The Role of RANTES (CCL5) In The Immune Response to Bacterial Infections

Background: Sepsis is a lethal condition that causes organ dysfunction due to a dysregulated host response to an infection. It is one of the leading causes of morbidity and mortality globally with approximately 6 million deaths occurring every year. Transfusion-associated sepsis (T-AS) can occur through the transfusion of contaminated blood components, commonly platelet concentrates (PCs). The “cytokine storm” is thought to be the main pathophysiology behind sepsis and the cytokines secreted within bacterial contaminated PCs could play a key role in the development of T-AS in recipients. This study investigated the effect of bacterially-primed platelet releasates on the activation status of neutrophils and monocytes, with the aim of understanding the link between platelet product contamination, the cytokine storm, and the severity of clinical symptoms in transfusion recipients. Findings: The cytometric bead array assay demonstrated that RANTES was significantly elevated in comparison with IL-1β, IL-6, and TNF-α when platelet rich plasma samples were incubated with planktonic and biofilm forms of Staphylococcus epidermidis and Serratia marcescens. Flow cytometric analysis of the surface markers CD54, CD11b and CD66b on U937 and HL-60 cell lines demonstrated no changes in expression when treated platelet releasates that had been primed with S. epidermidis and wild type (WT) Escherichia coli. Yet treating these cells with platelet releasates primed with multi-resistant E. coli (planktonic or biofilm form) caused a highly significant upregulation in CD54 expression. Platelet-free plasma alone was found to cause a degree of upregulation of all three surface markers in some cases suggesting minor immunomodulatory activity of plasma proteins. Despite its significant release from bacterially-primed platelets, recombinant RANTES (rhRANTES) at different concentrations did not induce significant changes in surface expression of the activation markers on U937 and HL-60 cells however, variable effects on CD54 and CD11b expression were seen on primary human neutrophils. Curiously, CD66b appeared to be downregulated with increasing exogenous rhRANTES concentration. Conclusions: The results may indicate that RANTES requires synergy with additional cytokines/chemokines in order to induce activation of neutrophils and monocytes and cannot act in isolation. Bacterial virulence appears to play a role in the resultant cytokine profiles of platelets evidenced by the stark difference in cell activation caused by multi-resistant E. coli-primed platelets in comparison with WT E. coli and S. epidermidis

Implantation Serine Proteinases heterodimerize and are critical in hatching and implantation

BACKGROUND: We have recently reported the expression of murine Implantation Serine Proteinase genes in pre-implantation embryos (ISP1) and uterus (ISP1 and ISP2). These proteinases belong to the S1 proteinase family and are similar to mast cell tryptases, which function as multimers. RESULTS: Here, we report the purification and initial characterization of ISP1 and 2 with respect to their physico-chemical properties and physiological function. In addition to being co-expressed in uterus, we show that ISP1 and ISP2 are also co-expressed in the pre-implantation embryo. Together, they form a heterodimer with an approximate molecular weight of 63 kD. This complex is the active form of the enzyme, which we have further characterized as being trypsin-like, based on substrate and inhibitor specificities. In addition to having a role in embryo hatching and outgrowth, we demonstrate that ISP enzyme is localized to the site of embryo invasion during implantation and that its activity is important for successful implantation in vivo. CONCLUSION: On the basis of similarities in structural, chemical, and functional properties, we suggest that this ISP enzyme complex represents the classical hatching enzyme, strypsin. Our results demonstrate a critical role for ISP in embryo hatching and implantation

A Glio-Protective Role of mir-263a by Tuning Sensitivity to Glutamate

Glutamate is a ubiquitous neurotransmitter, mediating information flow between neurons. Defects in the regulation of glutamatergic transmission can result in glutamate toxicity, which is associated with neurodegeneration. Interestingly, glutamate receptors are expressed in glia, but little is known about their function, and the effects of their misregulation, in these non-neuronal cells. Here, we report a glio-protective role for Drosophila mir-263a mediated by its regulation of glutamate receptor levels in glia. mir-263a mutants exhibit a pronounced movement defect due to aberrant overexpression of CG5621/Grik, Nmdar1, and Nmdar2. mir-263a mutants exhibit excitotoxic death of a subset of astrocyte-like and ensheathing glia in the CNS. Glial-specific normalization of glutamate receptor levels restores cell numbers and suppresses the movement defect. Therefore, microRNA-mediated regulation of glutamate receptor levels protects glia from excitotoxicity, ensuring CNS health. Chronic low-level glutamate receptor overexpression due to mutations affecting microRNA (miRNA) regulation might contribute to glial dysfunction and CNS impairment

Edible Bird’s Nest Prevents Menopause-Related Memory and Cognitive Decline in Rats via Increased Hippocampal Sirtuin-1 Expression

Menopause causes cognitive and memory dysfunction due to impaired neuronal plasticity in the hippocampus. Sirtuin-1 (SIRT1) downregulation in the hippocampus is implicated in the underlying molecular mechanism. Edible bird’s nest (EBN) is traditionally used to improve general wellbeing, and in this study, we evaluated its effects on SIRT1 expression in the hippocampus and implications on ovariectomy-induced memory and cognitive decline in rats. Ovariectomized female Sprague-Dawley rats were fed with normal pellet alone or normal pellet + EBN (6, 3, or 1.5%), compared with estrogen therapy (0.2 mg/kg/day). After 12 weeks of intervention, Morris water maze (four-day trial and one probe trial) was conducted, and serum estrogen levels, toxicity markers (alanine transaminase, alkaline phosphatase, urea, and creatinine), and hippocampal SIRT1 immunohistochemistry were estimated after sacrifice. The results indicated that EBN and estrogen enhanced spatial learning and memory and increased serum estrogen and hippocampal SIRT1 expression. In addition, the EBN groups did not show as much toxicity to the liver as the estrogen group. The data suggested that EBN treatment for 12 weeks could improve cognition and memory in ovariectomized female rats and may be an effective alternative to estrogen therapy for menopause-induced aging-related memory loss

Multidrug-Resistant Escherichia coli Remains Susceptible to Metal Ions and Graphene-Based Compounds

Escherichia coli is listed as a priority 1 pathogen on the World Health Organization (WHO) priority pathogen list. For this list of pathogens, new antibiotics are urgently needed to control the emergence and spread of multidrug-resistant strains. This study assessed eighteen metal ions, graphene, and graphene oxide for their antimicrobial efficacy against E. coli in both planktonic and biofilm growth states and the potential synergy between metal ions and graphene-based compounds. Molybdenum and tin ions exhibited the greatest antimicrobial activity against the planktonic states of the isolates with minimal inhibitory concentrations (MIC) ranging between 13 mg/L and 15.6 mg/L. Graphene oxide had no antimicrobial effect against any of the isolates, while graphene showed a moderate effect against E. coli (MIC, 62.5 mg/L). Combinations of metal ions and graphene-based compounds including tin–graphene, tin–graphene oxide, gold–graphene, platinum–graphene, and platinum–graphene oxide exhibited a synergistic antimicrobial effect (FIC ≤ 0.5), inhibiting the planktonic and biofilm formation of the isolates regardless of their antibiotic-resistant profiles. The bactericidal effect of the metal ions and the synergistic effects when combined with graphene/graphene oxide against medically relevant pathogens demonstrated that the antimicrobial efficacy was increased. Hence, such agents may potentially be used in the production of novel antimicrobial/antiseptic agents

Machine-Learning-Enabled Virtual Screening for Inhibitors of Lysine-Specific Histone Demethylase 1

A machine learning approach has been applied to virtual screening for lysine specific demethylase 1 (LSD1) inhibitors. LSD1 is an important anti-cancer target. Machine learning models to predict activity were constructed using Morgan molecular fingerprints. The dataset, consisting of 931 molecules with LSD1 inhibition activity, was obtained from the ChEMBL database. An evaluation of several candidate algorithms on the main dataset revealed that the support vector regressor gave the best model, with a coefficient of determination (R2) of 0.703. Virtual screening, using this model, identified five predicted potent inhibitors from the ZINC database comprising more than 300,000 molecules. The virtual screening recovered a known inhibitor, RN1, as well as four compounds where activity against LSD1 had not previously been suggested. Thus, we performed a machine-learning-enabled virtual screening of LSD1 inhibitors using only the structural information of the molecules

Modular Synthesis and Biological Investigation of 5-Hydroxymethyl Dibenzyl Butyrolactones and Related Lignans

Dibenzyl butyrolactone lignans are well known for their excellent biological properties, particularly for their notable anti-proliferative activities. Herein we report a novel, efficient, convergent synthesis of dibenzyl butyrolactone lignans utilizing the acyl-Claisen rearrangement to stereoselectively prepare a key intermediate. The reported synthetic route enables the modification of these lignans to give rise to 5-hydroxymethyl derivatives of these lignans. The biological activities of these analogues were assessed, with derivatives showing an excellent cytotoxic profile which resulted in programmed cell death of Jurkat T-leukemia cells with less than 2% of the incubated cells entering a necrotic cell death pathway

Decoding the spermatogonial stem cell niche under physiological and recovery conditions in adult mice and humans

The intricate interaction between spermatogonial stem cell (SSC) and testicular niche is essential for maintaining SSC homeostasis; however, this interaction remains largely uncharacterized. In this study, to characterize the underlying signaling pathways and related paracrine factors, we delineated the intercellular interactions between SSC and niche cell in both adult mice and humans under physiological conditions and dissected the niche-derived regulation of SSC maintenance under recovery conditions, thus uncovering the essential role of C-C motif chemokine ligand 24 and insulin-like growth factor binding protein 7 in SSC maintenance. We also established the clinical relevance of specific paracrine factors in human fertility. Collectively, our work on decoding the adult SSC niche serves as a valuable reference for future studies on the aetiology, diagnosis, and treatment of male infertility.</p

An innate pathogen sensing strategy involving ubiquitination of bacterial surface proteins.

Sensing of pathogens by ubiquitination is a critical arm of cellular immunity. However, universal ubiquitination targets on microbes remain unidentified. Here, using in vitro, ex vivo, and in vivo studies, we identify the first protein-based ubiquitination substrates on phylogenetically diverse bacteria by unveiling a strategy that uses recognition of degron-like motifs. Such motifs form a new class of intra-cytosolic pathogen-associated molecular patterns (PAMPs). Their incorporation enabled recognition of nonubiquitin targets by host ubiquitin ligases. We find that SCFFBW7 E3 ligase, supported by the regulatory kinase, glycogen synthase kinase 3β, is crucial for effective pathogen detection and clearance. This provides a mechanistic explanation for enhanced risk of infections in patients with chronic lymphocytic leukemia bearing mutations in F-box and WD repeat domain containing 7 protein. We conclude that exploitation of this generic pathogen sensing strategy allows conservation of host resources and boosts antimicrobial immunity