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 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 IQGAP1 binds AMPK and is required for maximum AMPK activation

2020 ◽  
pp. jbc.RA120.016193
Author(s):  
Andrew C. Hedman ◽  
Zhigang Li ◽  
Laëtitia Gorisse ◽  
Swetha Parvathaneni ◽  
Chase J. Morgan ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Direct Interaction ◽  
Mitogen Activated Protein Kinase ◽  
Null Cell ◽  
Ampk Signaling ◽  
In Cells

AMP-activated protein kinase (AMPK) is a fundamental component of a protein kinase cascade that is an energy sensor. AMPK maintains energy homeostasis in the cell by promoting catabolic and inhibiting anabolic pathways. Activation of AMPK requires phosphorylation by the liver kinase B1 or by the Ca2+ /calmodulin-dependent protein kinase kinase 2 (CaMKK2). The scaffold protein IQGAP1 regulates intracellular signaling pathways, such as the mitogen-activated protein kinase and AKT signaling cascades. Recent work implicates the participation of IQGAP1 in metabolic function, but the molecular mechanisms underlying these effects are poorly understood. Here, using several approaches including binding analysis with fusion proteins, siRNA-mediated gene silencing, RT-PCR, and knockout mice, we investigated whether IQGAP1 modulates AMPK signaling. In vitro analysis reveals that IQGAP1 binds directly to the α1 subunit of AMPK. In addition, we observed a direct interaction between IQGAP1 and CaMKK2, which is mediated by the IQ domain of IQGAP1. Both CaMKK2 and AMPK associate with IQGAP1 in cells. The ability of metformin and increased intracellular free Ca2+ concentrations to activate AMPK is reduced in cells lacking IQGAP1. Importantly, Ca2+-stimulated AMPK phosphorylation was rescued by re-expression of IQGAP1 in IQGAP1-null cell lines. Comparison of the fasting response in wild-type and IQGAP1-null mice revealed that transcriptional regulation of the gluconeogenesis genes PCK1 and G6PC and the fatty acid synthesis genes FASN and ACC1 is impaired in IQGAP1-null mice. Our data disclose a previously unidentified functional interaction between IQGAP1 and AMPK and suggest that IQGAP1 modulates AMPK signaling.

scholarly journals Cell Models to Study Regulation of Cell Transformation in Pathologies of Retinal Pigment Epithelium

2014 ◽  
Vol 2014 ◽  
pp. 1-18 ◽  
Author(s):  
Alla V. Kuznetsova ◽  
Alexander M. Kurinov ◽  
Maria A. Aleksandrova
Keyword(s):  
Retinal Pigment Epithelium ◽  
Molecular Mechanisms ◽  
Cell Transformation ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Specific Treatment ◽  
Target Cells ◽  
Signal Pathways ◽  
Culture Models

The retinal pigment epithelium (RPE) plays a key role in the development of many eye diseases leading to visual impairment and even blindness. Cell culture models of pathological changes in the RPE make it possible to study factors responsible for these changes and signaling pathways coordinating cellular and molecular mechanisms of cell interactions under pathological conditions. Moreover, they give an opportunity to reveal target cells and develop effective specific treatment for degenerative and dystrophic diseases of the retina. In this review, data are presented on RPE cell sources for culture models, approaches to RPE cell culturing, phenotypic changes of RPE cellsin vitro, the role of signal pathways, and possibilities for their regulation in pathological processes.

scholarly journals Potent Neutralizing Antibodies Directed to Multiple Epitopes on SARS-CoV-2 Spike

2020 ◽  
Author(s):  
Lihong Liu ◽  
Pengfei Wang ◽  
Manoj S. Nair ◽  
Jian Yu ◽  
Micah Rapp ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Global Economy ◽  
Epitope Mapping ◽  
Severe Disease ◽  
Clinical Development ◽  
Receptor Binding Domain ◽  
Cryo Electron Microscopy ◽  
Novel Coronavirus

AbstractThe SARS-CoV-2 pandemic rages on with devasting consequences on human lives and the global economy1,2. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this novel coronavirus. Here we report the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies from 5 infected patients hospitalized with severe disease. Among these are 19 antibodies that potently neutralized the authentic SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng/mL. Epitope mapping showed this collection of 19 antibodies to be about equally divided between those directed to the receptor-binding domain (RBD) and those to the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that are overlapping with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody targeting RBD, a second targeting NTD, and a third bridging two separate RBDs revealed recognition of the closed, “all RBD-down” conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.

scholarly journals Conjunctivitis and other ocular findings in patients with COVID-19 infection

2021 ◽  
Vol 41 (5) ◽  
pp. 280-284
Author(s):  
Haider Aswad Layikh ◽  
Zainab Adel Hashim ◽  
Alyaa A. Kadum
Keyword(s):  
Viral Infection ◽  
Care Center ◽  
Severe Disease ◽  
Respiratory Illness ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Ocular Findings ◽  
Standard Deviation Range ◽  
Severity Of The Disease ◽  
Novel Coronavirus

BACKGROUND: COVID-19 is an acute respiratory illness caused by a novel coronavirus (SARS-CoV-2). COVID-19 that might affect the eye in the form of conjunctivitis and other ocular features. OBJECTIVES: Assess the frequency and clinical profile of conjunctivitis and other ocular findings in Iraqi patients with confirmed COVID-19 infection. DESIGN: Analytical cross-sectional study. SETTING: Secondary care center. PATIENTS AND METHODS: This study involved patients diagnosed with SARS-CoV-2 viral infection of variable disease severity from June 2020 to December 2020. Ocular history and the severity of SARS-CoV-2 viral infection was assessed for all of the patients. MAIN OUTCOME MEASURES: Frequency of conjunctival inflammation and other ocular findings in patients with coronavirus infection. SAMPLE SIZE: 186 patients. RESULTS: The patients had a mean (standard deviation, range) age of 44.4 (18.8, 18–78) years. Conjunctivitis was present in 25 patients (13.4%). There was no significant association between prevalence of conjunctivitis and patient gender ( P =.868). However, conjunctivitis was significantly associated with the severity of the disease ( P =.018): the rate of conjunctivitis was significantly higher in cases with severe disease (28%) in comparison with those with mild to moderate clinical presentation (9.3%). The natural course of conjunctivitis seemed to be mild with no effect on visual acuity and no short-term complications. CONCLUSION: Conjunctivitis can occur in patients with SARS-CoV-2 viral infection, and could be a presenting sign. Conjunctivitis is more common in cases of severe COVID-19 infection and since it could be a presenting sign it might be of benefit in the early diagnosis and treatment of COVID-19. LIMITATION: Single-center study, safety limitations in the examination of the patients. CONFLICT OF INTEREST: None.

Psoralen photoactivation promotes morphological and functional changes in fibroblasts in vitro reminiscent of cellular senescence

1998 ◽  
Vol 111 (6) ◽  
pp. 759-767
Author(s):  
G. Herrmann ◽  
P. Brenneisen ◽  
M. Wlaschek ◽  
J. Wenk ◽  
K. Faisst ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
De Novo ◽  
Molecular Data ◽  
Cellular Aging ◽  
Premature Aging ◽  
Functional Changes ◽  
Uva Irradiation ◽  
High Level

Premature aging of the skin is a prominent side effect of psoralen photoactivation, a treatment used widely for various skin disorders. The molecular mechanisms underlying premature aging upon psoralen photoactivation are as yet unknown. Here we show that treatment of fibroblasts with 8-methoxypsoralen (8-MOP) and subsequent ultraviolet A (UVA) irradiation resulted in a permanent switch of mitotic to stably postmitotic fibroblasts which acquired a high level of de novo expression of SA-beta-galactosidase, a marker for fibroblast senescence in vitro and in vivo. A single exposure of fibroblasts to 8-MOP/UVA resulted in a 5.8-fold up-regulation of two matrix-degrading enzymes, interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3), over a period of >120 days, while TIMP-1, the major inhibitor of MMP-1 and MMP-3, was only slightly induced. This imbalance between matrix-degrading metalloproteases and their inhibitor may lead to connective tissue damage, a hallmark of premature aging. Superoxide anion and hydrogen peroxide, but not singlet oxygen, were identified as important intermediates in the downstream signaling pathway leading to these complex fibroblast responses upon psoralen photoactivation. Collectively, the end phenotype induced upon psoralen photoactivation shares several criteria of senescent cells. In the absence of detailed molecular data on what constitutes normal aging, it is difficult to decide whether the changes reported here reflect mechanisms underlying normal cellular aging/senescence or rather produce a mimic of cellular aging/senescence by quite different pathways.

Interferon-Gamma Induces Monopoiesis and Inhibits Neutrophil Development During Inflammation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1320-1320
Author(s):  
Alexander M. de Bruin ◽  
Marijke G. Valkhof ◽  
Louis Boon ◽  
Ivo P. Touw ◽  
Martijn A. Nolte
Keyword(s):  
Viral Infection ◽  
Interferon Gamma ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Myeloid Cell ◽  
Cell Types ◽  
In Vitro Assays ◽  
Stat3 Phosphorylation ◽  
Proliferation And Differentiation

Abstract Abstract 1320 Steady-state hematopoiesis is altered upon infection, but the cellular and molecular mechanisms driving these changes are largely unknown. Modulation of hematopoiesis is essential to increase the output of the appropriate type of effector cell required to combat the invading pathogen. Here we demonstrate that the pro-inflammatory cytokine interferon-gamma (IFNγ) is involved in orchestrating inflammation-induced myelopoiesis. Using both mouse models and in vitro assays we show that IFNg induces differentiation of monocytes over neutrophils at the level of myeloid progenitors. We show that acute viral infection induces monopoiesis in WT mice, but a strongly increased neutrophil production in IFNγ−/− mice. When exploring the underlying molecular mechanism, we found that IFNγ increases expression of the monocyte-inducing transcription factors PU.1 and IRF8 in granulocyte-macrophage progenitors (GMPs) and enhances the response of these cells to M-CSF. On the contrary, IFNγ inhibits proliferation and differentiation of GMPs in response to G-CSF. We demonstrate that IFNγ reduces G-CSF-induced phosphorylation of STAT3, an important transcription factor in neutrophil development. Moreover, IFNγ also induces expression of SOCS3, which is a negative feedback regulator of G-CSFR signaling; by using G-CSFR mutants we demonstrate that the IFNγ-mediated inhibition of G-CSF-driven STAT3 phosphorylation is dependent on the recruitment of SOCS3 to the G-CSFR. In conclusion, our findings illustrate that IFNγ is an important factor in shaping the hematopoietic response during inflammation. IFNγ is able to regulate myelopoiesis in the bone marrow upon viral infection by promoting the production of the appropriate myeloid cell type, but also by actively suppressing formation of cells less important for anti-viral defense. In addition, our data provide a molecular explanation for the observed aberrant hematopoietic remodeling observed in pathogen-challenged IFNγ-deficient mice. As both monocytes and neutrophils play important, but distinct roles in the defense against numerous pathogens, this study provides important new insight in the mechanism that regulates the formation of these vital myeloid cell types during infections. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Stem cell factor affects fate determination of human gonocytes in vitro

Reproduction ◽  
2007 ◽  
Vol 134 (6) ◽  
pp. 757-765 ◽  
Author(s):  
Jiongjiong Tu ◽  
Liqing Fan ◽  
Ke Tao ◽  
Wenbing Zhu ◽  
Jianjun Li ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Factor ◽  
Molecular Mechanisms ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Tyrosine Kinase Receptor ◽  
Dependent Manner ◽  
Fate Determination

The stem cell factor (SCF), binding its tyrosine kinase receptor c-Kit, has been shown to play essential roles in the proliferation, differentiation, and survival of germline cells. However, few reports are available about the effect of SCF on the development of human gonocytes within the fetal testis. The objective of this study was to investigate whether SCF affects the biological behaviors of human gonocytes before or after they enter the mitotic arrest stage. Employing an organ culture system, we observed that addition of exogenous SCF could influence the morphology of human gonocytesin vitro. Moreover, SCF was able to trigger the colony formation of round gonocytes, which were characterized positive for alkaline phosphatase activity, Oct-4, SSEA-4, and c-Kit as well. We found that SCF exerted actions in a dose- and age-dependent manner, although the stimulatory effect lasted no more than 14 days. We also showed that SCF played a role in suppressing the apoptosis of human gonocytes. Blocking of SCF signaling with either phosphatidylinositol 3-kinase or mitogen-activated protein kinase inhibitor resulted in similar apoptotic features as well as the SCF-withdrawal cultures. Taken together, we report that SCF acts as a potent regulator in the fate determination of human gonocytes. Our studies should form the basis forin vitrostudies and facilitate investigation of the molecular mechanisms underlying this unique stage.

Stimulation of innate immune responses by malarial glycosylphosphatidylinositol via pattern recognition receptors

Parasitology ◽  
2005 ◽  
Vol 130 (S1) ◽  
pp. S45-S62 ◽  
Author(s):  
T. NEBL ◽  
M. J. DE VEER ◽  
L. SCHOFIELD
Keyword(s):  
Pattern Recognition ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Severe Disease ◽  
Pattern Recognition Receptors ◽  
Innate Immune ◽  
Proinflammatory Responses ◽  
Cellular Immune

The glycosylphosphatidylinositol (GPI) anchor ofPlasmodium falciparumis thought to function as a critical toxin that contributes to severe malarial pathogenesis by eliciting the production of proinflammatory responses by the innate immune system of mammalian hosts. Analysis of the fine structure ofP. falciparumGPI suggests a requirement for the presence of both core glycan and lipid moieties in the recognition and signalling of parasite glycolipids by host immune cells. It has been demonstrated that GPI anchors of various parasitic protozoa can mediate cellular immune responses via members of the Toll-like family of pattern recognition receptors (TLRs). Recent studies indicate that GPI anchors ofP. falciparumand other protozoa are preferentially recognized by TLR-2, involving the MyD88-dependent activation of specific signalling pathways that mediate the production of proinflammatory cytokines and nitric oxide from host macrophagesin vitro. However, the contribution of malaria GPI toxin to severe disease syndromes and the role of specific TLRs or other pattern recognition receptors in innate immunityin vivois only just beginning to be characterized. A better understanding of the molecular mechanisms underlying severe malarial pathogenesis may yet lead to substantial new insights with important implications for the development of novel therapeutics for malaria treatment.

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.

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