scholarly journals Molecular Insights into the MAPK Cascade during Viral Infection: Potential Crosstalk between HCQ and HCQ Analogues

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Tapan Kumar Mohanta ◽  
Nanaocha Sharma ◽  
Pietro Arina ◽  
Paola Defilippi
Keyword(s):  
Viral Infection ◽  
Molecular Mechanisms ◽  
Defense Mechanism ◽  
Viral Infections ◽  
Mapk Pathway ◽  
Virus Disease ◽  
Specific Treatment ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Surface Receptors

The mitogen-activated protein kinase (MAPK) pathway links the cell-surface receptors to the transcription machinery, transducing the extracellular signals into several outputs, which may also adapt the host defense mechanism to viral attacks. The Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) that causes the COrona VIrus Disease 2019 (COVID-19) has infected upwards of nearly 70 million people and worldwide has claimed more than 1,600,000 deaths. So far, there continues to be no specific treatment for this novel coronavirus-induced disease. In the search to control the global COVID-19 pandemic, some eastern and developing countries have approved a variety of treatments with controversial efficacy, among which is the use of the antimalarial hydroxychloroquine (HCQ). Interestingly, prior data had indicated that the HCQ/CQ could influence the MAPK cascade. The main aim of this review is to address molecular mechanisms, beyond drugs, that can be helpful against viral infection for this and future pandemics. We will highlight (1) the contribution of the MAPK cascade in viral infection and (2) the possible use of MAPK inhibitors in curbing viral infections, alone or in combination with HCQ and quinoline analogues. We are convinced that understanding the molecular patterns of viral infections will be critical for new therapeutical approaches to control this and other severe diseases.

scholarly journals Molecular Insights on Potential Combination of Mapk Inhibitors Together with HCQ and HCQs Analogs in Viral Infection

2020 ◽  
Author(s):  
Tapan Kumar Mohanta ◽  
Nanaocha Sharma ◽  
Pietro Arina ◽  
Paola Defilippi
Keyword(s):  
Viral Infection ◽  
Molecular Mechanisms ◽  
Severe Disease ◽  
Specific Treatment ◽  
Molecular Data ◽  
Mitogen Activated Protein Kinase ◽  
Molecular Approaches ◽  
Mapk Inhibitors ◽  
Novel Coronavirus

The outbreak of coronavirus disease-19 (COVID-19) has infected more than 11 million people and has claimed more than 530.000 deaths world-wide. In July 2020, still, there is no specific treatment for disease caused by the novel coronavirus. In the search to curb the global pandemic COVID-19, some eastern and developing countries have approved various treatment with controversial efficacy, among that the use of the antimalarial Hydroxychloroquine (HCQ), so far with inconclusive clinical evidence of effectiveness. On the other hand, computer-based screening suggest that HCQs analog are promising molecules, to impair viral replication in vitro[1]. Therefore, what is emerging from this complex background, is the need to understand molecular mechanism beyond drugs that can be helpful against viral infection for this and future pandemic. The intent of this Brief Report is to highlight: i) the involvement of the Mitogen Activated Protein Kinase (MAPK) cascade in viral infection and ii) the urgent need to have molecular data on the effectiveness of the combination of MAPK inhibitors together with HCQ and HCQs analogs in curbing viral infection. We are convinced that a better understanding of the patterns of elicited molecular mechanisms will be critical for new molecular approaches to this severe disease

scholarly journals MAP Kinase Pathways in the YeastSaccharomyces cerevisiae

1998 ◽  
Vol 62 (4) ◽  
pp. 1264-1300 ◽  
Author(s):  
Michael C. Gustin ◽  
Jacobus Albertyn ◽  
Matthew Alexander ◽  
Kenneth Davenport
Keyword(s):  
Gene Expression ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Regulation Of Gene Expression ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Future Research ◽  
Mapk Pathways ◽  
Mapk Cascades

SUMMARY A cascade of three protein kinases known as a mitogen-activated protein kinase (MAPK) cascade is commonly found as part of the signaling pathways in eukaryotic cells. Almost two decades of genetic and biochemical experimentation plus the recently completed DNA sequence of the Saccharomyces cerevisiae genome have revealed just five functionally distinct MAPK cascades in this yeast. Sexual conjugation, cell growth, and adaptation to stress, for example, all require MAPK-mediated cellular responses. A primary function of these cascades appears to be the regulation of gene expression in response to extracellular signals or as part of specific developmental processes. In addition, the MAPK cascades often appear to regulate the cell cycle and vice versa. Despite the success of the gene hunter era in revealing these pathways, there are still many significant gaps in our knowledge of the molecular mechanisms for activation of these cascades and how the cascades regulate cell function. For example, comparison of different yeast signaling pathways reveals a surprising variety of different types of upstream signaling proteins that function to activate a MAPK cascade, yet how the upstream proteins actually activate the cascade remains unclear. We also know that the yeast MAPK pathways regulate each other and interact with other signaling pathways to produce a coordinated pattern of gene expression, but the molecular mechanisms of this cross talk are poorly understood. This review is therefore an attempt to present the current knowledge of MAPK pathways in yeast and some directions for future research in this area.

scholarly journals Molecular Mechanisms of Liver Injury and Hepatocarcinogenesis: Focusing on the Role of Stress-Activated MAPK

2012 ◽  
Vol 2012 ◽  
pp. 1-14 ◽  
Author(s):  
Hayato Nakagawa ◽  
Shin Maeda
Keyword(s):  
Liver Injury ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Effects ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Compensatory Proliferation

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH2-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway.

scholarly journals Positive and negative selection invoke distinct signaling pathways.

1996 ◽  
Vol 184 (1) ◽  
pp. 9-18 ◽  
Author(s):  
J Alberola-Ila ◽  
K A Hogquist ◽  
K A Swan ◽  
M J Bevan ◽  
R M Perlmutter
Keyword(s):  
T Cell ◽  
Positive Selection ◽  
Negative Selection ◽  
Mapk Pathway ◽  
Cell Receptor ◽  
Dominant Negative ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

During T cell development, interaction of the T cell receptor (TCR) with cognate ligands in the thymus may result in either maturation (positive selection) or death (negative selection). The intracellular pathways that control these opposed outcomes are not well characterized. We have generated mice expressing dominant-negative Ras (dnRas) and Mek-1 (dMek) transgenes simultaneously, either in otherwise normal animals, or in animals expressing a transgenic TCR, thereby permitting a comprehensive analysis of peptide-specific selection. In this system, thymocyte maturation beyond the CD4+8+ stage is blocked almost completely, whereas negative selection, assessed using an in vitro deletion protocol, is quantitatively intact. This suggests that activation of the mitogen-activated protein kinase (MAPK) cascade is necessary for positive selection, but irrelevant for negative selection. Generation of gamma/delta and of CD4-8- alpha/beta T cells proceeds normally despite blockade of the MAPK cascade. Hence, only cells that mature via conventional, TCR-mediated repertoire selection require activation of the MAPK pathway to complete their maturation.

scholarly journals MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

2008 ◽  
Vol 115 (7) ◽  
pp. 203-218 ◽  
Author(s):  
Anthony J. Muslin
Keyword(s):  
Molecular Mechanisms ◽  
Cardiovascular Health ◽  
Mapk Pathway ◽  
Science Research ◽  
Pharmacological Therapy ◽  
Model Systems ◽  
Mitogen Activated Protein Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

scholarly journals Molecular Mechanisms Behind the Chemopreventive Effects of Anthocyanidins

2004 ◽  
Vol 2004 (5) ◽  
pp. 321-325 ◽  
Author(s):  
De-Xing Hou ◽  
Makoto Fujii ◽  
Norihiko Terahara ◽  
Makoto Yoshimoto
Keyword(s):  
Fruits And Vegetables ◽  
Molecular Mechanisms ◽  
Cell Transformation ◽  
Mapk Pathway ◽  
Animal Experiments ◽  
Cancer Chemoprevention ◽  
Mitogen Activated Protein Kinase ◽  
Blue Color ◽  
Activator Protein 1 ◽  
Mitogen Activated Protein

Anthocyanins are polyphenolic ring-based flavonoids, and are widespread in fruits and vegetables of red-blue color. Epidemiological investigations and animal experiments have indicated that anthocyanins may contribute to cancer chemoprevention. The studies on the mechanism have been done recently at molecular level. This review summarizes current molecular bases for anthocyanidins on several key steps involved in cancer chemoprevention: (i) inhibition of anthocyanidins in cell transformation through targeting mitogen-activated protein kinase (MAPK) pathway and activator protein 1 (AP-1) factor; (ii) suppression of anthocyanidins in inflammation and carcinogenesis through targeting nuclear factorkappaB (NF-κB) pathway andcyclooxygenase2 (COX-2) gene; (iii) apoptotic induction of cancer cells by anthocyanidins through reactive oxygen species (ROS) / c-Jun NH2-terminal kinase (JNK)-mediated caspase activation. These data provide a first molecular view of anthocyanidins contributing to cancer chemoprevention.

scholarly journals ETV2/ER71 regulates the generation of FLK1+ cells from mouse embryonic stem cells through miR-126-MAPK signaling

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Ju Young Kim ◽  
Dong Hun Lee ◽  
Joo Kyung Kim ◽  
Hong Seo Choi ◽  
Bhakti Dwivedi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Embryonic Stem ◽  
Mapk Signaling ◽  
Mouse Embryonic Stem Cells ◽  
Micro Rna ◽  
Mitogen Activated Protein Kinase ◽  
The Novel

AbstractPrevious studies including ours have demonstrated a critical function of the transcription factor ETV2 (ets variant 2; also known as ER71) in determining the fate of cardiovascular lineage development. However, the underlying mechanisms of ETV2 function remain largely unknown. In this study, we demonstrated the novel function of the miR (micro RNA)-126-MAPK (mitogen-activated protein kinase) pathway in ETV2-mediated FLK1 (fetal liver kinase 1; also known as VEGFR2)+ cell generation from the mouse embryonic stem cells (mESCs). By performing a series of experiments including miRNA sequencing and ChIP (chromatin immunoprecipitation)-PCR, we found that miR-126 is directly induced by ETV2. Further, we identified that miR-126 can positively regulate the generation of FLK1+ cells by activating the MAPK pathway through targeting SPRED1 (sprouty-related EVH1 domain containing 1). Further, we showed evidence that JUN/FOS activate the enhancer region of FLK1 through AP1 (activator protein 1) binding sequences. Our findings provide insight into the novel molecular mechanisms of ETV2 function in regulating cardiovascular lineage development from mESCs.

scholarly journals Cell Proliferation in Cutaneous Malignant Melanoma: Relationship with Neoplastic Progression

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
G. E. Piérard
Keyword(s):  
Cell Cycle ◽  
Growth Rate ◽  
Malignant Melanoma ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Cutaneous Malignant Melanoma ◽  
Mitogen Activated Protein Kinase ◽  
Growth Fraction ◽  
Neoplastic Progression ◽  
Cell Cycle Phases

The establishment of the diagnosis of cutaneous malignant melanoma (CMM) always calls for histopathological confirmation. Further to the recognition of the CMM aspects, immunohistochemistry is helpful, in particular, in determining the size of the replicative compartment and the activity in each of the cell cycle phases (G1, S, G2, M). The involvement of cancer stem cells and transient amplifier cells in CMM genesis is beyond doubt. The proliferation activity is indicative of the neoplastic progression and is often related to the clinical growth rate of the neoplasm. It allows to distinguish high-risk CMM commonly showing a high growth rate, from those CMMs of lower malignancy associated with a more limited growth rate. The recruitment and progression of CMM cells in the cell cycle of proliferation depend on mitogen-activated protein kinase (MAPK) pathway and result from a loss of control normally involving a series of key regulatory cyclins. In addition, the apoptotic pathways potentially counteracting any excess in proliferative activity are out of the dependency of specific regulatory molecular mechanisms. Key molecular components involved in the deregulation of the growth fraction, the cell cycle phases of proliferation, and apoptosis are presently described in CMM.

scholarly journals Redox Imbalance and Viral Infections in Neurodegenerative Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Dolores Limongi ◽  
Sara Baldelli
Keyword(s):  
Neurodegenerative Diseases ◽  
Viral Infection ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Second Messengers ◽  
Chronic Viral Infections ◽  
Ros Accumulation ◽  
Simplex Virus

Reactive oxygen species (ROS) are essential molecules for many physiological functions and act as second messengers in a large variety of tissues. An imbalance in the production and elimination of ROS is associated with human diseases including neurodegenerative disorders. In the last years the notion that neurodegenerative diseases are accompanied by chronic viral infections, which may result in an increase of neurodegenerative diseases progression, emerged. It is known in literature that enhanced viral infection risk, observed during neurodegeneration, is partly due to the increase of ROS accumulation in brain cells. However, the molecular mechanisms of viral infection, occurring during the progression of neurodegeneration, remain unclear. In this review, we discuss the recent knowledge regarding the role of influenza, herpes simplex virus type-1, and retroviruses infection in ROS/RNS-mediated Parkinson’s disease (PD), Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS).

scholarly journals When human guanylate-binding proteins meet viral infections

2021 ◽  
Vol 28 (1) ◽  
Author(s):  
Rongzhao Zhang ◽  
Zhixin Li ◽  
Yan-Dong Tang ◽  
Chenhe Su ◽  
Chunfu Zheng
Keyword(s):  
Innate Immunity ◽  
Viral Infection ◽  
Binding Proteins ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Innate Immune ◽  
Type I Interferons ◽  
Type I ◽  
Downstream Signaling ◽  
Antiviral Innate Immunity

AbstractInnate immunity is the first line of host defense against viral infection. After invading into the cells, pathogen-associated-molecular-patterns derived from viruses are recognized by pattern recognition receptors to activate the downstream signaling pathways to induce the production of type I interferons (IFN-I) and inflammatory cytokines, which play critical functions in the host antiviral innate immune responses. Guanylate-binding proteins (GBPs) are IFN-inducible antiviral effectors belonging to the guanosine triphosphatases family. In addition to exerting direct antiviral functions against certain viruses, a few GBPs also exhibit regulatory roles on the host antiviral innate immunity. However, our understanding of the underlying molecular mechanisms of GBPs' roles in viral infection and host antiviral innate immune signaling is still very limited. Therefore, here we present an updated overview of the functions of GBPs during viral infection and in antiviral innate immunity, and highlight discrepancies in reported findings and current challenges for future studies, which will advance our understanding of the functions of GBPs and provide a scientific and theoretical basis for the regulation of antiviral innate immunity.

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