MAP kinase phosphatase 1: a novel mediator of biological effects of glucocorticoids?

Synthetic glucocorticoids (GCs) potently inhibit the expression of pro-inflammatory genes and are widely used in the treatment of inflammatory diseases. However, some patients are resistant to the therapeutic effects of GCs, and many suffer deleterious side effects from these drugs. Furthermore, the precise mechanisms by which GCs inhibit pro-inflammatory gene expression remain unclear. A number of recent papers report that GCs induce the sustained expression of MAP kinase (MAPK) phosphatase 1 (MKP-1), a negative regulator of MAPK signal transduction pathways. The potential relevance of MKP-1 to some of the biological effects of GCs is discussed.

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Hydrogen, a Novel Therapeutic Molecule, Regulates Oxidative Stress, Inflammation, and Apoptosis

Frontiers in Physiology ◽

10.3389/fphys.2021.789507 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yan Tian ◽

Yafang Zhang ◽

Yu Wang ◽

Yunxi Chen ◽

Weiping Fan ◽

...

Keyword(s):

Treatment Guidelines ◽

Ischemia Reperfusion Injury ◽

Inflammatory Diseases ◽

Biological Effects ◽

Ischemia Reperfusion ◽

Underlying Mechanism ◽

Therapeutic Effects ◽

Mitochondrial Energy Metabolism ◽

Wide Range ◽

Anti Inflammatory

Molecular hydrogen (H2) is a colorless and odorless gas. Studies have shown that H2 inhalation has the therapeutic effects in many animal studies and clinical trials, and its application is recommended in the novel coronavirus pneumonia treatment guidelines in China recently. H2 has a relatively small molecular mass, which helps it quickly spread and penetrate cell membranes to exert a wide range of biological effects. It may play a role in the treatment and prevention of a variety of acute and chronic inflammatory diseases, such as acute pancreatitis, sepsis, respiratory disease, ischemia reperfusion injury diseases, autoimmunity diseases, etc.. H2 is primarily administered via inhalation, drinking H2-rich water, or injection of H2 saline. It may participate in the anti-inflammatory and antioxidant activity (mitochondrial energy metabolism), immune system regulation, and cell death (apoptosis, autophagy, and pyroptosis) through annihilating excess reactive oxygen species production and modulating nuclear transcription factor. However, the underlying mechanism of H2 has not yet been fully revealed. Owing to its safety and potential efficacy, H2 has a promising potential for clinical use against many diseases. This review will demonstrate the role of H2 in antioxidative, anti-inflammatory, and antiapoptotic effects and its underlying mechanism, particularly in coronavirus disease-2019 (COVID-19), providing strategies for the medical application of H2 for various diseases.

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Essential Role for Mitogen-activated Protein (MAP) Kinase Phosphatase-1 in Stress-responsive MAP Kinase and Cell Survival Signaling

Journal of Biological Chemistry ◽

10.1074/jbc.m501762200 ◽

2005 ◽

Vol 280 (16) ◽

pp. 16461-16466 ◽

Cited By ~ 118

Author(s):

J. Julie Wu ◽

Anton M. Bennett

Keyword(s):

Cell Death ◽

Cell Growth ◽

Map Kinase ◽

Cell Survival ◽

P38 Mapk ◽

Essential Role ◽

Mapk Pathway ◽

Negative Regulator ◽

Map Kinase Phosphatase ◽

Mitogen Activated Protein

Mitogen-activated protein kinase (MAPK) phosphatases (MKPs) constitute a family of 11 dual-specificity phosphatases that inactivate the MAPKs by dephosphorylation. Although the contribution of MAPKs to cell growth and cell death has been examined extensively, it remains unclear whether MKPs play an essential role in the regulation of these processes. To clarify the role of MKP-1, we determined the effects on the MAPKs and cell growth and death in primary fibroblasts derived from mice lacking MKP-1. Here we have shown that MKP-1 is critical for the inactivation of p38 MAPK and JNK following stimulation with serum, anisomycin, and osmotic stress. In addition, MKP-1 was identified as a critical negative regulator of the cAMP-mediated p38 MAPK pathway. MKP-1-deficient mouse embryonic fibroblasts (MEFs) displayed enhanced p38 MAPK activity and cAMP-response element-dependent transcriptional activation in response to forskolin. Surprisingly, MKP-1-deficient fibroblasts exhibited reduced cell growth compared with wild type MEFs as a result of enhanced cell death. The enhanced level of cell death in MKP-1-deficient MEFs was rescued by SB203580, an inhibitor of p38 MAPK. MKP-1-deficient MEFs were also sensitive to anisomycin-induced apoptosis. Collectively, these data demonstrate that MKP-1 promotes cell survival by attenuating stress-responsive MAPK-mediated apoptosis.

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MAP kinase phosphatase MKP-1 regulates p-ERK1/2 signaling pathway with fluoride treatment

10.21203/rs.3.rs-38922/v1 ◽

2020 ◽

Author(s):

Lin Zhao ◽

Jiali Su ◽

Sijia Liu ◽

Yang Li ◽

Tao Li ◽

...

Keyword(s):

Map Kinase ◽

Molecular Mechanisms ◽

Tooth Enamel ◽

Dental Fluorosis ◽

Critical Role ◽

Negative Regulator ◽

Erk Signaling ◽

High Dose ◽

Dependent Manner ◽

Map Kinase Phosphatase

Abstract Background Dental fluorosis is characterized by hypomineralization of tooth enamel caused by ingestion of excessive fluoride during enamel formation. Excess fluoride could have effects on the ERK signaling, which is essential for the ameloblasts differentiation and tooth development. MAP kinase phosphatase-1 (MKP-1) plays a critical role in regulating ERK related kinases. However, the role of MKP-1 in ameloblast and the mechanisms of MKP-1/ERK signaling in the pathogenesis of dental fluorosis are incompletely understood. Results Here, we adopted an in vitro fluorosis cell model using murine ameloblasts-like LS8 cells by employing sodium fluoride (NaF) as inducer. Using this system, we demonstrated that fluoride exposure led to an inhibition of p- MEK and p-ERK1/2 with a subsequent increase in MKP-1 expression in a dose-dependent manner. We further identified, under high dose fluoride, MKP-1 acted as a negative regulator of the fluoride-induced p-ERK1/2 signaling, leading to downregulation of CREB, c-myc, and Elk-1. Conclusion Our results identify a novel MKP-1/ERK signaling mechanism that regulates dental fluorosis and provide a framework for studying the molecular mechanisms of intervention and fluorosis remodeling under normal and pathological conditions. MKP-1 inhibitors may prove to be a benefit therapeutic strategy for dental fluorosis treatment.

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Therapeutic Perspectives of Food Bioactive Peptides: A Mini Review

Protein and Peptide Letters ◽

10.2174/0929866526666190617092140 ◽

2019 ◽

Vol 26 (9) ◽

pp. 664-675

Author(s):

Sulochana Priya

Keyword(s):

Bioactive Peptides ◽

Marine Organism ◽

Biological Effects ◽

Amide Bond ◽

Therapeutic Effects ◽

Specific Sequence ◽

The Past ◽

Cancer Immunity ◽

Microbial Infections ◽

Diverse Origin

Bioactive peptides are short chain of amino acids (usually 2-20) that are linked by amide bond in a specific sequence which have some biological effects in animals or humans. These can be of diverse origin like plant, animal, fish, microbe, marine organism or even synthetic. They are successfully used in the management of many diseases. In recent years increased attention has been raised for its effects and mechanism of action in various disease conditions like cancer, immunity, cardiovascular disease, hypertension, inflammation, diabetes, microbial infections etc. Bioactive peptides are more bioavailable and less allergenic when compared to total proteins. Food derived bioactive peptides have health benefits and its demand has increased tremendously over the past decade. This review gives a view on last two years research on potential bioactive peptides derived from food which have significant therapeutic effects.

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Therapeutic Potential of Amniotic Fluid Derived Mesenchymal Stem Cells Based on their Differentiation Capacity and Immunomodulatory Properties

Current Stem Cell Research & Therapy ◽

10.2174/1574888x14666190222201749 ◽

2019 ◽

Vol 14 (4) ◽

pp. 327-336 ◽

Cited By ~ 9

Author(s):

Carl R. Harrell ◽

Marina Gazdic ◽

Crissy Fellabaum ◽

Nemanja Jovicic ◽

Valentin Djonov ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Animal Models ◽

Amniotic Fluid ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Therapeutic Effects ◽

Differentiation Potential ◽

Differentiation Capacity ◽

Cell Based Therapy

Background: Amniotic Fluid Derived Mesenchymal Stem Cells (AF-MSCs) are adult, fibroblast- like, self-renewable, multipotent stem cells. During the last decade, the therapeutic potential of AF-MSCs, based on their huge differentiation capacity and immunomodulatory characteristics, has been extensively explored in animal models of degenerative and inflammatory diseases. Objective: In order to describe molecular mechanisms responsible for the therapeutic effects of AFMSCs, we summarized current knowledge about phenotype, differentiation potential and immunosuppressive properties of AF-MSCs. Methods: An extensive literature review was carried out in March 2018 across several databases (MEDLINE, EMBASE, Google Scholar), from 1990 to present. Keywords used in the selection were: “amniotic fluid derived mesenchymal stem cells”, “cell-therapy”, “degenerative diseases”, “inflammatory diseases”, “regeneration”, “immunosuppression”. Studies that emphasized molecular and cellular mechanisms responsible for AF-MSC-based therapy were analyzed in this review. Results: AF-MSCs have huge differentiation and immunosuppressive potential. AF-MSCs are capable of generating cells of mesodermal origin (chondrocytes, osteocytes and adipocytes), neural cells, hepatocytes, alveolar epithelial cells, insulin-producing cells, cardiomyocytes and germ cells. AF-MSCs, in juxtacrine or paracrine manner, regulate proliferation, activation and effector function of immune cells. Due to their huge differentiation capacity and immunosuppressive characteristic, transplantation of AFMSCs showed beneficent effects in animal models of degenerative and inflammatory diseases of nervous, respiratory, urogenital, cardiovascular and gastrointestinal system. Conclusion: Considering the fact that amniotic fluid is obtained through routine prenatal diagnosis, with minimal invasive procedure and without ethical concerns, AF-MSCs represents a valuable source for cell-based therapy of organ-specific or systemic degenerative and inflammatory diseases.

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Cucurbitacins as Anticancer Agents: A Patent Review

Recent Patents on Anti-Cancer Drug Discovery ◽

10.2174/1574892813666181119123035 ◽

2019 ◽

Vol 14 (2) ◽

pp. 133-143 ◽

Cited By ~ 3

Author(s):

Hidayat Hussain ◽

Ivan R. Green ◽

Muhammad Saleem ◽

Khanzadi F. Khattak ◽

Muhammad Irshad ◽

...

Keyword(s):

Anticancer Agents ◽

Wide Spectrum ◽

Biological Effects ◽

Therapeutic Effects ◽

Cytotoxic Effects ◽

Natural Sources ◽

Oh Groups ◽

Drug Candidates ◽

The Past ◽

Wide Range

Background: Cucurbitacins belong to a group of tetracyclic triterpenoids that display a wide range of biological effects. In the past, numerous cucurbitacins have been isolated from natural sources and many active compounds have been synthesized using the privileged scaffold in order to enhance its cytotoxic effects. Objective: his review covers patents on the therapeutic effects of natural cucurbitacins and their synthetic analogs published during the past decade. By far, the majority of patents published are related to cancer and Structure-Activity Relationships (SAR) of these compounds are included to lend gravitas to this important class of natural products. Methods: The date about the published patents was downloaded via online open access patent databases. Results: Cucurbitacins display significant cytotoxic properties, in particular cucurbitacins B and D which possess very potent effects towards a number of cancer cells. Numerous cucurbitacins isolated from natural sources have been derivatized through chemical modification at the C(2)-OH and C(25)- OH groups. Most importantly, an acyl ester of the C(25)-OH and, iso-propyl, n-propyl and ethyl ether groups of the C(2)-OH demonstrated the most increased cytotoxic activity. Conclusion: The significant cytotoxic effects of natural and semi-synthetic cucurbitacins make them attractive as new drug candidates. Moreover, cucurbitacins have the capability to form conjugates with other anticancer drugs which will synergistically enhance their anticancer effects. The authors believe that in order to get lead compounds, there should be a greater focus on the synthesis of homodimers, heterodimers, and halo derivatives of cucurbitacins. In the opinion of the authors the analysis of the published patents on the cucurbitacins indicates that these compounds can be developed into a regimen to treat a wide spectrum of cancers.

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Expression and function of Smad7 in autoimmune and inflammatory diseases

Journal of Molecular Medicine ◽

10.1007/s00109-021-02083-1 ◽

2021 ◽

Author(s):

Yiping Hu ◽

Juan He ◽

Lianhua He ◽

Bihua Xu ◽

Qingwen Wang

Keyword(s):

Posttranscriptional Regulation ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Inflammatory Diseases ◽

Kidney Diseases ◽

Critical Role ◽

Transforming Growth Factor Β ◽

Negative Regulator ◽

Signaling Mechanism ◽

And Function

AbstractTransforming growth factor-β (TGF-β) plays a critical role in the pathological processes of various diseases. However, the signaling mechanism of TGF-β in the pathological response remains largely unclear. In this review, we discuss advances in research of Smad7, a member of the I-Smads family and a negative regulator of TGF-β signaling, and mainly review the expression and its function in diseases. Smad7 inhibits the activation of the NF-κB and TGF-β signaling pathways and plays a pivotal role in the prevention and treatment of various diseases. Specifically, Smad7 can not only attenuate growth inhibition, fibrosis, apoptosis, inflammation, and inflammatory T cell differentiation, but also promotes epithelial cells migration or disease development. In this review, we aim to summarize the various biological functions of Smad7 in autoimmune diseases, inflammatory diseases, cancers, and kidney diseases, focusing on the molecular mechanisms of the transcriptional and posttranscriptional regulation of Smad7.

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