Human Infrapatellar Fat Pad Mesenchymal Stem Cells Show Immunomodulatory Exosomal Signatures

Within the human knee infrapatellar fat pad (IFP) and synovium, resident synoviocytes and macrophages contribute to the onset and progression of inflammatory joint diseases. Our hypothesis is that IFP-derived mesenchymal stem cells (IFP-MSC) robust immunomodulatory therapeutic effects are largely exerted via their exosomal (IFP-MSC EXOs) secretome by attenuating synoviocyte and macrophage pro-inflammatory activation. IFP-MSC EXOs showed distinct miRNA and protein immunomodulatory profiles. Reactome analysis of 24 miRNAs highly present in exosomes showed their involvement in the regulation of six gene groups, including immune system. Exosomes were enriched for immunomodulatory and reparative proteins that are involved in positive regulation of cell proliferation, response to stimulus, signal transduction, signal receptor activity, and protein phosphorylation. Stimulated synoviocytes or macrophages exposed to IFP-MSC EXOs demonstrated significantly reduced proliferation, altered inflammation-related molecular profiles, and reduced secretion of pro-inflammatory molecules compared to stimulated alone. In an acute synovial/IFP inflammation rat model, IFP-MSC EXOs therapeutic treatment resulted in robust macrophage polarization towards an anti-inflammatory therapeutic M2 phenotype within the synovium/IFP tissues. Based on these findings, we propose a viable cell-free alternative to MSC-based therapeutics as an alternative approach to treating synovitis and IFP fibrosis.

Role of Claudin-4 and Matrix Metalloproteinase-2 in Tumor Invasion of Colorectal Adenocarcinoma

Colorectal adenocarcinoma is positioned as the third of most common cancer which the cases rise in Indonesia lately. More than 90% of colorectal carcinoma are adenocarcinoma type. One of prognostic factor of colorectal adenocarcinoma is invasion state of the tumor (T). Uncontrollable proliferation of tumor cell causes transformation of paracellular permeability that increase claudin-4 expression (a protein located on main integral membrane). Claudin-4 activation influence the expression and activity of MMP-2 directly or by altering transduction signal. Expression of claudin-4 and MMP-2 play a role in tumor invasion. Analyzing correlation of claudin-4 and MMP-2 toward invasion state of the tumor (T stadium) on colorectal adenocarcinoma. Analytical observation was conducted on 47 samples of colorectal adenocarcinoma with different invasion state collected by Laboratory of Pathological Anatomy, Dr. Soetomo General Academic Hospital during 2015-2018. Immunohistochemistry was conducted using both claudin-4 and MMP-2 antibodies. Expression of claudin-4 and MMP-2 were semiquantitatively measured then statistically analyzed. Significant result could be obtained in comparison between claudin-4 and tumor invasion state (p=0.773). The significant result could be obtained in comparison between MMP-2 and tumor invasion state (p=0.920). It also could be observed in comparison between claudin-4 and MMP-2 (p=0.638). In summary, claudin-4 and MMP-2 play a role on tumor invasion colorectal adenocarcinoma. It was showed by significant result between claudin-4 and MMP-2 expressions compared to invasion state of colorectal adenocarcinoma.

Recent advances of using personal glucose meter as a biosensor readout for non-glucose targets

Background: Personal glucose meter (PGM) has become the most successful biosensor in past decades due to its advantages of small size, convenient operation, and low cost. To take advantage of many years of research and development of PGMs, new signal transduction methods has been developed to expand the PGM from simple monitoring blood glucose to detection of numerous non-glucose targets. Objectives: This review summarizes recent advance of PGM-based biosensors for non-glucose targets including signal transduction, signal amplification and target molecule recognition and analysis. Current challenges and future directions are also discussed. Conclusion: PGM can be used as biosensor readout to detect various non-glucose targets from metal ion, small molecule to protein and even living organisms such as bacteria and other pathogens by using different signal transduction elements such as invertase and amylase, and different signal amplification methods such as nanomaterials, nucleic acid reaction, liposome encapsulation, hydrogel trapping, DNAzyme amplification and biotin-streptavidin reaction.

The Activating Receptors of Natural Killer Cells and Their Inter-Switching Potentials

The global incidence of cancer is on the increase and researchers are prospecting for specific and non-selective therapies derived from the immune system. The killer activating receptors of NK cells are known to be involved in immunosurveillance against tumor and virally-infected cells. These receptors belong to two main categories, namely the immunoglobulin like and C-lectin like families. Though they have different signal pathways, all the killer activating receptors have similar effector functions which include direct cytotoxicity and the release of inflammatory cytokines such as IFN-gamma and TNF-alpha. To transduce signals that exceed the activation threshold for cytotoxicity, most of these receptors require synergistic effort. This review profiles 21 receptors: 13 immunoglobulin-like, 5 lectin-like, and 3 others. It critically explores their structural uniqueness, role in disease, respective transduction signal pathways and their status as current and prospective targets for cancer immunotherapy. While the native ligands of most of these receptors are known, much work is required to prospect for specific antibodies, peptides and multi-target small molecules with high binding affinities.

Proteomic characterization of idiopathic pulmonary fibrosis patients: stable versus acute exacerbation

Acute exacerbations (AEs) are among the main causes of death in idiopathic pulmonary fibrosis (IPF) patients. In this study proteomic comparative analysis of bronchoalveolar lavage (BAL) fluid samples was performed in stable IPF patients versus AEs IPF group to identify AE pathogenetic mechanisms and novel potential predictive biomarkers. A functional proteomic analysis of BAL fluid samples from stable and AE-IPF patients was conducted in a population of 27 IPF patients. Fifty-one differentially abundant spots were observed and identified by mass spectrometry. Enrichment analysis found proteins of interest involved in the regulation of macrophages and lipid metabolism receptors. In acute exacerbation IPF group, differentially abundant proteins were involved in propagation of the β-catenin WNT transduction signal, and proteins up-regulated in lung carcinogenesis (IGKC, S100A9, PEDF, IGHG1, ALDOA, A1AT, HPT, CO3 and PIGR) and acute phase proteins involved in protease-antiprotease imbalance (such as A1AT fragments). Dot-blot analysis of A1AT C-36 peptide allowed validating our findings, confirming up-regulation in AE IPF patients and suggesting its potential pathogenetic role. A crucial role of protease/antiprotease imbalance, clathrin-mediated endocytosis signalling and carcinogenesis emerged in IPF patients developing acute exacerbations.

Optical Sensors based on Surface Plasmon Resonance

This brief review presents the recent process in optical sensors based on surface plasmon resonance (SPR). In particular, it will focus on the optical sensors that employ the change of refractive index as the sensing transduction signal. Various detection schemes of optical sensors which include phase modulation, wavelength modulation and intensity modulation are discussed. The performance advantageous and disadvantageous of the description of optical sensors structure and their respective experimental configurations are also described. The examples of detection in chemistry, biology and heavy metals will be presented. Future prospects of surface plasmon resonance (SPR) sensing technology is also discussed.

Cytosolic Acidification Is the First Transduction Signal of Lactoferrin-induced Regulated Cell Death Pathway

In yeast, we reported the critical role of K+-efflux for the progress of the regulated cell death (RCD) induced by human lactoferrin (hLf), an antimicrobial protein of the innate immune system that blocks Pma1p H+-ATPase. In the present study, the K+ channel Tok1p was identified as the K+ channel-mediating K+-efflux, as indicated by the protective effect of extracellular K+ (30 mM), K+-channel blockers, and the greater hLf-resistance of TOK1-disrupted strains. K+-depletion was necessary but not sufficient to induce RCD as inferred from the effects of valinomycin, NH4Cl or nigericin which released a percentage of K+ similar to that released by lactoferrin without affecting cell viability. Cytosolic pH of hLf-treated cells decreased transiently (0.3 pH units) and its inhibition prevented the RCD process, indicating that cytosolic acidification was a necessary and sufficient triggering signal. The blocking effect of lactoferrin on Pma1p H+-ATPase caused a transitory decrease of cytosolic pH, and the subsequent membrane depolarization activated the voltage-gated K+ channel, Tok1p, allowing an electrogenic K+-efflux. These ionic events, cytosolic accumulation of H+ followed by K+-efflux, constituted the initiating signals of this mitochondria-mediated cell death. These findings suggest, for the first time, the existence of an ionic signaling pathway in RCD.

Role of C-type Lectin Receptor to C.albicans on Promotion of Inflamantory Diseases

<p><em>In early 2010 there was a very rapid progress in the development of immunity to fungi, i.e the discovery of CLR. CLR is one of the PRR receptors found in immune cells that recognize the cell wall of fungi and then trigger a transduction signal that eventually provoke the production of various proinflamatory include IL1β, IL6, TNF α and induce polarization Th17. In the condition of infection the number of innate immune cells increases dramatically, lead to increasing of cytokines produced. Both cytokines and the cells that produce them enter the bloodstream. If there is unbalance level of pro and anti inflammatory cytokine, various inflammatory and/or autoimmune diseases can be occur. Unlike the focal concept infection, where the agent will cause disease if enters the blood vessels, through this concept a fungal infection at epithelium can lead to inflammatory diseases in other part of body without having to go through fungus</em></p><p><em> </em></p><p><strong><em>Keywords:</em></strong><em> C. albicans, CLR, Cytokine, Inflamatory Disease</em></p><p><strong><em> </em></strong></p><strong><em>Correspondence: </em></strong><em>Erna Sulistyani, Department of Oral Medicine, Faculty of Dentistry, Jember Bagian Penyakit Mulut, Fakultas Kedokteran Gigi, Universitas Jember, Kalimantan 37 Jember, Email: </em><a href="mailto:[email protected]"><em>[email protected]</em></a>

The Role of JAK2 in Myeloproliferative Diseases Diagnosis

Janus Kinase 2 (JAK2) plays an important role in mediating transduction signal of hematopoiesis, including in the pathogenesis of Myeloproliferative diseases (MPD). Various studies have been carried out to identify the position of aleles in tyrosine encoding mutations. Although the effect of JAK2 mutations is still not fully understood, the discovery of these mutations might be able to differentiate the types of polycythaemia vera, essential thrombocytemia, and primary myelofibrosis with malignant abnormalities. WHO has revised the MPD diagnosis criteria following this finding. This review will discuss the role of JAK2.