(NMP) is especially promising, and is now the subject of a multi-center randomized control trial (RCT) comparing it to CS alone in DCD kidneys 10-13. Most pharmacotherapeutics shown to ameliorate renal IRI have been unable to bridge the 'valley of death' (translational gap) to the clinic. This is at least partly attributable to the inherent difficulties and ethical considerations associated with the systemic use of such therapies in donors or recipients 14,15. NMP can serve as a bridge across this valley by providing a platform for direct, non-systemic drug treatment of the kidney whilst it is undergoing normal metabolic processes 15,16. Amongst the multiple anti-IRI agents tested in pre-clinical models, CD47-blocking antibody (αCD47Ab), recombinant thrombomodulin (rTM), and soluble complement receptor 1 (sCR1) are especially translatable as they have been safely employed for other clinical applications 17-25. However, the comparative efficacy of these agents has not been established. αCD47Ab ameliorates thrombospondin (TSP)-1 mediated IRI signaling, including inhibition of nitric oxide and promotion of oxidative stress 21. sCR1 is an inhibitor of the classical and alternative complement pathways, activation of which is important in IRI 26. rTM is an anti-coagulant molecule involved in the generation of activated protein C, although its efficacy in IRI may be more attributable to anti-inflammatory effects 17,27. Because IRI is characterized by the activation of multiple intersecting pathways 28,29 , it is also plausible that synergistic anti-IRI effects may be derived by delivering two or more of these agents together. The aims of this study were to directly compare the acute effects of αCD47Ab, sCR1, and rTM in a murine model of renal IRI and to establish the combined efficacy of two of the best agents. We then show that the chosen drug could be directly delivered to porcine DCD kidneys using NMP to enhance renal perfusion parameters and ameliorate IRI. The primary focus of this study is the immediate phase of IRI, which correlates to the immediate post-transplant setting and the risk of delayed graft function in higher risk renal allografts. Methods Animal work-ethics. All protocols were approved by the Western Sydney Local Health District Animal Ethics Committee, in accordance with the Australian code for the care and use of animals for scientific purposes (8 th Ed., 2013), developed by the National Health and Medical Research Council. Animal experiments adhere to the ARRIVE guidelines.
A marine-derived compound, abalone hemocyanin, from Haliotis rubra was shown to have a unique mechanism of antiviral activity against herpes simplex virus 1 (HSV-1) infections. In vitro assays demonstrated the dose-dependent and inhibitory effect of purified hemocyanin against HSV-1 infection in Vero cells with a 50% effective dose (ED 50 ) of 40 to 50 nM and no significant toxicity. In addition, hemocyanin specifically inhibited viral attachment and entry by binding selectively to the viral surface glycoproteins gD, gB, and gC, probably by mimicking their receptors. However, hemocyanin had no effect on postentry events and did not block infection by binding to cellular receptors for HSV. By the use of different mutants of gD and gB and a competitive heparin binding assay, both protein charge and conformation were shown to be the driving forces of the interaction between hemocyanin and viral glycoproteins. These findings also suggested that hemocyanin may have different motifs for binding to each of the viral glycoproteins B and D. The dimer subunit of hemocyanin with a 10-fold-smaller molecular mass exhibited similar binding to viral surface glycoproteins, showing that the observed inhibition did not require the entire multimer. Therefore, a small hemocyanin analogue could serve as a new antiviral candidate for HSV infections.T he predominant antiviral therapies for herpes simplex virus (HSV) infections are nucleoside analogue inhibitors, such as acyclovir, its prodrug valacyclovir, famciclovir (a prodrug of penciclovir), and the second line of drugs for resistant virus, foscarnet and cidofovir. These drugs are all inhibitors of viral DNA polymerase (1). The variety is limited despite the fact that HSV has more than 80 genes that are required for its functionality and, therefore, could potentially be targeted by multiple types of inhibitors (2). Thus, improving the efficacy of current HSV treatment relies on the discovery of new antiviral compounds targeting various functions of the virus, preferably earlier stages of the HSV viral life cycle such as viral attachment and entry. Viral attachment and entry are regulated by surface glycoproteins gC, gB, gD, and gH-gL (3, 4). Attachment is a two-step process involving the primary interaction of gC and/or gB with heparan sulfate proteoglycans (HSPG), followed by the secondary gD-mediated binding to its receptors, such as herpesvirus entry mediator (HVEM), nectin-1, or 3-O-sulfated heparan sulfate. This interaction triggers the activation of gH-gL and gB, which leads to the fusion of viral envelope and plasma membrane of the host cell either at the surface or in the endosomes (3, 4). Many steps in the entry process of HSV remain unclear; however, it is known that gD determines HSV tropism and that the conformational changes in gD upon binding to its receptors are critical in triggering an activation cascade (5, 6).Viral attachment or entry could be inhibited by mimicking cellular receptors that are involved in these events. For example, heparin interacts with HSPG bi...
The alarming increase of antimicrobial resistance has led to a growing number of studies aiming to develop novel antimicrobial therapeutics. Natural antimicrobial peptides possess a potent and broad-spectrum antimicrobial activity combined with diverse and unique structural motifs, which confer their different mechanisms of action. These peptides are ubiquitous in organisms and are integral to the innate immune system. Recently, identification of antimicrobial peptides from marine crustaceans has become the centre of attention of many researchers. This increasing interest stems from the remarkable diversity in the structural and genetic composition of these peptides compared to terrestrial counterparts. Thus, peptides from marine crustaceans can serve as future templates for novel antimicrobial agents. Here, we provide an overview of various antimicrobial peptides from the marine crustaceans, their antimicrobial activity and structure- activity relationships. We also discuss the potential and challenges of their development as new antimicrobial agents.
Understanding the immunological phenotype of transplant recipients is important to improve outcomes and develop new therapies. Immunophenotyping of whole peripheral blood (WPB) by flow cytometry is a rapid method to obtain large amounts of data relating to the outcomes of different transplant treatments with limited patient impact. Healthy individuals and patients with type 1 diabetes (T1D) enrolled in islet transplantation were recruited and WPB was collected. 46 fluorochrome-conjugated mouse-anti-human antibodies were used (43 of 46 antibodies were titrated). BD cytometer setup and tracking beads were used to characterize and adjust for cytometer performance. Antibody cocktails were pre-mixed <60 minutes before staining. Multicolour panels were designed based on fluorochrome brightness, antigen density, co-expression, and fluorochrome spillover into non-primary detectors in each panel on a 5 laser flow cytometer. WPB sample staining used 50–300 μl WPB for each panel and was performed within 2 hours of blood sample collection. Samples were acquired on a BD-LSRFortessa. The operating procedures, including specimen collection, antibody cocktails, staining protocol, flow-cytometer setup and data analysis, were standardized. The staining index of 43 antibodies and the spillover spreading matrix for each panel was calculated. The final concentrations for the 46 antibodies used was determined for staining of WPB samples. Absolute cell-count and 7 leukocyte profiling panels consisting of subsets and/or status of granulocytes, monocytes, dendritic, B, NK, and T cells including regulatory T cells (Tregs) and NKT were designed and established on a 5 laser BD-LSR Fortessa. 13 T1D patients, including 4 islet transplant recipients and 8 healthy controls, were evaluated. The ability to reproducibly measure immune subsets and immune-profiles of islet transplant patients up to 18 months post transplantation has been established as a tool to measure immune cell reconstitution after transplantation.
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