Coriandrum sativumSuppresses Aβ42-Induced ROS Increases, Glial Cell Proliferation, and ERK Activation

2016 ◽  
Vol 44 (07) ◽  
pp. 1325-1347 ◽  
Author(s):  
Quan Feng Liu ◽  
Haemin Jeong ◽  
Jang Ho Lee ◽  
Yoon Ki Hong ◽  
Youngje Oh ◽  
...  
Keyword(s):  
Glial Cell ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Active Form ◽  
Growth Factor Receptor ◽  
Ethanol Extract ◽  
Cell Number ◽  
Mitogen Activated Protein Kinase ◽  
Neuroprotective Effects ◽  
Protective Function

Alzheimer’s disease (AD), the most common neurodegenerative disease, has a complex and widespread pathology that is characterized by the accumulation of amyloid [Formula: see text]-peptide (A[Formula: see text]) in the brain and various cellular abnormalities, including increased oxidative damage, an amplified inflammatory response, and altered mitogen-activated protein kinase signaling. Based on the complex etiology of AD, traditional medicinal plants with multiple effective components are alternative treatments for patients with AD. In the present study, we investigated the neuroprotective effects of an ethanol extract of Coriandrum sativum (C. sativum) leaves on A[Formula: see text] cytotoxicity and examined the molecular mechanisms underlying the beneficial effects. Although recent studies have shown the benefits of the inhalation of C. sativum oil in an animal model of AD, the detailed molecular mechanisms by which C. sativum exerts its neuroprotective effects are unclear. Here, we found that treatment with C. sativum extract increased the survival of both A[Formula: see text]-treated mammalian cells and [Formula: see text]42-expressing flies. Moreover, C. sativum extract intake suppressed [Formula: see text]-induced cell death in the larval imaginal disc and brain without affecting A[Formula: see text]42 expression and accumulation. Interestingly, the increases in reactive oxygen species levels and glial cell number in AD model flies were reduced by C. sativum extract intake. Additionally, C. sativum extract inhibited the epidermal growth factor receptor- and A[Formula: see text]-induced phosphorylation of extracellular signal-regulated kinase (ERK). The constitutively active form of ERK abolished the protective function of C. sativum extract against the [Formula: see text]-induced eye defect phenotype in Drosophila. Taken together, these results suggest that C. sativum leaves have antioxidant, anti-inflammatory, and ERK signaling inhibitory properties that are beneficial for patients with AD.

scholarly journals Bcl-2 does not require Raf kinase activity for its death-protective function

1997 ◽  
Vol 324 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Reynald OLIVIER ◽  
Isabelle OTTER ◽  
Laurent MONNEY ◽  
Markus WARTMANN ◽  
Christoph BORNER
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Kinase Activity ◽  
Survival Function ◽  
Active Form ◽  
Signal Transduction Pathway ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Protective Function

It has been widely accepted that the oncogene product bcl-2 protects mammalian cells from programmed cell death (apoptosis). The molecules and signalling pathways upon which bcl-2 acts are, however, still ill-defined. Recently, bcl-2 was shown to interact with c-raf-1 in vitro. Furthermore, an active form of c-raf-1 delayed apoptosis induced by trophic factor deprivation and enhanced the death-suppressive function of bcl-2 when co-expressed. This has led to the hypothesis that bcl-2 communicates cell-death protection via a raf-dependent signal transduction pathway. Here we show, by various immunological and biochemical methods, that bcl-2 does not stably associate with c-raf-1 in cellular extracts prepared from fibroblasts before or after treatment with agents that induce apoptosis. Unexpectedly, bcl-2 function is entirely maintained, if not improved, when raf-dependent signalling is experimentally abrogated. In fact, bcl-2 allows the stable overexpression of a kinase-defective dominant-negative raf mutant that usually interferes with cell viability and/or proliferation. Our results indicate that bcl-2 does not require c-raf-1 kinase activity and an associated mitogen-activated protein kinase signalling pathway for its survival function. This property may be exploited to dissect cellular events that are dependent or independent of c-raf-1 kinase activity.

scholarly journals The Neuroprotective Effects ofRatanasampilon Oxidative Stress-Mediated Neuronal Damage in Human Neuronal SH-SY5Y Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Aiqin Zhu ◽  
Zhou Wu ◽  
Jie Meng ◽  
Patrick L. McGeer ◽  
Yi Zhu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Oxidative Dna Damage ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Mitogen Activated Protein Kinase ◽  
Tibetan Medicine ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Human Neuroblastoma ◽  
Traditional Tibetan Medicine

We previously found thatRatanasampil(RNSP), a traditional Tibetan medicine, improves the cognitive function of mild-to-moderate AD patients living at high altitude, as well as learning and memory in an AD mouse model (Tg2576); however, mechanism underlying the effects of RNSP is unknown. In the present study, we investigated the effects and molecular mechanisms of RNSP on oxidative stress-induced neuronal toxicity using human neuroblastoma SH-SY5Y cells. Pretreatment with RNSP significantly ameliorated the hydrogen peroxide- (H2O2-) induced cytotoxicity of SH-SY5Y cells in a dose-dependent manner (up to 60 μg/mL). Furthermore, RNSP significantly reduced the H2O2-induced upregulation of 8-oxo-2′-deoxyguanosine (8-oxo-dG, the oxidative DNA damage marker) but significantly reversed the expression of repressor element-1 silencing transcription factor (REST) from H2O2associated (100 μM) downregulation. Moreover, RNSP significantly attenuated the H2O2-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase 1/2 (ERK 1/2) in SH-SY5Y cells. These observations strongly suggest that RNSP may protect the oxidative stress-induced neuronal damage that occurs through the properties of various antioxidants and inhibit the activation of MAPKs. We thus provide the principle molecular mechanisms of the effects of RNSP and indicate its role in the prevention and clinical management of AD.

scholarly journals 1,25(OH)2D3 Alleviates Aβ(25-35)-Induced Tau Hyperphosphorylation, Excessive Reactive Oxygen Species, and Apoptosis Through Interplay with Glial Cell Line-Derived Neurotrophic Factor Signaling in SH-SY5Y Cells

2020 ◽  
Vol 21 (12) ◽  
pp. 4215 ◽  
Author(s):  
Ching-I Lin ◽  
Yi-Chen Chang ◽  
Ning-Jo Kao ◽  
Wei-Ju Lee ◽  
Tzu-Wen Cross ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Vitamin D ◽  
Cell Line ◽  
Glial Cell ◽  
Neurotrophic Factor ◽  
Molecular Mechanisms ◽  
Active Form ◽  
Reactive Oxygen ◽  
Nuclear Hormone Receptor ◽  
Oxygen Species

Amyloid beta (Aβ) accumulation in the brain is one of the major pathological features of Alzheimer’s disease. The active form of vitamin D (1,25(OH)2D3), which acts via its nuclear hormone receptor, vitamin D receptor (VDR), has been implicated in the treatment of Aβ pathology, and is thus considered as a neuroprotective agent. However, its underlying molecular mechanisms of action are not yet fully understood. Here, we aim to investigate whether the molecular mechanisms of 1,25(OH)2D3 in ameliorating Aβ toxicity involve an interplay of glial cell line-derived neurotrophic factor (GDNF)-signaling in SH-SY5Y cells. Cells were treated with Aβ(25-35) as the source of toxicity, followed by the addition of 1,25(OH)2D3 with or without the GDNF inhibitor, heparinase III. The results show that 1,25(OH)2D3 modulated Aβ-induced reactive oxygen species, apoptosis, and tau protein hyperphosphorylation in SH-SY5Y cells. Additionally, 1,25(OH)2D3 restored the decreasing GDNF and the inhibited phosphorylation of the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) protein expressions. In the presence of heparinase III, these damaging effects evoked by Aβ were not abolished by 1,25(OH)2D3. It appears 1,25(OH)2D3 is beneficial for the alleviation of Aβ neurotoxicity, and it might elicit its neuroprotection against Aβ neurotoxicity through an interplay with GDNF-signaling.

Cellular and molecular mechanisms of HGF/Met in the cardiovascular system

2015 ◽  
Vol 129 (12) ◽  
pp. 1173-1193 ◽  
Author(s):  
Simona Gallo ◽  
Valentina Sala ◽  
Stefano Gatti ◽  
Tiziana Crepaldi
Keyword(s):  
Growth Factor ◽  
Blood Vessels ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Tissue Injury ◽  
Mitogen Activated Protein Kinase ◽  
Tyrosine Kinase Receptor ◽  
Ischaemic Injury ◽  
Protective Function

Met tyrosine kinase receptor, also known as c-Met, is the HGF (hepatocyte growth factor) receptor. The HGF/Met pathway has a prominent role in cardiovascular remodelling after tissue injury. The present review provides a synopsis of the cellular and molecular mechanisms underlying the effects of HGF/Met in the heart and blood vessels. In vivo, HGF/Met function is particularly important for the protection of the heart in response to both acute and chronic insults, including ischaemic injury and doxorubicin-induced cardiotoxicity. Accordingly, conditional deletion of Met in cardiomyocytes results in impaired organ defence against oxidative stress. After ischaemic injury, activation of Met provides strong anti-apoptotic stimuli for cardiomyocytes through PI3K (phosphoinositide 3-kinase)/Akt and MAPK (mitogen-activated protein kinase) cascades. Recently, we found that HGF/Met is also important for autophagy regulation in cardiomyocytes via the mTOR (mammalian target of rapamycin) pathway. HGF/Met induces proliferation and migration of endothelial cells through Rac1 (Ras-related C3 botulinum toxin substrate 1) activation. In fibroblasts, HGF/Met antagonizes the actions of TGFβ1 (transforming growth factor β1) and AngII (angiotensin II), thus preventing fibrosis. Moreover, HGF/Met influences the inflammatory response of macrophages and the immune response of dendritic cells, indicating its protective function against atherosclerotic and autoimmune diseases. The HGF/Met axis also plays an important role in regulating self-renewal and myocardial regeneration through the enhancement of cardiac progenitor cells. HGF/Met has beneficial effects against myocardial infarction and endothelial dysfunction: the cellular and molecular mechanisms underlying repair function in the heart and blood vessels are common and include pro-angiogenic, anti-inflammatory and anti-fibrotic actions. Thus administration of HGF or HGF mimetics may represent a promising therapeutic agent for the treatment of both coronary and peripheral artery disease.

scholarly journals Allosteric activation of preformed EGF receptor dimers by a single ligand binding event

2021 ◽  
Author(s):  
Endang R. Purba ◽  
Ei-ichiro Saita ◽  
Reetesh R. Akhouri ◽  
Lars-Göran Öfverstedt ◽  
Gunnar Wilken ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Single Molecule ◽  
Molecular Mechanisms ◽  
Egf Receptor ◽  
Active Form ◽  
Growth Factor Receptor ◽  
Full Length ◽  
Receptor Dimer

Abstract Aberrant activation of the epidermal growth factor receptor (EGFR) by mutations has been implicated in a variety of human cancers. Elucidation of the structure of the full-length receptor is essential to understand the molecular mechanisms underlying its activation. Unlike previously anticipated, here, we report that purified full-length EGFR adopts a homodimeric form in vitro before and after ligand binding. Cryo-electron tomography analysis of the purified receptor also showed that the extracellular domains of the receptor dimer, which are conformationally flexible before activation, are stabilized by ligand binding. This conformational flexibility stabilization most likely accompanies rotation of the entire extracellular domain and the transmembrane a-helix, resulting in dissociation of the intracellular kinase dimer and, thus, rearranging it into an active form. Consistently, mutations of amino acid residues at the interface of the inactive, symmetric kinase dimer spontaneously activate the receptor in vivo. Optical single-molecule observation also demonstrated that binding of only one ligand activates the receptor dimer on the cell surface. Based on these results, we propose an allosteric model for the activation of EGFR dimers by ligand binding. Our results demonstrate how oncogenic mutations spontaneously activate the receptor and shed light on the development of novel cancer therapies.

scholarly journals The EGFR-ERK/JNK-CCL20 Pathway in Scratched Keratinocytes May Underpin Koebnerization in Psoriasis Patients

2020 ◽  
Vol 21 (2) ◽  
pp. 434 ◽  
Author(s):  
Kazuhisa Furue ◽  
Takamichi Ito ◽  
Yuka Tanaka ◽  
Akiko Hashimoto-Hachiya ◽  
Masaki Takemura ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Epidermal Keratinocytes ◽  
Egfr Inhibitor ◽  
Independent Manner ◽  
Koebner Phenomenon ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Epidermal Growth

Epidermal keratinocytes represent a rich source of C-C motif chemokine 20 (CCL20) and recruit CCR6+ interleukin (IL)-17A–producing T cells that are known to be pathogenic for psoriasis. A previous study revealed that scratch injury on keratinocytes upregulates CCL20 production, which is implicated in the Koebner phenomenon characteristically seen in psoriasis patients. However, the molecular mechanisms leading to scratch-induced CCL20 production remain elusive. In this study, we demonstrate that scratch injury upregulates the phosphorylation of epidermal growth factor receptor (EGFR) and that the specific EGFR inhibitor PD153035 attenuates scratch-induced CCL20 upregulation in an extracellular signal-related kinase (ERK)-dependent, and to a lesser extent, a c-Jun N-terminal kinase (JNK)-dependent but p38 mitogen-activated protein kinase (MAPK)–independent manner. Immunoreactive CCL20 was visualized in the keratinocytes that lined the scratched wound. IL-17A also induced the phosphorylation of EGFR and further augmented scratch-induced CCL20 upregulation. The EGFR-ERK/JNK-CCL20 pathway in scratched keratinocytes may explain why Koebnerization is frequently seen in psoriasis patients.

Endothelin-1 induces VCAM-1 expression-mediated inflammation via receptor tyrosine kinases and Elk/p300 in human tracheal smooth muscle cells

2015 ◽  
Vol 309 (3) ◽  
pp. L211-L225 ◽  
Author(s):  
Chih-Chung Lin ◽  
Wei-Ning Lin ◽  
Wei-Chen Hou ◽  
Li-Der Hsiao ◽  
Chuen-Mao Yang
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Muscle Cells ◽  
Mitogen Activated Protein Kinase ◽  
Tracheal Smooth Muscle ◽  
Adhesion Assay ◽  
Endothelin 1

The elevated level of endothelin-1 (ET-1) has been detected in the bronchoalveolar lavage of patients with severe asthma, acute lung injury, acute respiratory distress syndrome, and sepsis. ET-1 may affect vessel tone together with lung physiology and pathology. Vascular cell adhesion molecule-1 (VCAM-1) is one kind of adhesion molecules participating in the process of polymorphonuclear leukocyte transmigration and regulating the occurrence and amplification of tissue inflammation. However, the molecular mechanisms underlying ET-1-mediated expression of VCAM-1 on human tracheal smooth muscle cells (HTSMCs) were largely unknown. Here we reported that ET-1 stimulated expression of VCAM-1 gene on HTSMCs, which was blocked by pretreatment with the inhibitors of ET receptors, Src, matrix metalloproteinases (MMPs), epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), phosphatidylinositol 3-kinase (PI3K), AKT, MEK1/2, and p300, suggesting the participation of these signaling components in ET-1-regulated HTSMC responses. Furthermore, transfection with small-interfering RNA (siRNA) of Src, AKT, p42 mitogen-activated protein kinase (MAPK), or p300 downregulated the respective proteins and significantly attenuated ET-1-induced VCAM-1 expression. ET-1 also stimulated phosphorylation of Src, EGFR, PDGFR, AKT, p42/p44 MAPK, and Elk-1 and acetylation of histone H4 on HTSMCs. Immunoprecipitation assay showed the association between Elk-1 and p300 in the nucleus. Adhesion assay revealed that the adhesion of THP-1 to HTSMCs challenged with ET-1 was increased, which was attenuated by the inhibitors of ET receptors, Src, MMPs, EGFR, PDGFR, PI3K, AKT, p42/p44 MAPK, and p300. Taken together, these data suggested that ET-1 promotes occurrence and amplification of pathology-related airway inflammation via enhancing VCAM-1 expression in an ET receptor/Src/MMP/EGFR, PDGFR/PI3K/AKT/p42/p44 MAPK/Elk-1/p300 pathway in HTSMCs.

scholarly journals Signaling pathways involved in colorectal cancer progression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zahra Koveitypour ◽  
Farnoush Panahi ◽  
Mehrdad Vakilian ◽  
Maryam Peymani ◽  
Farzad Seyed Forootan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Cascades

AbstractColorectal cancer (CRC) is the fourth leading cause of the worldwide cancer mortality. Different molecular mechanisms have been attributed to the development and progress of CRC. In this review, we will focus on the mitogen-activated protein kinase (MAPK) cascades downstream of the epidermal growth factor receptor (EGFR), Notch, PI3K/AKT pathway, transforming growth factor-β (TGF-β), and Wnt signaling pathways. Various mutations in the components of these signaling pathways have been linked to the development of CRC. Accordingly, numerous efforts have been carried out to target the signaling pathways to develop novel therapeutic approaches. Herein, we review the signaling pathways involved in the incidence and progression of CRC, and the strategies for the therapy targeting components of signaling pathways in CRC.

scholarly journals Phosphate as a Signaling Molecule and Its Sensing Mechanism

2018 ◽  
Vol 98 (4) ◽  
pp. 2317-2348 ◽  
Author(s):  
Toshimi Michigami ◽  
Masanobu Kawai ◽  
Miwa Yamazaki ◽  
Keiichi Ozono
Keyword(s):  
Signal Transduction ◽  
Mammalian Cells ◽  
Higher Plants ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Ectopic Calcification ◽  
Sensing Mechanism ◽  
Phosphate Sensing ◽  
Mitogen Activated Protein

In mammals, phosphate balance is maintained by influx and efflux via the intestines, kidneys, bone, and soft tissue, which involves multiple sodium/phosphate (Na+/Pi) cotransporters, as well as regulation by several hormones. Alterations in the levels of extracellular phosphate exert effects on both skeletal and extra-skeletal tissues, and accumulating evidence has suggested that phosphate itself evokes signal transduction to regulate gene expression and cell behavior. Several in vitro studies have demonstrated that an elevation in extracellular Piactivates fibroblast growth factor receptor, Raf/MEK (mitogen-activated protein kinase/ERK kinase)/ERK (extracellular signal-regulated kinase) pathway and Akt pathway, which might involve the type III Na+/Picotransporter PiT-1. Excessive phosphate loading can lead to various harmful effects by accelerating ectopic calcification, enhancing oxidative stress, and dysregulating signal transduction. The responsiveness of mammalian cells to altered extracellular phosphate levels suggests that they may sense and adapt to phosphate availability, although the precise mechanism for phosphate sensing in mammals remains unclear. Unicellular organisms, such as bacteria and yeast, use some types of Pitransporters and other molecules, such as kinases, to sense the environmental Piavailability. Multicellular animals may need to integrate signals from various organs to sense the phosphate levels as a whole organism, similarly to higher plants. Clarification of the phosphate-sensing mechanism in humans may lead to the development of new therapeutic strategies to prevent and treat diseases caused by phosphate imbalance.

scholarly journals Therapeutic targets and signaling mechanisms of vitamin C activity against sepsis: a bioinformatics study

2020 ◽  
Author(s):  
Rong Li ◽  
Chao Guo ◽  
Yu Li ◽  
Zuqian Qin ◽  
Wenjun Huang
Keyword(s):  
Vitamin C ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Network Pharmacology ◽  
Future Clinical Practice ◽  
Mitogen Activated Protein ◽  
Life Threatening ◽  
Epidermal Growth

Abstract Sepsis is a life-threatening complication of pneumonia, including coronavirus disease-2019 (COVID-19)-induced pneumonia. Evidence of the benefits of vitamin C (VC) for the treatment of sepsis is accumulating. However, data revealing the targets and molecular mechanisms of VC action against sepsis are limited. In this report, a bioinformatics analysis of network pharmacology was conducted to demonstrate screening targets, biological functions, and the signaling pathways of VC action against sepsis. As shown in network assays, 63 primary causal targets for the VC action against sepsis were identified from the data, and four optimal core targets for the VC action against sepsis were identified. These core targets were epidermal growth factor receptor (EGFR), mitogen-activated protein kinase-1 (MAPK1), proto-oncogene c (JUN), and signal transducer and activator of transcription-3 (STAT3). In addition, all biological processes (including a top 20) and signaling pathways (including a top 20) potentially involved in the VC action against sepsis were identified. The hub genes potentially involved in the VC action against sepsis and interlaced networks from the Kyoto Encyclopedia of Genes and Genomes Mapper assays were highlighted. Considering all the bioinformatic findings, we conclude that VC antisepsis effects are mechanistically and pharmacologically implicated with suppression of immune dysfunction-related and inflammation-associated functional processes and other signaling pathways. These primary predictive biotargets may potentially be used to treat sepsis in future clinical practice.

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