scholarly journals Mechanisms of Wheat Allergenicity in Mice: Comparison of Adjuvant-Free vs. Alum-Adjuvant Models

2020 ◽  
Vol 21 (9) ◽  
pp. 3205
Author(s):  
Yining Jin ◽  
Haoran Gao ◽  
Rick Jorgensen ◽  
Jillian Salloum ◽  
Dan Ioan Jian ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Cell Protein ◽  
Major Type ◽  
Mucosal Mast Cell ◽  
Wheat Protein ◽  
Immune Markers ◽  
Activation Patterns ◽  
Skin Exposure ◽  
The Usa ◽  
Baking Industry

Wheat protein is considered a major type of food allergen in many countries including the USA. The mechanisms of allergenicity of wheat proteins are not well understood at present. Both adjuvant-based and adjuvant-free mouse models are reported for this food allergy. However, it is unclear whether the mechanisms underlying wheat allergenicity in these two types of models are similar or different. Therefore, we compared the molecular mechanisms in a novel adjuvant-free (AF) model vs. a conventional alum-adjuvant (AA) model of wheat allergy using salt-soluble wheat protein (SSWP). In the AF model, Balb/cJ mice were sensitized with SSWP via skin exposure. In the AA model, mice were sensitized by an intraperitoneal injection of SSWP with alum. In both models, allergic reactions were elicited using an identical protocol. Robust IgE as well as mucosal mast cell protein-1 responses were elicited similarly in both models. However, an analysis of the spleen immune markers identified strikingly different molecular activation patterns in these two models. Furthermore, a number of immune markers associated with intrinsic allergenicity were also identified in both models. Since the AF model uses skin exposure without an adjuvant, the mechanisms in the AF model may more closely simulate the human wheat allergenicity mechanisms from skin exposure in occupational settings such as in the baking industry.

TAMM HORSFALL PROTEIN: THE MEN BEHIND THE EPONYM

2019 ◽  
Vol 23 (2) ◽  
pp. 117-119 ◽  
Author(s):  
D. N. Paskalev ◽  
B. T. Galunska ◽  
D. Petkova-Valkova
Keyword(s):  
Viral Replication ◽  
Research Team ◽  
Molecular Mechanisms ◽  
Thick Ascending Limb ◽  
Rockefeller Institute ◽  
The Usa ◽  
Natural Inhibitor ◽  
Simplex Virus ◽  
First Time ◽  
New Protein

Tamm–Horsfall Protein (uromodulin) is named after Igor Tamm and Franc Horsfall Jr who described it for the first time in 1952. It is a glycoprotein, secreted by the cells in the thick ascending limb of the loop of Henle. This protein will perform a number of important pathophysiological functions, including protection against uroinfections, especially caused by E. Сoli, and protection against formation of calcium concernments in the kidney. Igor Tamm (1922-1995) is an outstanding cytologist, virologist and biochemist. He is one of the pioneers in the study of viral replication. He was born in Estonia and died in the USA. In 1964 he was elected for a professorship in Rockefeller Institute for Medical Research, where has been working continuously. Since 1959, he became a head of the virology lab established by his mentor and co-author Franc Horsfall. In the course of studies on the natural inhibitor of viral replication, Tamm and Horsfall isolated and characterized biochemically a new protein named after their names. Franc Lappin Horsfall Jr (1906-1971) was a well-known clinician and virologist with remarkable achievements in internal medicine. He was born and died in the USA. He worked in the Rockefeller Hospital from 1934 to 1960, then in the Center for Cancer Research at the Sloan-Kettering Institute. Here he was a leader of a research team studying the molecular mechanisms of immunity, the effects of chemotherapy with benzimidazole compounds (together with I. Tamm), coxsackie viruses, herpes simplex virus, etc. 

scholarly journals Top-100 Most Cited Publications Concerning Network Pharmacology: A Bibliometric Analysis

2019 ◽  
Vol 2019 ◽  
pp. 1-7 ◽  
Author(s):  
Cuncun Lu ◽  
Zhitong Bing ◽  
Zhijiang Bi ◽  
Ming Liu ◽  
Tingting Lu ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Web Of Science ◽  
Drug Research ◽  
Research Field ◽  
Current Status ◽  
Network Pharmacology ◽  
The Past ◽  
The Usa ◽  
Number Of Citations

Background. Network pharmacology (NP) has become an increasingly important focus in the drug research field over the past decade. However, no study to date has mapped the current status of NP. Therefore, we performed a bibliometric study to evaluate the top 100 cited papers on NP. Methods. We searched the Web of Science Core Collection from its inception to February 25, 2019, using the terms “network pharmacology” and “systems pharmacology.” Key data, including title, publication year, number of citations, authors, countries/regions, organizations, and journals, were retrieved and analyzed using Excel 2016 and VOSviewer 1.6.10. Results. The total number of citations for the 100 cited papers ranged from 21 to 1,238, published in 53 journals, from 2005 to 2017. The top three journals with the most publications on NP were Clinical Pharmacology & Therapeutics (n = 8, IF2017 = 6.544), Journal of Ethnopharmacology (n = 8, IF2017 = 3.115), and PLoS One (n = 7, IF2017 = 2.766). Most published articles were from the USA (n = 41) and China (n = 35). The most active author was Wang Yonghua from the Northwest A&F University, and of the 100 publications, 14 listing his name. The most frequently used substantive terms included “drug discovery,” “traditional Chinese medicine (TCM),” “in-vitro,” “cancer,” and “cardiovascular disease.” Conclusions. The USA and China made the greatest contribution to NP research. The current NP research mainly focused on NP methods (including experimental validation) and using them to explore the molecular mechanisms of TCM for some critical diseases such as cardiovascular diseases and cancers. Furthermore, we believe some guidelines should be developed to regulate NP studies.

scholarly journals Hypothesis for changing models: current pharmaceutical paradigms, trends and approaches in drug discovery

2015 ◽  
Author(s):  
Domenico Fuoco
Keyword(s):  
Scientific Reasoning ◽  
Molecular Mechanisms ◽  
Annual Number ◽  
Web Based ◽  
Chemical Structures ◽  
New Drug ◽  
New Chemical Entities ◽  
The Usa ◽  
Total Investment

Despite the increasing availability of chemicals, the number of New Drug Approvals (NDA) from the Food and Drug Administration (FDA) remains unchanged. The number of chemical structures available online via web-based open source applications will reach the symbolic 1 billion in the 10 next years. However, for no apparent reasons, the number of NDA accepted yearly has not changed in the past 25 years. One of the emerging paradigms of Big Pharma is that the more we know about molecular mechanisms and cell signaling pathways, the less we understand how to use this knowledge to make New Chemical Entities (NCE). Moreover, the annual number of pharmaceutical patents collected in the OCSE database has virtually not increased. Unexpectedly, the number of patents originating in the USA is decreasing significantly, while Asia is doing very well. The comparison between the number of NCEs and the American investment in Research and Development (R&D) in the last 35 years shows that to obtain a new drug blockbuster, the total investment is quasi 4 USD billion. One of the peculiarities is the inverse relationship between the investment in R&D and the continued shortfall in productivity. A main reason for this decline is that the quality of scientific reasoning done by experienced chemists is too often replaced by Big Data . It is time to change the role of chemistry in Big Pharma and to re-position it as the central science to progress and to lead to much needed innovation.

The cytoprotective protein C pathway

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3161-3172 ◽  
Author(s):  
Laurent O. Mosnier ◽  
Berislav V. Zlokovic ◽  
John H. Griffin
Keyword(s):  
Protein C ◽  
Molecular Mechanisms ◽  
Clinical Success ◽  
Expression Profiles ◽  
Anticoagulant Activity ◽  
Purpura Fulminans ◽  
Factor V Leiden ◽  
In Vivo Studies ◽  
Cell Protein ◽  
Complex Disorders

Abstract Protein C is best known for its mild deficiency associated with venous thrombosis risk and severe deficiency associated with neonatal purpura fulminans. Activated protein C (APC) anticoagulant activity involves proteolytic inactivation of factors Va and VIIIa, and APC resistance is often caused by factor V Leiden. Less known is the clinical success of APC in reducing mortality in severe sepsis patients (PROWESS trial) that gave impetus to new directions for basic and preclinical research on APC. This review summarizes insights gleaned from recent in vitro and in vivo studies of the direct cytoprotective effects of APC that include beneficial alterations in gene expression profiles, anti-inflammatory actions, antiapoptotic activities, and stabilization of endothelial barriers. APC's cytoprotection requires its receptor, endothelial cell protein C receptor, and protease-activated receptor-1. Because of its pleiotropic activities, APC has potential roles in the treatment of complex disorders, including sepsis, thrombosis, and ischemic stroke. Although much about molecular mechanisms for APC's effects on cells remains unclear, it is clear that APC's structural features mediating anticoagulant actions and related bleeding risks are distinct from those mediating cytoprotective actions, suggesting the possibility of developing APC variants with an improved profile for the ratio of cytoprotective to anticoagulant actions.

scholarly journals Alpha-Synuclein: Mechanisms of Release and Pathology Progression in Synucleinopathies

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 375
Author(s):  
Inês C. Brás ◽  
Tiago F. Outeiro
Keyword(s):  
Molecular Mechanisms ◽  
Brain Regions ◽  
Alpha Synuclein ◽  
Therapeutic Strategies ◽  
Cell Protein ◽  
Protein Assemblies ◽  
Lewy Pathology ◽  
Tremendous Progress ◽  
The Brain ◽  
Made In

The accumulation of misfolded alpha-synuclein (aSyn) throughout the brain, as Lewy pathology, is a phenomenon central to Parkinson’s disease (PD) pathogenesis. The stereotypical distribution and evolution of the pathology during disease is often attributed to the cell-to-cell transmission of aSyn between interconnected brain regions. The spreading of conformationally distinct aSyn protein assemblies, commonly referred as strains, is thought to result in a variety of clinically and pathologically heterogenous diseases known as synucleinopathies. Although tremendous progress has been made in the field, the mechanisms involved in the transfer of these assemblies between interconnected neural networks and their role in driving PD progression are still unclear. Here, we present an update of the relevant discoveries supporting or challenging the prion-like spreading hypothesis. We also discuss the importance of aSyn strains in pathology progression and the various putative molecular mechanisms involved in cell-to-cell protein release. Understanding the pathways underlying aSyn propagation will contribute to determining the etiology of PD and related synucleinopathies but also assist in the development of new therapeutic strategies.

scholarly journals COVID-19: Characteristics and Therapeutics

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 206 ◽  
Author(s):  
Rameswari Chilamakuri ◽  
Saurabh Agarwal
Keyword(s):  
Molecular Mechanisms ◽  
Vaccine Development ◽  
Clinical Manifestations ◽  
Treatment Strategies ◽  
Drug Repurposing ◽  
World Health ◽  
Pharmacological Intervention ◽  
Multiple Treatment ◽  
The Usa ◽  
Novel Coronavirus

Novel coronavirus (COVID-19 or 2019-nCoV or SARS-CoV-2), which suddenly emerged in December 2019 is still haunting the entire human race and has affected not only the healthcare system but also the global socioeconomic balances. COVID-19 was quickly designated as a global pandemic by the World Health Organization as there have been about 98.0 million confirmed cases and about 2.0 million confirmed deaths, as of January 2021. Although, our understanding of COVID-19 has significantly increased since its outbreak, and multiple treatment approaches and pharmacological interventions have been tested or are currently under development to mitigate its risk-factors. Recently, some vaccine candidates showed around 95% clinical efficacy, and now receiving emergency use approvals in different countries. US FDA recently approved BNT162 and mRNA-1273 vaccines developed by Pfizer/BioNTech and Moderna Inc. for emergency use and vaccination in the USA. In this review, we present a succinct overview of the SARS-CoV-2 virus structure, molecular mechanisms of infection, COVID-19 epidemiology, diagnosis, and clinical manifestations. We also systematize different treatment strategies and clinical trials initiated after the pandemic outbreak, based on viral infection and replication mechanisms. Additionally, we reviewed the novel pharmacological intervention approaches and vaccine development strategies against COVID-19. We speculate that the current pandemic emergency will trigger detailed studies of coronaviruses, their mechanism of infection, development of systematic drug repurposing approaches, and novel drug discoveries for current and future pandemic outbreaks.

scholarly journals Comparative multiplexed interactomics of SARS-CoV-2 and homologous coronavirus non-structural proteins identifies unique and shared host-cell dependencies

2020 ◽  
Author(s):  
Jonathan P. Davies ◽  
Katherine M. Almasy ◽  
Eli F. McDonald ◽  
Lars Plate
Keyword(s):  
Host Cell ◽  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Sequence Similarity ◽  
Host Protein ◽  
Structural Proteins ◽  
Cell Protein ◽  
High Sequence Similarity ◽  
Innate Immune Signaling ◽  
Human Coronaviruses

ABSTRACTHuman coronaviruses (hCoV) have become a threat to global health and society, as evident from the SARS outbreak in 2002 caused by SARS-CoV-1 and the most recent COVID-19 pandemic caused by SARS-CoV-2. Despite high sequence similarity between SARS-CoV-1 and −2, each strain has distinctive virulence. A better understanding of the basic molecular mechanisms mediating changes in virulence is needed. Here, we profile the virus-host protein-protein interactions of two hCoV non-structural proteins (nsps) that are critical for virus replication. We use tandem mass tag-multiplexed quantitative proteomics to sensitively compare and contrast the interactomes of nsp2 and nsp4 from three betacoronavirus strains: SARS-CoV-1, SARS-CoV-2, and hCoV-OC43 – an endemic strain associated with the common cold. This approach enables the identification of both unique and shared host cell protein binding partners and the ability to further compare the enrichment of common interactions across homologs from related strains. We identify common nsp2 interactors involved in endoplasmic reticulum (ER) Ca2+ signaling and mitochondria biogenesis. We also identifiy nsp4 interactors unique to each strain, such as E3 ubiquitin ligase complexes for SARS-CoV-1 and ER homeostasis factors for SARS-CoV-2. Common nsp4 interactors include N-linked glycosylation machinery, unfolded protein response (UPR) associated proteins, and anti-viral innate immune signaling factors. Both nsp2 and nsp4 interactors are strongly enriched in proteins localized at mitochondrial-associated ER membranes suggesting a new functional role for modulating host processes, such as calcium homeostasis, at these organelle contact sites. Our results shed light on the role these hCoV proteins play in the infection cycle, as well as host factors that may mediate the divergent pathogenesis of OC43 from SARS strains. Our mass spectrometry workflow enables rapid and robust comparisons of multiple bait proteins, which can be applied to additional viral proteins. Furthermore, the identified common interactions may present new targets for exploration by host-directed anti-viral therapeutics.

scholarly journals Evaluation of the Binding Kinetics of RHEB with mTORC1 by In-cell and In vitro Assays

2021 ◽  
Author(s):  
Raef Shams ◽  
Yoshihiro Ito ◽  
Hideyuki Miyatake
Keyword(s):  
Molecular Mechanisms ◽  
Cancer Therapeutics ◽  
Kinase Domain ◽  
Binding Kinetics ◽  
In Vitro Assays ◽  
Cell Protein ◽  
Independent Manner ◽  
Growth And Survival ◽  
Kinetics Of

The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is activated by the small G-protein, RHEB-GTPase. On lysosome, RHEB activates mTORC1 by binding the domains of N-heat, M-heat, and FAT, which allosterically regulates ATP binding in the active site for further phosphorylation. The crucial role of RHEB in regulating growth and survival through mTORC1, makes it a targetable site for anti-cancer therapeutics. However, the binding kinetics of RHEB to mTORC1 is still unknown at the molecular level. Therefore, we studied the kinetics by in vitro and in-cell protein-protein interaction (PPI) assays. For this, we used the split-luciferase system (NanoBiT®) for in-cell studies, and prepared proteins for the in vitro measurements. Consequently, it was shown that RHEB binds to the whole mTOR both in the presence or absence of GTPɣS, with five-fold weaker affinity in the presence of GTPɣS. Also, RHEB bound to the truncated mTOR fragments of N-heat domain (60-167) and M-heat domain (967-1023) in a GTP independent manner. Furthermore, RHEB bound to the truncated kinase domain (2148-2300) with higher affinity also in GTP independently. In conclusion, RHEB binds two different binding sites of mTOR, which probably regulates the kinase activity of mTOR through multiple different molecular mechanisms.

scholarly journals Molecular Mechanisms Driving Progression of Liver Cirrhosis towards Hepatocellular Carcinoma in Chronic Hepatitis B and C Infections: A Review

2019 ◽  
Vol 20 (6) ◽  
pp. 1358 ◽  
Author(s):  
Tatsuo Kanda ◽  
Taichiro Goto ◽  
Yosuke Hirotsu ◽  
Mitsuhiko Moriyama ◽  
Masao Omata
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Cirrhosis ◽  
Hepatitis B ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Primary Liver Cancer ◽  
Immune Checkpoints ◽  
Major Type ◽  
Advanced Stages ◽  
Almost All

Almost all patients with hepatocellular carcinoma (HCC), a major type of primary liver cancer, also have liver cirrhosis, the severity of which hampers effective treatment for HCC despite recent progress in the efficacy of anticancer drugs for advanced stages of HCC. Here, we review recent knowledge concerning the molecular mechanisms of liver cirrhosis and its progression to HCC from genetic and epigenomic points of view. Because ~70% of patients with HCC have hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection, we focused on HBV- and HCV-associated HCC. The literature suggests that genetic and epigenetic factors, such as microRNAs, play a role in liver cirrhosis and its progression to HCC, and that HBV- and HCV-encoded proteins appear to be involved in hepatocarcinogenesis. Further studies are needed to elucidate the mechanisms, including immune checkpoints and molecular targets of kinase inhibitors, associated with liver cirrhosis and its progression to HCC.

scholarly journals Tetraspanin CD63 Bridges Autophagic and Endosomal Processes To Regulate Exosomal Secretion and Intracellular Signaling of Epstein-Barr Virus LMP1

2017 ◽  
Vol 92 (5) ◽  
Author(s):  
Stephanie N. Hurwitz ◽  
Mujeeb R. Cheerathodi ◽  
Dingani Nkosi ◽  
Sara B. York ◽  
David G. Meckes
Keyword(s):  
Host Cell ◽  
Intracellular Signaling ◽  
Epstein Barr Virus ◽  
Molecular Mechanisms ◽  
Negative Regulator ◽  
Cell Protein ◽  
Viral Oncoprotein ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT The tetraspanin protein CD63 has been recently described as a key factor in extracellular vesicle (EV) production and endosomal cargo sorting. In the context of Epstein-Barr virus (EBV) infection, CD63 is required for the efficient packaging of the major viral oncoprotein latent membrane protein 1 (LMP1) into exosomes and other EV populations and acts as a negative regulator of LMP1 intracellular signaling. Accumulating evidence has also pointed to intersections of the endosomal and autophagy pathways in maintaining cellular secretory processes and as sites for viral assembly and replication. Indeed, LMP1 can activate the mammalian target of rapamycin (mTOR) pathway to suppress host cell autophagy and facilitate cell growth and proliferation. Despite the growing recognition of cross talk between endosomes and autophagosomes and its relevance to viral infection, little is understood about the molecular mechanisms governing endosomal and autophagy convergence. Here, we demonstrate that CD63-dependent vesicle protein secretion directly opposes intracellular signaling activation downstream of LMP1, including mTOR-associated proteins. Conversely, disruption of normal autolysosomal processes increases LMP1 secretion and dampens signal transduction by the viral protein. Increases in mTOR activation following CD63 knockout are coincident with the development of serum-dependent autophagic vacuoles that are acidified in the presence of high LMP1 levels. Altogether, these findings suggest a key role of CD63 in regulating the interactions between endosomal and autophagy processes and limiting cellular signaling activity in both noninfected and virally infected cells. IMPORTANCE The close connection between extracellular vesicles and viruses is becoming rapidly and more widely appreciated. EBV, a human gamma herpesvirus that contributes to the progression of a multitude of lymphomas and carcinomas in immunocompromised or genetically susceptible populations, packages its major oncoprotein, LMP1, into vesicles for secretion. We have recently described a role of the host cell protein CD63 in regulating intracellular signaling of the viral oncoprotein by shuttling LMP1 into exosomes. Here, we provide strong evidence of the utility of CD63-dependent EVs in regulating global intracellular signaling, including mTOR activation by LMP1. We also demonstrate a key role of CD63 in coordinating endosomal and autophagic processes to regulate LMP1 levels within the cell. Overall, this study offers new insights into the complex intersection of cellular secretory and degradative mechanisms and the implications of these processes in viral replication.

Sign in / Sign up

Export Citation Format

Share Document