK-8 and clone formation assays were used to verify the radioresistance of the cell line. Transcriptome sequencing was used to identify the most important differential signaling pathway in the cell line. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot analysis were used to verify the sequencing results. GADD45B-siRNA was used to knock down the key gene so as to verify the downstream gene expression and analyze its mechanism. The transcriptome analysis showed that 702 genes were upregulated and 772 genes were downregulated in the HONE1-R cell lines. The core differential signaling pathway was mitogen-activated protein kinase (MAPK) signaling pathway, and the core differential gene was GADD45B. After GADD45B was knocked down, the cell viability and proliferation ability of HONE1-R cell lines significantly decreased under radiation, and the expression of cyclin B1 and p-CDK1 decreased significantly. MAPK is the core signaling pathway in radioresistance of NPC. GADD45B plays an important role by affecting cell viability and proliferation in NPC radioresistance. GADD45B is a potential target of radioresistance in NPC.

Age-Related Changes in Activation of Mitogen-Activated Protein Kinase Cascades by Oxidative Stress

1998 ◽  
Vol 3 (1) ◽  
pp. 23-27 ◽  
Author(s):  
Kathryn Z Guyton ◽  
Myriani Gorospe ◽  
Xiantao Wang ◽  
Yolanda D Mock ◽  
Gertrude C Kokkonen ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Mitogen Activated Protein Kinase ◽  
Age Related ◽  
Mitogen Activated Protein ◽  
Age Related Changes

scholarly journals Specific Functional Features of the Cell Integrity MAP Kinase Pathway in the Dimorphic Fission Yeast Schizosaccharomyces japonicus

2021 ◽  
Vol 7 (6) ◽  
pp. 482
Author(s):  
Elisa Gómez-Gil ◽  
Alejandro Franco ◽  
Beatriz Vázquez-Marín ◽  
Francisco Prieto-Ruiz ◽  
Armando Pérez-Díaz ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Environmental Changes ◽  
Yeast Species ◽  
Mapk Signaling ◽  
Fine Tuning ◽  
Mitogen Activated Protein Kinase ◽  
Major Influence ◽  
Cell Integrity ◽  
Mitogen Activated Protein ◽  
Functional Features

Mitogen activated protein kinase (MAPK) signaling pathways execute essential functions in eukaryotic organisms by transducing extracellular stimuli into adaptive cellular responses. In the fission yeast model Schizosaccharomyces pombe the cell integrity pathway (CIP) and its core effector, MAPK Pmk1, play a key role during regulation of cell integrity, cytokinesis, and ionic homeostasis. Schizosaccharomyces japonicus, another fission yeast species, shows remarkable differences with respect to S. pombe, including a robust yeast to hyphae dimorphism in response to environmental changes. We show that the CIP MAPK module architecture and its upstream regulators, PKC orthologs Pck1 and Pck2, are conserved in both fission yeast species. However, some of S. pombe’s CIP-related functions, such as cytokinetic control and response to glucose availability, are regulated differently in S. japonicus. Moreover, Pck1 and Pck2 antagonistically regulate S. japonicus hyphal differentiation through fine-tuning of Pmk1 activity. Chimeric MAPK-swapping experiments revealed that S. japonicus Pmk1 is fully functional in S. pombe, whereas S. pombe Pmk1 shows a limited ability to execute CIP functions and promote S. japonicus mycelial development. Our findings also suggest that a modified N-lobe domain secondary structure within S. japonicus Pmk1 has a major influence on the CIP signaling features of this evolutionarily diverged fission yeast.

scholarly journals Effect of Static Magnetic Field on Monascus ruber M7 Based on Transcriptome Analysis

2021 ◽  
Vol 7 (4) ◽  
pp. 256
Author(s):  
Shuyan Yang ◽  
Hongyi Zhou ◽  
Weihua Dai ◽  
Juan Xiong ◽  
Fusheng Chen
Keyword(s):  
Magnetic Field ◽  
Static Magnetic Field ◽  
Morphological Characteristics ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Primary Metabolism ◽  
Monascus Ruber ◽  
Growing Period ◽  
Monascus Pigments ◽  
Mitogen Activated Protein

The effects of a static magnetic field (SMF) on Monascus ruber M7 (M. ruber M7) cultured on potato dextrose agar (PDA) plates under SMF treatment at different intensities (5, 10, and 30 mT) were investigated in this paper. The results revealed that, compared with the control (CK, no SMF treatment), the SMF at all tested intensities did not significantly influence the morphological characteristics of M. ruber M7, while the intracellular and extracellular Monascus pigments (MPs) and extracellular citrinin (CIT) of M. ruber M7 were increased at 10 and 30 mT SMF but there was no impact on the MPs and CIT at 5 mT SMF. The transcriptome data of M. ruber M7 cultured at 30 mT SMF on PDA for 3 and 7 d showed that the SMF could increase the transcriptional levels of some relative genes with the primary metabolism, including the carbohydrate metabolism, amino acid metabolism, and lipid metabolism, especially in the early growing period (3 d). SMF could also affect the transcriptional levels of the related genes to the biosynthetic pathways of MPs, CIT, and ergosterol, and improve the transcription of the relative genes in the mitogen-activated protein kinase (MAPK) signaling pathway of M. ruber M7. These findings provide insights into a comprehensive understanding of the effects of SMF on filamentous fungi.

scholarly journals The Emerging Role of Macrophages in Immune System Dysfunction under Real and Simulated Microgravity Conditions

2021 ◽  
Vol 22 (5) ◽  
pp. 2333
Author(s):  
Yulong Sun ◽  
Yuanyuan Kuang ◽  
Zhuo Zuo
Keyword(s):  
Immune System ◽  
Mapk Signaling ◽  
Immune Defense ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Drugs ◽  
Physiological Processes ◽  
Immune System Dysfunction ◽  
Cell Immunity ◽  
Mitogen Activated Protein ◽  
Microgravity Conditions

In the process of exploring space, the astronaut’s body undergoes a series of physiological changes. At the level of cellular behavior, microgravity causes significant alterations, including bone loss, muscle atrophy, and cardiovascular deconditioning. At the level of gene expression, microgravity changes the expression of cytokines in many physiological processes, such as cell immunity, proliferation, and differentiation. At the level of signaling pathways, the mitogen-activated protein kinase (MAPK) signaling pathway participates in microgravity-induced immune malfunction. However, the mechanisms of these changes have not been fully elucidated. Recent studies suggest that the malfunction of macrophages is an important breakthrough for immune disorders in microgravity. As the first line of immune defense, macrophages play an essential role in maintaining homeostasis. They activate specific immune responses and participate in large numbers of physiological activities by presenting antigen and secreting cytokines. The purpose of this review is to summarize recent advances on the dysfunction of macrophages arisen from microgravity and to discuss the mechanisms of these abnormal responses. Hopefully, our work will contribute not only to the future exploration on the immune system in space, but also to the development of preventive and therapeutic drugs against the physiological consequences of spaceflight.

scholarly journals Topical Spilanthol Inhibits MAPK Signaling and Ameliorates Allergic Inflammation in DNCB-Induced Atopic Dermatitis in Mice

2019 ◽  
Vol 20 (10) ◽  
pp. 2490 ◽  
Author(s):  
Wen-Chung Huang ◽  
Chun-Hsun Huang ◽  
Sindy Hu ◽  
Hui-Ling Peng ◽  
Shu-Ju Wu
Keyword(s):  
Atopic Dermatitis ◽  
Mast Cells ◽  
Protein Kinase ◽  
Allergic Inflammation ◽  
Skin Lesions ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Pathways ◽  
Mitogen Activated Protein ◽  
Cox 2

Atopic dermatitis (AD) is a recurrent allergic skin disease caused by genetic and environmental factors. Patients with AD may experience immune imbalance, increased levels of mast cells, immunoglobulin (Ig) E and pro-inflammatory factors (Cyclooxygenase, COX-2 and inducible NO synthase, iNOS). While spilanthol (SP) has anti-inflammatory and analgesic activities, its effect on AD remains to be explored. To develop a new means of SP, inflammation-related symptoms of AD were alleviated, and 2,4-dinitrochlorobenzene (DNCB) was used to induce AD-like skin lesions in BALB/c mice. Histopathological analysis was used to examine mast cells and eosinophils infiltration in AD-like skin lesions. The levels of IgE, IgG1 and IgG2a were measured by enzyme-linked immunosorbent assay (ELISA) kits. Western blot was used for analysis of the mitogen-activated protein kinase (MAPK) pathways and COX-2 and iNOS protein expression. Topical SP treatment reduced serum IgE and IgG2a levels and suppressed COX-2 and iNOS expression via blocked mitogen-activated protein kinase (MAPK) pathways in DNCB-induced AD-like lesions. Histopathological examination revealed that SP reduced epidermal thickness and collagen accumulation and inhibited mast cells and eosinophils infiltration into the AD-like lesions skin. These results indicate that SP may protect against AD skin lesions through inhibited MAPK signaling pathways and may diminish the infiltration of inflammatory cells to block allergic inflammation.

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