A Resource for the Network Representation of Cell Perturbations Caused by SARS-CoV-2 Infection

The coronavirus disease 2019 (COVID-19) pandemic has caused more than 2.3 million casualties worldwide and the lack of effective treatments is a major health concern. The development of targeted drugs is held back due to a limited understanding of the molecular mechanisms underlying the perturbation of cell physiology observed after viral infection. Recently, several approaches, aimed at identifying cellular proteins that may contribute to COVID-19 pathology, have been reported. Albeit valuable, this information offers limited mechanistic insight as these efforts have produced long lists of cellular proteins, the majority of which are not annotated to any cellular pathway. We have embarked in a project aimed at bridging this mechanistic gap by developing a new bioinformatic approach to estimate the functional distance between a subset of proteins and a list of pathways. A comprehensive literature search allowed us to annotate, in the SIGNOR 2.0 resource, causal information underlying the main molecular mechanisms through which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and related coronaviruses affect the host–cell physiology. Next, we developed a new strategy that enabled us to link SARS-CoV-2 interacting proteins to cellular phenotypes via paths of causal relationships. Remarkably, the extensive information about inhibitors of signaling proteins annotated in SIGNOR 2.0 makes it possible to formulate new potential therapeutic strategies. The proposed approach, which is generally applicable, generated a literature-based causal network that can be used as a framework to formulate informed mechanistic hypotheses on COVID-19 etiology and pathology.

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MAPK/ERK Signaling Pathway in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13123026 ◽

2021 ◽

Vol 13 (12) ◽

pp. 3026

Author(s):

Hyuk Moon ◽

Simon-Weonsang Ro

Keyword(s):

Hepatocellular Carcinoma ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Therapeutic Strategies ◽

Erk Signaling ◽

Health Concern ◽

Alternative Mechanism ◽

Major Health ◽

Activating Mutations ◽

Genetic Events

Hepatocellular carcinoma (HCC) is a major health concern worldwide, and its incidence is increasing steadily. Recently, the MAPK/ERK signaling pathway in HCC has gained renewed attention from basic and clinical researchers. The MAPK/ERK signaling pathway is activated in more than 50% of human HCC cases; however, activating mutations in RAS and RAF genes are rarely found in HCC, which are major genetic events leading to the activation of the MAPK/ERK signaling pathway in other cancers. This suggests that there is an alternative mechanism behind the activation of the signaling pathway in HCC. Here, we will review recent advances in understanding the cellular and molecular mechanisms involved in the activation of the MAPK/ERK signaling pathway and discuss potential therapeutic strategies targeting the signaling pathway in the context of HCC.

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Bioinformatics Approaches to the Understanding of Molecular Mechanisms in Antimicrobial Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms21041363 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1363 ◽

Cited By ~ 5

Author(s):

Pieter-Jan Van Camp ◽

David B. Haslam ◽

Aleksey Porollo

Keyword(s):

Antimicrobial Resistance ◽

Laboratory Testing ◽

Molecular Mechanisms ◽

Clinical Laboratory ◽

Basic Research ◽

Bioinformatic Analysis ◽

Health Concern ◽

Major Health ◽

The Past ◽

Clinical Laboratory Testing

Antimicrobial resistance (AMR) is a major health concern worldwide. A better understanding of the underlying molecular mechanisms is needed. Advances in whole genome sequencing and other high-throughput unbiased instrumental technologies to study the molecular pathogenicity of infectious diseases enable the accumulation of large amounts of data that are amenable to bioinformatic analysis and the discovery of new signatures of AMR. In this work, we review representative methods published in the past five years to define major approaches developed to-date in the understanding of AMR mechanisms. Advantages and limitations for applications of these methods in clinical laboratory testing and basic research are discussed.

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MicroRNA-Mediated Regulation of the Virus Cycle and Pathogenesis in the SARS-CoV-2 Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222413192 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13192

Author(s):

Rosalia Battaglia ◽

Ruben Alonzo ◽

Chiara Pennisi ◽

Angela Caponnetto ◽

Carmen Ferrara ◽

...

Keyword(s):

Biomedical Applications ◽

Cellular Response ◽

Molecular Mechanisms ◽

Viral Infections ◽

In Silico Analysis ◽

Cell Physiology ◽

Virus Life Cycle ◽

Source Of Information ◽

Bioinformatic Approach ◽

Silico Analysis

In the last few years, microRNA-mediated regulation has been shown to be important in viral infections. In fact, viral microRNAs can alter cell physiology and act on the immune system; moreover, cellular microRNAs can regulate the virus cycle, influencing positively or negatively viral replication. Accordingly, microRNAs can represent diagnostic and prognostic biomarkers of infectious processes and a promising approach for designing targeted therapies. In the past 18 months, the COVID-19 infection from SARS-CoV-2 has engaged many researchers in the search for diagnostic and prognostic markers and the development of therapies. Although some research suggests that the SARS-CoV-2 genome can produce microRNAs and that host microRNAs may be involved in the cellular response to the virus, to date, not enough evidence has been provided. In this paper, using a focused bioinformatic approach exploring the SARS-CoV-2 genome, we propose that SARS-CoV-2 is able to produce microRNAs sharing a strong sequence homology with the human ones and also that human microRNAs may target viral RNA regulating the virus life cycle inside human cells. Interestingly, all viral miRNA sequences and some human miRNA target sites are conserved in more recent SARS-CoV-2 variants of concern (VOCs). Even if experimental evidence will be needed, in silico analysis represents a valuable source of information useful to understand the sophisticated molecular mechanisms of disease and to sustain biomedical applications.

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Inflammatory Cellular Phenotypes and Molecular Mechanisms of Glucocorticoid Resistance in Patients with Bronchial Asthma

Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry ◽

10.2174/18715230113129990010 ◽

2013 ◽

Vol 12 (3) ◽

pp. 189-200 ◽

Cited By ~ 3

Author(s):

Yasuhiro Matsumura

Keyword(s):

Bronchial Asthma ◽

Molecular Mechanisms ◽

Glucocorticoid Resistance ◽

Cellular Phenotypes

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Experimental Models of Hepatocellular Carcinoma—A Preclinical Perspective

Cancers ◽

10.3390/cancers13153651 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3651

Author(s):

Alexandru Blidisel ◽

Iasmina Marcovici ◽

Dorina Coricovac ◽

Florin Hut ◽

Cristina Adriana Dehelean ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanisms ◽

Prediction Models ◽

3D Models ◽

Experimental Models ◽

Health Concern ◽

Liver Carcinoma ◽

Tumor Type

Hepatocellular carcinoma (HCC), the most frequent form of primary liver carcinoma, is a heterogenous and complex tumor type with increased incidence, poor prognosis, and high mortality. The actual therapeutic arsenal is narrow and poorly effective, rendering this disease a global health concern. Although considerable progress has been made in terms of understanding the pathogenesis, molecular mechanisms, genetics, and therapeutical approaches, several facets of human HCC remain undiscovered. A valuable and prompt approach to acquire further knowledge about the unrevealed aspects of HCC and novel therapeutic candidates is represented by the application of experimental models. Experimental models (in vivo and in vitro 2D and 3D models) are considered reliable tools to gather data for clinical usability. This review offers an overview of the currently available preclinical models frequently applied for the study of hepatocellular carcinoma in terms of initiation, development, and progression, as well as for the discovery of efficient treatments, highlighting the advantages and the limitations of each model. Furthermore, we also focus on the role played by computational studies (in silico models and artificial intelligence-based prediction models) as promising novel tools in liver cancer research.

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Environmental Detection and Potential Transmission of Equine Herpesviruses

Pathogens ◽

10.3390/pathogens10040423 ◽

2021 ◽

Vol 10 (4) ◽

pp. 423

Author(s):

Anisha Dayaram ◽

Peter A. Seeber ◽

Alex D. Greenwood

Keyword(s):

Environmental Samples ◽

Environmental Stability ◽

Health Concern ◽

Viral Dynamics ◽

Major Health ◽

Environmental Detection ◽

Environmental Transmission ◽

Direct Exposure ◽

Equine Herpesviruses ◽

Important Disease

Equine herpesviruses (EHV) are a major health concern for domestic and wild equids and represent one of the most economically important disease agents of horses. Most known EHVs are transmitted directly between individuals as a result of direct exposure to exudates and aerosols. However, accumulating evidence suggests that environmental transmission may play a role including air, water, and fomites. Here, we reviewed studies on environmental stability and transmission of EHVs, which may influence viral dynamics and the use of environmental samples for monitoring EHV shedding.

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Feedback Regulation of O-GlcNAc Transferase through Translation Control to Maintain Intracellular O-GlcNAc Homeostasis

International Journal of Molecular Sciences ◽

10.3390/ijms22073463 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3463

Author(s):

Chia-Hung Lin ◽

Chen-Chung Liao ◽

Mei-Yu Chen ◽

Teh-Ying Chou

Keyword(s):

Molecular Mechanisms ◽

Mrna Level ◽

Feedback Regulation ◽

Translation Initiation Factor ◽

Initiation Factor ◽

Cell Physiology ◽

Hydroxyl Groups ◽

Post Translational Modification ◽

Translation Control ◽

Glcnac Transferase

Protein O-GlcNAcylation is a dynamic post-translational modification involving the attachment of N-acetylglucosamine (GlcNAc) to the hydroxyl groups of Ser/Thr residues on numerous nucleocytoplasmic proteins. Two enzymes are responsible for O-GlcNAc cycling on substrate proteins: O-GlcNAc transferase (OGT) catalyzes the addition while O-GlcNAcase (OGA) helps the removal of GlcNAc. O-GlcNAcylation modifies protein functions; therefore, dysregulation of O-GlcNAcylation affects cell physiology and contributes to pathogenesis. To maintain homeostasis of cellular O-GlcNAcylation, there exists feedback regulation of OGT and OGA expression responding to fluctuations of O-GlcNAc levels; yet, little is known about the molecular mechanisms involved. In this study, we investigated the O-GlcNAc-feedback regulation of OGT and OGA expression in lung cancer cells. Results suggest that, upon alterations in O-GlcNAcylation, the regulation of OGA expression occurs at the mRNA level and likely involves epigenetic mechanisms, while modulation of OGT expression is through translation control. Further analyses revealed that the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) contributes to the downregulation of OGT induced by hyper-O-GlcNAcylation; the S5A/S6A O-GlcNAcylation-site mutant of 4E-BP1 cannot support this regulation, suggesting an important role of O-GlcNAcylation. The results provide additional insight into the molecular mechanisms through which cells may fine-tune intracellular O-GlcNAc levels to maintain homeostasis.

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Paclitaxel Promotes Cell Apoptosis in Uterine Leiomyomas

Pharmacology ◽

10.1159/000479161 ◽

2017 ◽

Vol 100 (5-6) ◽

pp. 246-252 ◽

Cited By ~ 3

Author(s):

Haiping Liu ◽

Jianye Wang ◽

Lianbing Sheng ◽

Yan Zhang ◽

Ning Tang ◽

...

Keyword(s):

Mouse Model ◽

Critical Role ◽

Estradiol Benzoate ◽

Uterine Leiomyomas ◽

Health Concern ◽

Major Health ◽

Gynecological Tumors ◽

Dose Limiting Toxicity ◽

Insight Into ◽

Apoptosis Level

Uterine leiomyomas are common clinical gynecological tumors, which are a major health concern for many women. In the current study, we aimed to investigate the effect of paclitaxel (PTX) on uterine leiomyomas. A mouse model of uterine leiomyomas was established by estradiol benzoate, followed by treatment with increasing doses of PTX. PTX showed no dose-limiting toxicity that affected the survival of mice, and was able to restore the apoptosis level of uterus tissues of the model mice to normal levels. In this study, we discovered that PTX played a critical role in promoting apoptosis in the mouse model of uterine leiomyomas, which provides a new insight into the therapy of uterine leiomyomas.

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Salmonella Heidelberg Strain Responses to Essential Oil Components

Journal of Food Research ◽

10.5539/jfr.v4n5p73 ◽

2015 ◽

Vol 4 (5) ◽

pp. 73 ◽

Cited By ~ 2

Author(s):

Juliany Rivera Calo ◽

Christopher A. Baker ◽

Si Hong Park ◽

Steven C. Ricke

Keyword(s):

Foodborne Pathogens ◽

Food Production ◽

Antimicrobial Agents ◽

Health Concern ◽

Orange Oil ◽

Major Health ◽

Minimal Inhibitory Concentrations ◽

Color Changes ◽

Different Sources ◽

Strain Responses

Salmonella are one of the more prominent foodborne pathogens that represent a major health risk to humans. Salmonella serovar Heidelberg strains are increasingly becoming an important public health concern, since they have been identified as one of the primary Salmonella serovars responsible for human outbreaks. Over the years, Salmonella Heidelberg isolates have exhibited higher rates of resistance to multiple antimicrobial agents compared to other Salmonella serovars. Essential oils (EOs) have been widely used as alternatives to chemical-based antimicrobials. In the current research, five EOs were screened to determine their antimicrobial activity against 15 S. Heidelberg strains from different sources. Oils tested were R(+)-limonene, orange terpenes, cold compressed orange oil, trans-cinnamaldehyde and carvacrol. EOs were stabilized in nutrient broth by adding 0.15% (w/v) agar. Tube dilution assays and minimal inhibitory concentrations (MIC) were determined by observing color changes in samples during exposure to EOs. Carvacrol and trans-cinnamaldehyde completely inhibited the growth of S. Heidelberg strains, while R(+)-limonene and orange terpenes did not show any inhibitory activity against the strains tested. Cold compressed orange oil only inhibited growth of two of the strains exhibiting an MIC of 1%. All S. Heidelberg isolates evaluated exhibited similar responses to the respective EOs. The use of all natural antimicrobials such as specific EOs offers the potential to limit the majority of S. Heidelberg isolates that may occur in food production.

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Polypeptide-GalNAc-Transferase-13 Shows Prognostic Impact in Breast Cancer

Cancers ◽

10.3390/cancers13225616 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5616

Author(s):

Eugenia Fernandez ◽

Luis Ubillos ◽

Nabila Elgul ◽

María Florencia Festari ◽

Daniel Mazal ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Nodes ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Health Concern ◽

Breast Cancer Cell Lines ◽

Prognostic Impact ◽

Metastatic Lymph Nodes ◽

Metastatic Lymph

Breast cancer is a public health concern and is currently the fifth cause of mortality worldwide. Identification of different biological subtypes is essential for clinical management; therefore, the role of pathologists is essential and useful tools for immunohistochemistry diagnosis are needed. Polypeptide-GalNAc-transferases are emerging novel biomarkers related to cancer behavior and GalNAc-T13, correlated with aggressiveness in some tumors, is an interesting candidate. Few monoclonal antibodies reacting with native proteins, and not affected by fixation and paraffin embedding, have been reported. The aim of this work was to develop a useful monoclonal antibody anti-GalNAc-T13 and to assess its potential significance in breast cancer diagnosis. We evaluated 6 human breast cancer cell lines, 338 primary breast tumors and 48 metastatic lymph nodes and looked for clinical significance correlating GalNAc-T13 expression with patients’ clinical features and survival. We found high GalNAc-T13 expression in 43.8% of the cases and observed a significant higher expression in metastatic lymph nodes, correlating with worse overall survival. We hypothesized several possible molecular mechanisms and their implications. We conclude that GalNAc-T13 may be a novel biomarker in breast cancer, useful for routine pathological diagnosis. Elucidation of molecular mechanisms related to aggressiveness should contribute to understand the role of GalNAc-T13 in breast cancer biology.

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