scholarly journals Integrins Are the Necessary Links to Hypertrophic Growth in Cardiomyocytes

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Rebecca K. Harston ◽  
Dhandapani Kuppuswamy
Keyword(s):  
Intracellular Signaling ◽  
Drug Targets ◽  
Differential Survival ◽  
Cardiac Muscle Cells ◽  
Growth And Survival ◽  
Hypertrophic Growth ◽  
Hemodynamic Overload ◽  
Survival Signaling ◽  
Signaling Receptors

To compensate for hemodynamic overload of the heart, an event which stretches the myocardium, growth and survival signaling are activated in cardiac muscle cells (cardiomyocytes). Integrins serve as the signaling receptors of cardiomyocytes responsible for mechanotransduction toward intracellular signaling. The main integrin heterodimers on the cardiomyocyte surface are α5β1 and αvβ3, and elimination of either β1 or β3 integrins impedes pressure-induced hypertrophic signaling and leads to increased mortality. The growth signaling pathways downstream of β1 and β3 integrins are well characterized. However, new integrin pathways responsible for inhibiting apoptosis induced by hemodynamic overload are emerging. β1 and β3 integrins activate differential survival signaling, yet both integrins initiate survival signaling downstream of ubiquitination and the kinase pathway including phosphoinositol-3-kinase (PI3K)/Akt. Further characterization of these integrin-signaling mechanisms may lead to drug targets to prevent decompensation to heart failure.

Polyamine biosynthetic enzymes as drug targets in parasitic protozoa

2003 ◽  
Vol 31 (2) ◽  
pp. 415-419 ◽  
Author(s):  
O. Heby ◽  
S.C. Roberts ◽  
B. Ullman
Keyword(s):  
Chagas Disease ◽  
Ornithine Decarboxylase ◽  
Infected Patient ◽  
Drug Targets ◽  
Genetic Characterization ◽  
Biosynthetic Enzymes ◽  
Spermidine Synthase ◽  
Growth And Survival ◽  
Adenosylmethionine Decarboxylase

Molecular, biochemical and genetic characterization of ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase establishes that these polyamine-biosynthetic enzymes are essential for growth and survival of the agents that cause African sleeping sickness, Chagas' disease, leishmaniasis and malaria. These enzymes exhibit features that differ significantly between the parasites and the human host. Therefore it is conceivable that exploitation of such differences can lead to the design of new inhibitors that will selectively kill the parasites while exerting minimal, or at least tolerable, effects on the parasite-infected patient.

Molecular characterization of SARS-CoV-2

2020 ◽  
Vol 20 ◽  
Author(s):  
Miribane Dërmaku-Sopjani ◽  
Mentor Sopjani
Keyword(s):  
Public Health ◽  
Drug Targets ◽  
Virus Genome ◽  
Health Crisis ◽  
Public Health Crisis ◽  
Therapeutic Drugs ◽  
New Public Health ◽  
New Public ◽  
And Function

Abstract:: The coronavirus disease 2019 (COVID-19) is currently a new public health crisis threatening the world. This pandemic disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The virus has been reported to be originated in bats and by yet unknown intermediary animals were transmitted to humans in China 2019. The SARSCoV- 2 spreads faster than its two ancestors the SARS-CoV and Middle East respiratory syndrome coronavirus (MERSCoV) but has reduced fatality. At present, the SARS-CoV-2 has caused about a 1.16 million of deaths with more than 43.4 million confirmed cases worldwide, resulting in a serious threat to public health globally with yet uncertain impact. The disease is transmitted by inhalation or direct contact with an infected person. The incubation period ranges from 1 to 14 days. COVID-19 is accompanied by various symptoms, including cough, fatigue. In most people the disease is mild, but in some other people, such as in elderly and people with chronic diseases, it may progress from pneumonia to a multi-organ dysfunction. Many people are reported asymptomatic. The virus genome is sequenced, but new variants are reported. Numerous biochemical aspects of its structure and function are revealed. To date, no clinically approved vaccines and/or specific therapeutic drugs are available to prevent or treat the COVID-19. However, there are reported intensive researches on the SARSCoV- 2 to potentially identify vaccines and/or drug targets, which may help to overcome the disease. In this review, we discuss recent advances in understanding the molecular structure of SARS-CoV-2 and its biochemical characteristics.

scholarly journals DNA G-quadruplexes for native mass spectrometry in potassium: a database of validated structures in electrospray-compatible conditions

2021 ◽  
Author(s):  
Anirban Ghosh ◽  
Eric Largy ◽  
Valérie Gabelica
Keyword(s):  
Mass Spectrometry ◽  
Drug Targets ◽  
Native Mass Spectrometry ◽  
Drug Binding ◽  
Quadruplex Dna ◽  
Dna Structures ◽  
Nmr Structures ◽  
G Quadruplex ◽  
Screening Assays

Abstract G-quadruplex DNA structures have become attractive drug targets, and native mass spectrometry can provide detailed characterization of drug binding stoichiometry and affinity, potentially at high throughput. However, the G-quadruplex DNA polymorphism poses problems for interpreting ligand screening assays. In order to establish standardized MS-based screening assays, we studied 28 sequences with documented NMR structures in (usually ∼100 mM) potassium, and report here their circular dichroism (CD), melting temperature (Tm), NMR spectra and electrospray mass spectra in 1 mM KCl/100 mM trimethylammonium acetate. Based on these results, we make a short-list of sequences that adopt the same structure in the MS assay as reported by NMR, and provide recommendations on using them for MS-based assays. We also built an R-based open-source application to build and consult a database, wherein further sequences can be incorporated in the future. The application handles automatically most of the data processing, and allows generating custom figures and reports. The database is included in the g4dbr package (https://github.com/EricLarG4/g4dbr) and can be explored online (https://ericlarg4.github.io/G4_database.html).

The transcriptome of Echinostoma caproni adults: Further characterization of the secretome and identification of new potential drug targets

2013 ◽  
Vol 89 ◽  
pp. 202-214 ◽  
Author(s):  
Gagan Garg ◽  
Dolores Bernal ◽  
Maria Trelis ◽  
Javier Forment ◽  
Javier Ortiz ◽  
...  
Keyword(s):  
Drug Targets ◽  
Potential Drug ◽  
Echinostoma Caproni ◽  
Potential Drug Targets

scholarly journals Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies

2021 ◽  
Vol 11 ◽  
Author(s):  
Yuming Zhao ◽  
Dengyang Zhang ◽  
Yao Guo ◽  
Bo Lu ◽  
Zhizhuang Joe Zhao ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Malignant Tumors ◽  
Wnt Signaling Pathway ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Functional Features ◽  
Survival Signaling ◽  
Preclinical And Clinical Studies ◽  
Canonical Wnt

Receptor tyrosine kinase ROR1 plays an essential role in embryogenesis and is overexpressed in many types of malignant tumors. Studies have demonstrated that it plays an important role in oncogenesis by activating cell survival signaling events, particularly the non-canonical WNT signaling pathway. Antibody-based immunotherapies targeting ROR1 have been developed and evaluated in preclinical and clinical studies with promising outcomes. However, small molecule inhibitors targeting ROR1 are underappreciated because of the initial characterization of ROR1 as a peusdokinase. The function of ROR1 as a tyrosine kinase remains poorly understood, although accumulating evidence have demonstrated its intrinsic tyrosine kinase activity. In this review, we analyzed the structural and functional features of ROR1 and discussed therapeutic strategies targeting this kinase.

Culture and characterization of fetal human atrial and ventricular cardiac muscle cells

1989 ◽  
Vol 25 (12) ◽  
pp. 1114-1120 ◽  
Author(s):  
William C. Claycomb ◽  
Joseph B. Delcarpio ◽  
Sally E. Guice ◽  
R. L. Moses
Keyword(s):  
Cardiac Muscle ◽  
Muscle Cells ◽  
Cardiac Muscle Cells

scholarly journals Interrogation of kinase genetic interactions provides a global view of PAK1-mediated signal transduction pathways

2020 ◽  
Vol 295 (50) ◽  
pp. 16906-16919
Author(s):  
Jae-Hong Kim ◽  
Yeojin Seo ◽  
Myungjin Jo ◽  
Hyejin Jeon ◽  
Young-Seop Kim ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Migration ◽  
Intracellular Signaling ◽  
Mammalian Cells ◽  
Drug Targets ◽  
Large Scale ◽  
Genetic Interaction ◽  
Genetic Interactions ◽  
Signal Transduction Pathways ◽  
Global View

Kinases are critical components of intracellular signaling pathways and have been extensively investigated with regard to their roles in cancer. p21-activated kinase-1 (PAK1) is a serine/threonine kinase that has been previously implicated in numerous biological processes, such as cell migration, cell cycle progression, cell motility, invasion, and angiogenesis, in glioma and other cancers. However, the signaling network linked to PAK1 is not fully defined. We previously reported a large-scale yeast genetic interaction screen using toxicity as a readout to identify candidate PAK1 genetic interactions. En masse transformation of the PAK1 gene into 4,653 homozygous diploid Saccharomyces cerevisiae yeast deletion mutants identified ∼400 candidates that suppressed yeast toxicity. Here we selected 19 candidate PAK1 genetic interactions that had human orthologs and were expressed in glioma for further examination in mammalian cells, brain slice cultures, and orthotopic glioma models. RNAi and pharmacological inhibition of potential PAK1 interactors confirmed that DPP4, KIF11, mTOR, PKM2, SGPP1, TTK, and YWHAE regulate PAK1-induced cell migration and revealed the importance of genes related to the mitotic spindle, proteolysis, autophagy, and metabolism in PAK1-mediated glioma cell migration, drug resistance, and proliferation. AKT1 was further identified as a downstream mediator of the PAK1-TTK genetic interaction. Taken together, these data provide a global view of PAK1-mediated signal transduction pathways and point to potential new drug targets for glioma therapy.

scholarly journals PXO_RS20535, Encoding a Novel Response Regulator, Is Required for Chemotactic Motility, Biofilm Formation, and Tolerance to Oxidative Stress in Xanthomonas oryzae pv. oryzae

Pathogens ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 956
Author(s):  
Abdulwahab Antar ◽  
Mi-Ae Lee ◽  
Youngchul Yoo ◽  
Man-Ho Cho ◽  
Sang-Won Lee
Keyword(s):  
Oxidative Stress ◽  
Mutant Strain ◽  
Intracellular Signaling ◽  
Biofilm Formation ◽  
Response Regulator ◽  
Xanthomonas Oryzae ◽  
Knockout Mutant ◽  
Gene Encoding ◽  
Growth And Survival ◽  
Intracellular Signaling Pathway

Xanthomonas oryzae pv. oryzae (Xoo), a causal agent of bacterial leaf blight of rice, possesses two-component regulatory systems (TCSs) as an intracellular signaling pathway. In this study, we observed changes in virulence, biofilm formation, motility, chemotaxis, and tolerance against oxidative stress of a knockout mutant strain for the PXO_RS20535 gene, encoding an orphan response regulator (RR). The mutant strain lost virulence, produced significantly less biofilm, and showed remarkably reduced motility in swimming, swarming, and twitching. Furthermore, the mutant strain lost glucose-guided movement and showed clear diminution of growth and survival in the presence of H2O2. These results indicate that the RR protein encoded in the PXO_RS20535 gene (or a TCS mediated by the protein) is closely involved in regulation of biofilm formation, all types of motility, chemotaxis, and tolerance against reactive oxygen species (ROS) in Xoo. Moreover we found that the expression of most genes required for a type six secretion system (T6SS) was decreased in the mutant, suggesting that lack of the RR gene most likely leads to defect of T6SS in Xoo.

scholarly journals Phosphoproteomic analysis sheds light on intracellular signaling cascades triggered by Formyl-Peptide Receptor 2

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Fabio Cattaneo ◽  
Rosita Russo ◽  
Martina Castaldo ◽  
Angela Chambery ◽  
Cristiana Zollo ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Drug Targets ◽  
Large Scale ◽  
Cellular Proliferation ◽  
Biological Effects ◽  
Formyl Peptide Receptor ◽  
Ros Generation ◽  
Systematic Analysis ◽  
Phosphorylated Proteins ◽  
Formyl Peptide

AbstractFormyl peptide receptors (FPRs) belong to the family of seven transmembrane Gi-protein coupled receptors (GPCR). FPR2 is considered the most promiscuous member of this family since it recognizes a wide variety of ligands. It plays a crucial role in several physio-pathological processes and different studies highlighted the correlation between its expression and the higher propensity to invasion and metastasis of some cancers. FPR2 stimulation by its synthetic agonist WKYMVm triggers multiple phosphorylations of intracellular signaling molecules, such as ERKs, PKC, PKB, p38MAPK, PI3K, PLC, and of non-signaling proteins, such as p47phox and p67phox which are involved in NADPH oxidase-dependent ROS generation. Biological effects of FPR2 stimulation include intracellular Ca2+ mobilization, cellular proliferation and migration, and wound healing. A systematic analysis of the phosphoproteome in FPR2-stimulated cells has not been yet reported. Herein, we describe a large-scale phosphoproteomic study in WKYMVm-stimulated CaLu-6 cells. By using high resolution MS/MS we identified 290 differentially phosphorylated proteins and 53 unique phosphopeptides mapping on 40 proteins. Phosphorylations on five selected phospho-proteins were further validated by western blotting, confirming their dependence on FPR2 stimulation. Interconnection between some of the signalling readout identified was also evaluated. Furthermore, we show that FPR2 stimulation with two anti-inflammatory agonists induces the phosphorylation of selected differentially phosphorylated proteins, suggesting their role in the resolution of inflammation. These data provide a promising resource for further studies on new signaling networks triggered by FPR2 and on novel molecular drug targets for human diseases.

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