The Design and Synthesis of Biologically Active Organophosphorus Compounds – The Role of a Central Research Laboratory

: Emerging evidence supports an intertwining framework for the involvement of different inflammatory pathways in a common pathological background for a number of disorders. Of importance are pathways involving arachidonic acid metabolism by cyclooxygenase-2 (COX-2) and 15-lipoxygenase (15-LOX). Both enzyme activities and their products are implicated in a range of pathophysiological processes encompassing metabolic impairment leading to adipose inflammation and the subsequent vascular and neurological disorders, in addition to various pro-and anti-tumorigenic effects. A further layer of complexity is encountered by the disparate, and often reciprocal, modulatory effect COX-2 and 15-LOX activities and metabolites exert on each other or on other cellular targets, the most prominent of which is peroxisome proliferator-activated receptor gamma (PPARγ). Thus, effective therapeutic intervention with such multifaceted disorders requires the simultaneous modulation of more than one target. Here, we describe the role of COX-2, 15-LOX, and PPARγ in cancer and complications of metabolic disorders, highlight the value of designing multi-target directed ligands (MTDLs) modifying their activity, and summarize the available literature regarding the rationale and feasibility of design and synthesis of these ligands together with their known biological effects. We speculate on the potential impact of MTDLs in these disorders as well as emphasize the need for structured future effort to translate these early results facilitating the adoption of these, and similar, molecules in clinical research.

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Anti-Hypertensive Potential and Epigenetics of Angiotensin II type 2 Receptor (AT2R)

Current Hypertension Reviews ◽

10.2174/1573402116999201209203015 ◽

2020 ◽

Vol 16 ◽

Author(s):

Mayank Chaudhary

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Renin Angiotensin System ◽

Blood Pressure Regulation ◽

Biologically Active ◽

Pressure Regulation ◽

Tissue Remodelling ◽

Critical Pathway

Background:: Renin angiotensin system (RAS) is a critical pathway involved in blood pressure regulation. Octapeptide, angiotensin II (Ang aII), is biologically active compound of RAS pathway which mediates its action by binding to either angiotensin II type 1 receptor (AT1R) or angiotensin II type 2 receptor (AT2R). Binding of Ang II to AT1R facilitates blood pressure regulation whereas AT2R is primarily involved in wound healing and tissue remodelling. Objective:: Recent studies have highlighted additional role of AT2R to counter balance detrimental effects of AT1R. Activation of angiotensin II type 2 receptor using AT2R agonist has shown effect on natriuresis and release of nitric oxide. Additionally, AT2R activation has been found to inhibit angiotensin converting enzyme (ACE) and enhance angiotensin receptor blocker (ARB) activity. These findings highlight the potential of AT2R as novel therapeutic target against hypertension. Conclusion:: The potential role of AT2R highlights the importance of exploring additional mechanisms that might be crucial for AT2R expression. Epigenetic mechanisms including DNA methylation and histone modification have been explored vastly with relation to cancer but role of such mechanisms on expression of AT2R has recently gained interest.

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Reconstitution in Proteoliposomes of the Recombinant Human Riboflavin Transporter 2 (SLC52A2) Overexpressed in E. coli

International Journal of Molecular Sciences ◽

10.3390/ijms20184416 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4416 ◽

Cited By ~ 2

Author(s):

Lara Console ◽

Maria Tolomeo ◽

Matilde Colella ◽

Maria Barile ◽

Cesare Indiveri

Keyword(s):

Cardiovascular Disease ◽

Amino Acids ◽

Risk Factor ◽

Biologically Active ◽

Suitable Model ◽

Native Protein ◽

E Coli ◽

Few Data ◽

Riboflavin Transport

Background: the SLC52A2 gene encodes for the riboflavin transporter 2 (RFVT2). This transporter is ubiquitously expressed. It mediates the transport of Riboflavin across cell membranes. Riboflavin plays a crucial role in cells since its biologically active forms, FMN and FAD, are essential for the metabolism of carbohydrates, amino acids, and lipids. Mutation of the Riboflavin transporters is a risk factor for anemia, cancer, cardiovascular disease, neurodegeneration. Inborn mutations of SLC52A2 are associated with Brown-Vialetto-van Laere syndrome, a rare neurological disorder characterized by infancy onset. In spite of the important metabolic and physio/pathological role of this transporter few data are available on its function and regulation. Methods: the human recombinant RFVT2 has been overexpressed in E. coli, purified and reconstituted into proteoliposomes in order to characterize its activity following the [3H]Riboflavin transport. Results: the recombinant hRFVT2 showed a Km of 0.26 ± 0.07 µM and was inhibited by lumiflavin, FMN and Mg2+. The Riboflavin uptake was also regulated by Ca2+. The native protein extracted from fibroblast and reconstituted in proteoliposomes also showed inhibition by FMN and lumiflavin. Conclusions: proteoliposomes represent a suitable model to assay the RFVT2 function. It will be useful for screening the mutation of RFVT2.

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Extracellular Vesicles: Novel Opportunities to Understand and Detect Neoplastic Diseases

Veterinary Pathology ◽

10.1177/0300985821999328 ◽

2021 ◽

pp. 030098582199932

Author(s):

Laura Bongiovanni ◽

Anneloes Andriessen ◽

Marca H. M. Wauben ◽

Esther N. M. Nolte-’t Hoen ◽

Alain de Bruin

Keyword(s):

Extracellular Vesicles ◽

Biologically Active ◽

Liquid Biopsies ◽

Donor Cells ◽

Recent Developments ◽

Veterinary Pathology ◽

Cell Components ◽

Potential Applications ◽

Intercellular Communications

With a size range from 30 to 1000 nm, extracellular vesicles (EVs) are one of the smallest cell components able to transport biologically active molecules. They mediate intercellular communications and play a fundamental role in the maintenance of tissue homeostasis and pathogenesis in several types of diseases. In particular, EVs actively contribute to cancer initiation and progression, and there is emerging understanding of their role in creation of the metastatic niche. This fact underlies the recent exponential growth in EV research, which has improved our understanding of their specific roles in disease and their potential applications in diagnosis and therapy. EVs and their biomolecular cargo reflect the state of the diseased donor cells, and can be detected in body fluids and exploited as biomarkers in cancer and other diseases. Relatively few studies have been published on EVs in the veterinary field. This review provides an overview of the features and biology of EVs as well as recent developments in EV research including techniques for isolation and analysis, and will address the way in which the EVs released by diseased tissues can be studied and exploited in the field of veterinary pathology. Uniquely, this review emphasizes the important contribution that pathologists can make to the field of EV research: pathologists can help EV scientists in studying and confirming the role of EVs and their molecular cargo in diseased tissues and as biomarkers in liquid biopsies.

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Search for Role of Milk-Borne Biologically Active Peptides for the Suckling

Journal of Nutrition ◽

10.1093/jn/119.11.1543 ◽

1989 ◽

Vol 119 (11) ◽

pp. 1543-1551 ◽

Cited By ~ 98

Author(s):

Otakar Koldovský

Keyword(s):

Biologically Active ◽

Active Peptides ◽

Biologically Active Peptides

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Design and synthesis of a novel 5-(aminomethylene)thiazolidine-2,4-dione derivatives as potent hepatitis-B virus polymerase inhibitors

Bangladesh Journal of Pharmacology ◽

10.3329/bjp.v10i2.21876 ◽

2015 ◽

Vol 10 (2) ◽

pp. 271

Author(s):

Wei-Guo Li ◽

He-Qun Wang

Keyword(s):

Hbv Dna ◽

Biologically Active ◽

Secondary Amines ◽

Design And Synthesis ◽

H Nmr ◽

Viral Antigens ◽

Polymerase Inhibitors ◽

Potent Inhibition ◽

B Virus ◽

C Nmr

A series of novel thiazolidinedione analogues (TZD) were designed and synthesized potent inhibitors of HBV capsid assembly. The synthesis of thiazolidine-2,4-dione derivatives (4a–4o), starting from the condensation of 5-(ethoxymethylene)thiazolidine-2,4-dione (1) with various secondary amines (3) derived from biologically active compounds. The newly synthesized TZD analogues 4a-4o were characterized by 1H NMR, 13C NMR, and MS and evaluated for their anti-HBV activity. Most of the compounds inhibited the expression of viral antigens at low concentration. Six compounds, 4g, 4h, 4l, 4m, 4n, and 4o, demonstrated potent inhibition of HBV DNA replication at submicromolar range. Of these five initial hits, compound 4o was the most active when compared with lamivudine.

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Role of Platelet-Activating Factor in Cardiovascular Pathophysiology

Physiological Reviews ◽

10.1152/physrev.2000.80.4.1669 ◽

2000 ◽

Vol 80 (4) ◽

pp. 1669-1699 ◽

Cited By ~ 245

Author(s):

Giuseppe Montrucchio ◽

Giuseppe Alloatti ◽

Giovanni Camussi

Keyword(s):

Cardiovascular System ◽

Cell Biology ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Critical Role ◽

Experimental Studies ◽

Platelet Activating Factor ◽

Biologically Active ◽

Endothelial Cell Migration

Platelet-activating factor (PAF) is a phospholipid mediator that belongs to a family of biologically active, structurally related alkyl phosphoglycerides. PAF acts via a specific receptor that is coupled with a G protein, which activates a phosphatidylinositol-specific phospholipase C. In this review we focus on the aspects that are more relevant for the cell biology of the cardiovascular system. The in vitro studies provided evidence for a role of PAF both as intercellular and intracellular messenger involved in cell-to-cell communication. In the cardiovascular system, PAF may have a role in embryogenesis because it stimulates endothelial cell migration and angiogenesis and may affect cardiac function because it exhibits mechanical and electrophysiological actions on cardiomyocytes. Moreover, PAF may contribute to modulation of blood pressure mainly by affecting the renal vascular circulation. In pathological conditions, PAF has been involved in the hypotension and cardiac dysfunctions occurring in various cardiovascular stress situations such as cardiac anaphylaxis and hemorrhagic, traumatic, and septic shock syndromes. In addition, experimental studies indicate that PAF has a critical role in the development of myocardial ischemia-reperfusion injury. Indeed, PAF cooperates in the recruitment of leukocytes in inflamed tissue by promoting adhesion to the endothelium and extravascular transmigration of leukocytes. The finding that human heart can produce PAF, expresses PAF receptor, and is sensitive to the negative inotropic action of PAF suggests that this mediator may have a role also in human cardiovascular pathophysiology.

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