A fibroblast mutant cell line devoid of Na+/H+ exchange was used to stably express cDNAs encoding the NHE1, NHE2, and NHE3 antiporters. Pharmacological studies using amiloride two its 5-N-substituted derivatives, 5-N-dimethyl 5-N-(methyl-propyl)amiloride (MPA), demonstrate that NHE1 isoform is ubiquitously expressed amiloride-sensitive antiporter (Ki 0.08 microM for MPA), whereas NHE2 isoforms exhibit a lower affinity these inhibitors 0.5 10 microM, respectively, MPA) are therefore likely be...

1. The benzoylguanidine derivative Hoe 694 ((3-methylsulphonyl-4- piperidino-benzoyl) guanidine methanesulphonate) was characterized as an inhibitor of Na+/H+ exchange in rabbit erythrocytes, rat platelets and bovine endothelial cells. potency the compound slightly lower or comparable to ethylisopropyl amiloride (EIPA). 2. To investigate a possible cardioprotective role 694, isolated working hearts were subjected ischaemia reperfusion. In these experiments all untreated suffered ventricular...

A first-of-its-kind (18)F pretargeted PET imaging approach based on the bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction between tetrazine (Tz) and trans-cyclooctene (TCO) is presented. As proof-of-principle, a TCO-bearing immunoconjugate of anti-CA19.9 antibody 5B1 an Al[(18)F]NOTA-labeled radioligand were harnessed for visualization CA19.9-expressing BxPC3 pancreatic cancer xenografts. Biodistribution (18)F-PET data clearly demonstrate that this methodology effectively...

The serum- and glucocorticoid-inducible kinase 1 (SGK1) is transcriptionally upregulated by mineralocorticoids activated insulin. enhances renal tubular Na+-reabsorption accounts for blood pressure increase following high salt diet in mice made hyperinsulinemic dietary fructose or fat. present study describes the vitro vivo efficacy of a novel SGK1 inhibitor (EMD638683). EMD638683 was tested determination SGK1-dependent phosphorylation NDRG1 (N-Myc downstream-regulated gene 1) human cervical...

5B1 is a fully human, monoclonal antibody that has shown promise for the PET imaging of cancers expressing carbohydrate antigen 19.9 (CA19.9)—a prevalent in cells with aberrant glycosylation and an established effector metastasis. The long physiologic half-life interference from circulating CA19.9 may increase time required to generate quality images as well risk radiation exposure healthy tissues during repeated imaging. Pretargeting methodologies are effective approach expeditiously...

Abstract The pretargeting system based on the inverse electron demand Diels-Alder reaction (IEDDA) between trans-cyclooctene (TCO) and tetrazine (Tz) combines favorable pharmacokinetic properties of radiolabeled small molecules with affinity specificity antibodies. This strategy has proven to be an efficient method for molecularly targeted delivery pharmaceuticals, including isotopes radiological imaging. Despite encouraging results from in vivo PET imaging studies, this promising yet...

Abstract Purpose: Interest in targeted alpha-therapy has surged due to α-particles' high cytotoxicity. However, the widespread clinical use of this approach could be limited by on-/off-target toxicities. Here, we investigated inverse electron-demand Diels–Alder ligation between an 225Ac-labeled tetrazine radioligand and a trans-cyclooctene–bearing anti-CA19.9 antibody (5B1) for pretargeted α-radioimmunotherapy (PRIT) pancreatic ductal adenocarcinoma (PDAC). This alternative strategy is...

For almost two years, the COVID-19 pandemic has constituted a major challenge to human health, particularly due lack of efficient antivirals be used against virus during routine treatment interventions. Multiple options have been investigated for their potential inhibitory effect on SARS-CoV-2. Natural products, such as plant extracts, may promising option, they shown an antiviral activity other viruses in past. Here, quantified extract

A brain biopsy from a 20-year-old patient whose clinical course was marked by progressive dementia and chorea since age 10 years showed increased amounts of lipofuscin, abnormal mitochondria, other organelles in cortical neurons, neurites, astrocytes. Juvenile Huntington confirmed at autopsy. High levels three histone-like proteins (molecular weight 10,000 to 16,000) the microsomal fraction purified neurons were found SDS-polyacrylamide gel electrophoresis. Fatty acids white matter...

Significance Pancreatic cancer will soon be the second leading cause of deaths annually, yet no adequate molecular imaging tools exist to aid in staging, monitoring, and treatment disease. Here we describe development preclinical evaluation three unique immunoconjugates for positron emission tomography, near-infrared fluorescent optical imaging, multimodal pancreatic ductal adenocarcinoma (PDAC). The probes were developed using a site-specific, chemoenzymatic methodology that is robust,...

Abstract Purpose: The carbohydrate antigen sialyl-Lewisa (sLea), also known as CA19.9, is widely expressed on epithelial tumors of the gastrointestinal tract and breast small-cell lung cancers. Since overexpression sLea appears to be a key event in invasion metastasis many results susceptibility antibody-mediated lysis, an attractive molecular target for tumor therapy. Experimental Design: We generated characterized fully human monoclonal antibodies (mAb) from blood lymphocytes individuals...

Na(+)/H(+) exchange inhibition with HOE642 (cariporide) improves postischemic recovery of cardiac function, but the mechanisms action remain speculative. Because is activated on reperfusion, it was hypothesized that its delays realkalinization and decreases intracellular Na(+) and, via Na(+)/Ca(2+) exchange, Ca(2+) overload. Attenuated overload prolonged acidosis are known to be cardioprotective.Left ventricular developed end-diastolic pressures were measured in isolated buffer-perfused rat...

Results obtained indicate that a site-directed polyclonal antibody specific for synthetic peptide based on the predicted amino-terminal sequence of human C5aR (anti-C5aR(9-29)) is capable binding to both normal and transfected cells bearing C5aR. Flow cytometric analysis stable murine L cell transfectants (C5aR-neo), neutrophils, monocytes indicated these bound anti-C5aR(9-29) in manner. Moreover, F(ab')2 fragments specifically neutralized proinflammatory immunoregulatory activities induced...

Sodium/hydrogen exchange (NHE) inhibitors show promise as potential therapeutic agents for the treatment of heart failure, but it is not known whether they can reverse maladaptive remodeling that results in failure. We sought to determine effect NHE-1-specific inhibitor EMD-87580 (EMD) on failure produced by myocardial infarction rat and assess up 4 wk delay beneficial effects. Male Sprague-Dawley rats were subjected coronary artery ligation (or a sham procedure) followed 3 mo, at which time...

ABSTRACT Prevention of inhalation anthrax requires early and extended antibiotic therapy, therefore, alternative treatment strategies are needed. We investigated whether a human monoclonal antibody (AVP-21D9) to protective antigen (PA) would protect mice, guinea pigs, rabbits against anthrax. Control animals challenged with Bacillus anthracis Ames spores by the intranasal route died within 3 7 days. AVP-21D9 alone provided minimal protection in murine model, but its efficacy was notably...

The serum and glucocorticoid inducible kinase SGK1, which was originally cloned from mammary tumor cells, is highly expressed in some but not all tumors. SGK1 confers survival to several cells. Along those lines, the number of colonic tumors following chemical carcinogenesis decreased knockout mice. Recently, a selective SGK inhibitor (EMD638683) has been developed. present study explored whether EMD638683 affects colon carcinoma cells vitro impacts on development vivo. Colon (Caco-2) were...

Despite their considerable advantages, many circulating biomarkers have well-documented limitations. One prominent shortcoming in oncology is a high frequency of false-positive indications for malignant disease upfront diagnosis. Because one common cause false positivism biomarker production from benign disorders unrelated host tissues, we hypothesized that probing the sites secretion with an imaging tool could be broadly useful strategy to deconvolute meaning foreboding but inconclusive...

In patients with cancer who have an abnormal biomarker finding, the source of in bloodstream must be located for confirmation diagnosis, staging, and therapy planning. We evaluated if immuno-PET radiolabeled high-affinity antibody HuMab-5B1 (MVT-2163), binding to antigen CA19-9, can identify elevated biomarkers pancreatic cancer.In this phase I dose-escalating study, 12 CA19-9-positive metastatic malignancies were injected MVT-2163. Within 7 days, all underwent a total four whole-body PET/CT...