R-954, a bradykinin B1 receptor antagonist, as a potential therapy in a preclinical endometriosis model.

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues outside of the uterine cavity. Currently available drugs are efficacious in treating endometriosis-related pain, however it's not a targeted treatment. The aim of this work is to evaluate the effects of R-954, a bradykinin B1 receptor antagonist, in a murine model of endometriosis.

Genetic Ablation and Pharmacological Blockade of Bradykinin B1 Receptor Unveiled a Detrimental Role for the Kinin System in Chagas Disease Cardiomyopathy.

Chagas disease, the parasitic infection caused by , afflicts about 6 million people in Latin America. Here, we investigated the hypothesis that may fuel heart parasitism by activating B1R, a G protein-coupled (brady) kinin receptor whose expression is upregulated in inflamed tissues. Studies in WT and B1R mice showed that DNA levels (15 days post infection-dpi) were sharply reduced in the transgenic heart.

Functionalized Nanogels with Endothelin-1 and Bradykinin Receptor Antagonist Peptides Decrease Inflammatory and Cartilage Degradation Markers of Osteoarthritis in a Horse Organoid Model of Cartilage.

Osteoarthritis (OA) is a degenerative and heterogeneous disease that affects all types of joint structures. Current clinical treatments are only symptomatic and do not manage the degenerative process in animals or humans. One of the new orthobiological treatment strategies being developed to treat OA is the use of drug delivery systems (DDS) to release bioactive molecules over a long period of time directly into the joint to limit inflammation, control pain, and reduce cartilage degradation.

The role of kallikrein-kinin and renin-angiotensin systems in COVID-19 infection.

In November 2019 the first cases of a novel acute respiratory syndrome has been reported in Wuhan province, China. Soon after, in January 2020 the World Health Organization declared a pandemic state due to the dissemination of a virus named SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19). Being an unknown disease, it is essential to assess not only its main characteristic features and overall clinical symptomatology but also its patient infection mode and propagation to design appropriate clinical interventions and treatments.

Primerless Amplification for Circulating Tumor DNA Assays.

A primerless amplification suitable for enrichment of particular genotype cfDNA which is a one-dimensional material has been developed. This primerless amplification coordinated by two thermostable enzymes of endonuclease and proofreading polymerase, functions as a genotype switch in analyzing cfDNA. The endonuclease digests the wild-typed fragments into mega-primer and discriminately destroys the wild-type DNA alleles.

Leukotrienes: One step in our understanding of asthma.

The steps leading to the discovery of leukotrienes and the researchers that played a major part in this long process are presented. The pharmacology of these exquisitely potent compounds shows that they express bronchoconstrictor activity and numerous cellular effects via very specific receptors. Experimental evidence strongly suggests that these mediators play a significant role in asthma physiopathology.

Oxidative stress in the optic nerve and cortical visual area of steptozotocin-induced diabetic Wistar rats: Blockade with a selective bradykinin B receptor antagonist.

The role of bradykinin B receptors on the oxidative stress as measured by the levels of Na+/K+ ATPase activity, malondialdehyde (MDA) and glutathione (GSH) in male Wistar rat optic nerve and visual cortex area 1 and 4weeks after STZ treatment was studied. Rats were divided into 4 groups (n=6-7): 1. Controls (non-diabetics); 2.

CRISPR/Cas: A Faster and More Efficient Gene Editing System.

Gene editing technology has been at its mature stage with the successful development of TALENs and CRISPR/Cas enzymes. The genetically modified endonucleases of ZFNs, TALENs, and CRISPR/Cas are widely used in the development of genetically modified cells or organisms. Among the enzymes that possess gene editing ability, CRISPR/Cas is the latest member with high efficiency in gene editing and simplicity in cloning.

Preclinical pharmacology, metabolic stability, pharmacokinetics and toxicology of the peptidic kinin B1 receptor antagonist R-954.

We previously showed that R-954 (AcOrn[Oic(2),(αMe)Phe(5),dβNal(7),Ile(8)]desArg(9)-bradykinin) is a potent, selective and stable peptide antagonist of the inducible GPCR kinin B1 receptor. This compound shows potential applications for the treatment of several diseases, including cancer and neurological disturbances of diabetes. To enable clinical translation, more information regarding its pharmacological, pharmacokinetics (PK) and toxicological properties at preclinical stage is warranted.

The role of kinin receptors in cancer and therapeutic opportunities.

Kinins are generated within inflammatory tissue microenvironments, where they exert diverse functions, including cell proliferation, leukocyte activation, cell migration, endothelial cell activation and nociception. These pleiotropic functions depend on signaling through two cross talking receptors, the constitutively expressed kinin receptor 2 (B2R) and the inducible kinin receptor 1 (B1R). We have reviewed evidence, which supports the concept that kinin receptors, especially kinin receptor 1, are promising targets for cancer therapy, since (1) many tumor cells express aberrantly high levels of these receptors; (2) some cancers produce kinins and use them as autocrine factors to stimulate their growth; (3) activation of kinin receptors leads to activation of macrophages, dendritic cells and other cells from the tumor microenvironment; (4) kinins have pro-angiogenic properties; (5) kinin receptors have been implicated in cancer migration, invasion and metastasis; and (6) selective antagonists for either B1R or B2R have shown anti-proliferative, anti-inflammatory, anti-angiogenic and anti-migratory properties.

Understanding of and possible strategies to avian influenza outbreak.

Swine flu and avian flu outbreaks have occurred in recent years in addition to seasonal flu. As mortality rate records are not available at the early stage of an outbreak, two parameters may be useful to assess the viral virulence : 1. the time required for the first domestic case in a newly involved region, and 2.

Biological and biomedical applications of engineered nucleases.

The development of engineered nucleases is the fruit of a new technological approach developed in the last two decades which has led to significant benefits on genome engineering, particularly on gene therapy. These applications enable efficient and specific genetic modifications via the induction of a double-strand break (DSB) in a specific genomic target sequence, followed by the homology-directed repair (HDR) or non-homologous end joining (NHEJ) pathways. In addition to the application on gene modification in cells and intact organisms, a number of recent papers have reported that this gene editing technology can be applied effectively to human diseases.

Blockade of early and late retinal biochemical alterations associated with diabetes development by the selective bradykinin B1 receptor antagonist R-954.

The chronic hyperglycemia measured alongside diabetes development is associated with significant long-term damage and failure of various organs. In the present study it was shown that hyperglycemia induced early and long term increases in nitric oxide (NO) levels, kallikrein activity and vascular capillary permeability measured as plasma extravasation, and decreases of Na/K ATPase activity in diabetic rat retina 4 and 12 weeks after streptozotocin (STZ) injection. Treatment of the animals for 5 consecutive days with a novel selective bradykinin B(1) receptor (BKB(1)-R) antagonist R-954 (2mg/kg s.

Downregulation of ferroportin 1 expression in hFOB1.19 osteoblasts by hepcidin.

The present study was designed to address the relationship between iron homeostasis and bone metabolism. Cultured hFOB 1.19 osteoblasts were incubated with selected concentrations of hepcidin (50, 100, and 200 nmol/L) for 20 h, harvested for extraction of total RNA and proteins, and the expression of ferroportin 1 was analyzed by RT-PCR and western blotting.

Hepcidin increases intracellular Ca2+ of osteoblast hFOB1.19 through L-type Ca2+ channels.

Hepcidin is a key player in the regulation of iron homeostasis. Several pathological conditions associated with iron overload are attributed to the depressed expression of hepcidin and are often associated with bone diseases including osteoporosis. Hepcidin was suggested to have anti-osteoporosis effects by preventing iron overload.

A new strategy for next generation sequencing: merging the Sanger's method and the sequencing by synthesis through replacing extension.

The present paper describes a feasible protocol enabling a merge of the classical Sanger sequencing method with the sequencing by DNA synthesis: The cycled proofreading sequencing. This new protocol involves partial chain termination and replacing extension. The first step is done with mixed ddNTP/dNTP targeting one type of nucleotide per subcycle and its relevant replacing extension with unlabeled phosphorothioate-modified dNTP of the same nucleotide type used in partial chain termination.

The bradykinin B1 receptor antagonist R-954 inhibits Ehrlich tumor growth in rodents.

The present study investigated the effects of a new bradykinin B(1) receptor antagonist, R-954, on the development of Ehrlich ascitic tumor (EAT) induced by the intraperitoneal inoculation of EAT cells in mice and the formation of a solid tumor by the subcutaneous injection of the cells in rat paw. The development of the tumor was associated with an increase in mouse total cell counts in bone marrow (10.8-fold), ascitic fluid (14.

Nociceptive tolerance is improved by bradykinin receptor B1 antagonism and joint morphology is protected by both endothelin type A and bradykinin receptor B1 antagonism in a surgical model of osteoarthritis.

Introduction: Endothelin-1, a vasoconstrictor peptide, influences cartilage metabolism mainly via endothelin receptor type A (ETA). Along with the inflammatory nonapeptide vasodilator bradykinin (BK), which acts via bradykinin receptor B1 (BKB1) in chronic inflammatory conditions, these vasoactive factors potentiate joint pain and inflammation. We describe a preclinical study of the efficacy of treatment of surgically induced osteoarthritis with ETA and/or BKB1 specific peptide antagonists.

An excess of G over C nucleotides in mutagenesis of human genetic diseases.

Strand asymmetries in DNA evolution, including indel and single nucleotide substitutions, were reported in prokaryotes. Recently, an excess of G>A over C>T substitutions in hemophilia B patients was recognized in our molecular diagnostic practices. Further analysis demonstrated biased point mutations between sense and antisense strands when unique changes in factor IX were counted.

In vivo evaluation of cerebral transplantation of resovist-labeled bone marrow stromal cells in Parkinson's disease rats using magnetic resonance imaging.

The effectiveness of Resovist-labeled bone marrow stem cells (BMSCs) was evaluated in vivo following their cerebral transplantation in a model of Parkinson's disease (PD) in rats using MRI, and the MRI findings were further compared with the behavior and histopathological manifestations of these rats. Forty PD rats were randomly assigned into five groups according to the cell doses injected into the rat brain site: control group (normal saline injection) and groups injected with 1 × 10(5), 1.5 × 10(5), 2 × 10(5), and 2.

Antidiabetic efficacy of bradykinin antagonist R-954 on glucose tolerance test in diabetic type 1 mice.

Insulin-dependent diabetes mellitus (type 1 diabetes) is an inflammatory autoimmune disease associated with many complications including nephropathy, retinopathy, neuropathy and hyperalgesia. Experimental evidence has shown that the bradykinin B1 receptor (BKB1-R) is involved in the development of type 1 diabetes and found to be upregulated alongside the disease. In the present study the effects of the selective BKB1-R antagonist the R-954 (Ac-Orn-[Oic(2), alpha-MePhe(5), D-beta Nal(7), Ile(8) ]des-Arg(9)-BK and the BKB1-R agonist des Arg(9)-BK (DBK) were studied on diabetic hyperglycemia.

Bradykinin B(1) receptor antagonist R954 inhibits eosinophil activation/proliferation/migration and increases TGF-beta and VEGF in a murine model of asthma.

In the present study the effects of bradykinin receptor antagonists were investigated in a murine model of asthma using BALB/c mice immunized with ovalbumin/alum and challenged twice with aerosolized ovalbumin. Twenty four hours later eosinophil proliferation in the bone marrow, activation (lipid bodies formation), migration to lung parenchyma and airways and the contents of the pro-angiogenic and pro-fibrotic cytokines TGF-beta and VEGF were determined. The antagonists of the constitutive B(2) (HOE 140) and inducible B(1) (R954) receptors were administered intraperitoneally 30min before each challenge.

Transforming viral sequences to A (H1N1) flu diagnosis: the current status and future prospects of rtPCR based assays.

A variety of technologies can be used in the detection of contagious pathogens. In the early stage of an outbreak of a new infectious disease, rtPCR is advantageous over many other assays. The rtPCR can be developed either using low fidelity DNA polymerase or high fidelity DNA polymerase.