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Special Issue "Diagnostic Challenge and Therapeutic Approaches in Human Sepsis Based on the Appearance of Endotoxemia and Beta-D-Glucanemia"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Toxicology".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 18598

Special Issue Editors

Dr. Hiroshi Tamura
E-Mail Website
Guest Editor
1. LPS (Laboratory Program Support) Consulting Office, Tokyo 160-0023, Japan
2. Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8431, Japan
3. Tokyo University of Pharmacy and Life Science, Tokyo 192-0392, Japan
Interests: endotoxin(LPS), (1→3)-beta-D-glucan, LAL assay; sepsis; TLR4; host defense peptides; anti-endotoxin therapy
Dr. Yoshiyuki Adachi
E-Mail Website
Guest Editor
Laboratory for Immunopharmacology of Microbial Products, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan
Interests: innate immunity; (1→3)-beta-D-glucan; mycosis; allergy; C-type lectin receptor; Dectin-1; beta-glucan binding protein

Special Issue Information

Dear Colleagues,

We are pleased to introduce to you this Special Issue of Molecular Toxicology Section of the International Journal of Molecular Sciences, on "Diagnostic Challenge and Therapeutic Approaches in Human Sepsis Based on the Appearance of Endotoxemia and Beta-D-Glucanemia".

Endotoxins, also called lipopolysaccharides (LPS), are the major constituent of the outer membrane of Gram-negative bacteria and possess a wide variety of biological effects and pathogenicity in human, such as pyrogenesity, lethality, inflammatory cytokine response via TLR4 signaling, or excessive activation of the coagulation system, leading to disseminated intravascular coagulation (DIC). Cytokine and chemokine production by a broad range of immune cells result in a substantial part of the pathophysiology of endotoxin shock, suggesting a relationship with a number of endogenous risk factors, including enhanced intestinal epithelial permeability and bacterial translocation along with underlying conditions. In addition, invasive fungal infections are an increasingly frequent cause of sepsis. Thus, fungal (1→3)-beta-D-glucan, a major component of the cell wall as well as endotoxin, have attracted a considerable amount of interest in applications as potential prognostic, diagnostic, and therapeutic markers in blood or body fluids.

 In this Special Issue, we will focus on cellular and molecular mechanisms of endotoxin/beta-D-glucan activities; recent advances, limitations, and further challenges to the early detection of endotoxemia/beta-D-glucanemia, primarily with the Limulus amebocyte lysate assay (conventional/recombinant); and promising therapeutic approaches based on cytokine/chemokine blockades, anti-endotoxin agents, host defense (antimicrobial) peptides, antifungal agents, highly effective anticoagulants, or direct hemoperfusion, with the aim to pave the way to successful innovative treatments and management of sepsis or septic shock. 

Dr. Hiroshi Tamura
Dr. Yoshiyuki Adachi
Guest Editors

Manuscript Submission Information

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Keywords

  • Endotoxin (LPS)
  • (1→3)-beta-D-glucan
  • Limulus amebocyte lysate (LAL)
  • sepsis
  • TLR4
  • Dectin-1
  • host defense peptides
  • anti-endotoxin therapy

Published Papers (12 papers)

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Editorial

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Editorial
Diagnostic Challenge and Therapeutic Approaches in Human Sepsis Based on the Appearance of Endotoxemia and Beta-d-Glucanemia
Int. J. Mol. Sci. 2021, 22(23), 12900; https://doi.org/10.3390/ijms222312900 - 29 Nov 2021
Cited by 1 | Viewed by 591
Abstract
Circulating endotoxin, also called lipopolysaccharide (LPS) and (1→3)-β-d-Glucan (β-d-glucan), major constituents of bacterial and fungal cell walls, respectively, are determined as biomarkers for Gram-negative sepsis and invasive fungal diseases [...] Full article

Research

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Article
Development of a Highly Sensitive β-Glucan Detection System Using Scanning Single-Molecule Counting Method
Int. J. Mol. Sci. 2021, 22(11), 5977; https://doi.org/10.3390/ijms22115977 - 01 Jun 2021
Cited by 1 | Viewed by 1041
Abstract
To overcome the limitations of the Limulus amebocyte lysate (LAL) assay method for the diagnosis of invasive fungal infection, we applied a reaction system combining recombinant β-glucan binding proteins and a scanning single-molecule counting (SSMC) method. A novel (1→3)-β-D-glucan recognition protein (S-BGRP) and [...] Read more.
To overcome the limitations of the Limulus amebocyte lysate (LAL) assay method for the diagnosis of invasive fungal infection, we applied a reaction system combining recombinant β-glucan binding proteins and a scanning single-molecule counting (SSMC) method. A novel (1→3)-β-D-glucan recognition protein (S-BGRP) and a (1→6)-β-glucanase mutant protein were prepared and tested for the binding of (1→6)-branched (1→3)-β-D-glucan from fungi. S-BGRP and (1→6)-β-glucanase mutant proteins reacted with β-glucan from Candida and Aspergillus spp. Although LAL cross-reacted with plant-derived β-glucans, the new detection system using the SSMC method showed low sensitivity to plant (1→3)-β-D-glucan, which significantly improved the appearance of false positives, a recognized problem with the LAL method. Measurement of β-glucan levels by the SSMC method using recombinant β-glucan-binding proteins may be useful for the diagnosis of fungal infections. This study shows that this detection system could be a new alternative diagnostic method to the LAL method. Full article
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Article
Possibility of Japanese Cedar Pollen Causing False Positives in the Deep Mycosis Test
Int. J. Mol. Sci. 2021, 22(4), 2135; https://doi.org/10.3390/ijms22042135 - 21 Feb 2021
Cited by 2 | Viewed by 1078
Abstract
Because Japanese cedar pollen (JCP) contains beta-1,3-d-glucan (BG), there is concern that its lingering presence in the atmosphere, especially during its scattering period, may cause false positives in the factor-G-based Limulus amebocyte lysate (LAL) assay used to test for deep mycosis [...] Read more.
Because Japanese cedar pollen (JCP) contains beta-1,3-d-glucan (BG), there is concern that its lingering presence in the atmosphere, especially during its scattering period, may cause false positives in the factor-G-based Limulus amebocyte lysate (LAL) assay used to test for deep mycosis (i.e., G-test). Hence, we examined whether the LAL assay would react positively with substances contained in JCP by using the G-test to measure JCP particles and extracts. BG was purified from the JCP extract on a BG-specific affinity column, and the percentage extractability was measured using three different BG-specific quantitative methods. The G-test detected 0.4 pg BG in a single JCP particle and 10 fg from a single particle in the extract. The percentage extractability of JCP-derived BG was not significantly different among the three quantitative methods. As the JCP particles should technically have been removed during serum separation, they should be less likely to be a direct false-positive factor. However, given that the LAL-assay-positive substances in the JCP extract were not distinguishable by the three BG-specific quantitative methods, we conclude that they may cause the background to rise. Therefore, in Japan false positives arising from JCP contamination should be considered when testing patients for deep mycosis. Full article
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Article
Split Enzyme-Based Biosensors for Structural Characterization of Soluble and Insoluble β-Glucans
Int. J. Mol. Sci. 2021, 22(4), 1576; https://doi.org/10.3390/ijms22041576 - 04 Feb 2021
Cited by 4 | Viewed by 1286
Abstract
β-Glucan is widely distributed in various plants and microorganisms and is composed of β-1,3-linked d-glucose units. It may have a branched short or long side chain of glucose units with β-1,6- or β-1,4-linkage. Numerous studies have investigated different β-glucans and revealed their [...] Read more.
β-Glucan is widely distributed in various plants and microorganisms and is composed of β-1,3-linked d-glucose units. It may have a branched short or long side chain of glucose units with β-1,6- or β-1,4-linkage. Numerous studies have investigated different β-glucans and revealed their bioactivities. To understand the structure-function relationship of β-glucan, we constructed a split-luciferase complementation assay for the structural analysis of long-chain β-1,6-branched β-1,3-glucan. The N- and C-terminal fragments of luciferase from deep-sea shrimp were fused to insect-derived β-1,3-glucan recognition protein and fungal endo-β-1,6-glucanase (Neg1)-derived β-1,6-glucan recognition protein, respectively. In this approach, two β-glucan recognition proteins bound to β-glucan molecules come into close proximity, resulting in the assembly of the full-length reporter enzyme and induction of transient luciferase activity, indicative of the structure of β-glucan. To test the applicability of this assay, β-glucan and two β-glucan recognition proteins were mixed, resulting in an increase in the luminescence intensity in a β-1,3-glucan with a long polymer of β-1,6-glucan in a dose-dependent manner. This simple test also allows the monitoring of real-time changes in the side chain structure and serves as a convenient method to distinguish between β-1,3-glucan and long-chain β-1,6-branched β-1,3-glucan in various soluble and insoluble β-glucans. Full article
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Review

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Review
Development of a Method of Measuring β-D-Glucan and Its Use in Preemptive Therapy for Invasive Fungal Infections
Int. J. Mol. Sci. 2021, 22(17), 9265; https://doi.org/10.3390/ijms22179265 - 27 Aug 2021
Cited by 3 | Viewed by 917
Abstract
Invasive fungal infections (IFIs) are serious infections that develop in conjunction with neutropenia after chemotherapy for acute leukemia or with hematopoietic stem cell transplantation. Conventionally, empirical antifungal therapy was recommended to treat IFIs for patient safety despite a lack of evidence of fungal [...] Read more.
Invasive fungal infections (IFIs) are serious infections that develop in conjunction with neutropenia after chemotherapy for acute leukemia or with hematopoietic stem cell transplantation. Conventionally, empirical antifungal therapy was recommended to treat IFIs for patient safety despite a lack of evidence of fungal infections. However, many studies have indicated that antifungals were not necessary for over half of patients, and several detriments of empirical therapy were noted, e.g., antifungals caused adverse reactions, an increase in drug-resistant fungi was a possibility, and medical costs soared. β-D-glucan (BDG) is a component of clinically important fungi such as Aspergillus and Candida. The G-test was developed in Japan as a way to measure BDG in serum using a coagulation factor from the blood of the horseshoe crab. Pre-emptive antifungal therapy based upon serodiagnosis with a BDG or galactomannan assay and CT imaging has been introduced. With pre-emptive antifungal therapy, the prognosis is equivalent to that with empirical therapy, and the dose of the antifungal has been successfully reduced. Measurement of BDG has been adopted widely as a method of diagnosing IFIs and is listed in the key guidelines for fungal infections and febrile neutropenia. Full article
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Review
Insights on the Functional Role of Beta-Glucans in Fungal Immunity Using Receptor-Deficient Mouse Models
Int. J. Mol. Sci. 2021, 22(9), 4778; https://doi.org/10.3390/ijms22094778 - 30 Apr 2021
Cited by 6 | Viewed by 1308
Abstract
Understanding the host anti-fungal immunity induced by beta-glucan has been one of the most challenging conundrums in the field of biomedical research. During the last couple of decades, insights on the role of beta-glucan in fungal disease progression, susceptibility, and resistance have been [...] Read more.
Understanding the host anti-fungal immunity induced by beta-glucan has been one of the most challenging conundrums in the field of biomedical research. During the last couple of decades, insights on the role of beta-glucan in fungal disease progression, susceptibility, and resistance have been greatly augmented through the utility of various beta-glucan cognate receptor-deficient mouse models. Analysis of dectin-1 knockout mice has clarified the downstream signaling pathways and adaptive effector responses triggered by beta-glucan in anti-fungal immunity. On the other hand, assessment of CR3-deficient mice has elucidated the compelling action of beta-glucans in neutrophil-mediated fungal clearance, and the investigation of EphA2-deficient mice has highlighted its novel involvement in host sensing and defense to oral mucosal fungal infection. Based on these accounts, this review focuses on the recent discoveries made by these gene-targeted mice in beta-glucan research with particular emphasis on the multifaceted aspects of fungal immunity. Full article
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Review
Variation, Modification and Engineering of Lipid A in Endotoxin of Gram-Negative Bacteria
Int. J. Mol. Sci. 2021, 22(5), 2281; https://doi.org/10.3390/ijms22052281 - 25 Feb 2021
Cited by 7 | Viewed by 1131
Abstract
Lipid A of Gram-negative bacteria is known to represent a central role for the immunological activity of endotoxin. Chemical structure and biosynthetic pathways as well as specific receptors on phagocytic cells had been clarified by the beginning of the 21st century. Although the [...] Read more.
Lipid A of Gram-negative bacteria is known to represent a central role for the immunological activity of endotoxin. Chemical structure and biosynthetic pathways as well as specific receptors on phagocytic cells had been clarified by the beginning of the 21st century. Although the lipid A of enterobacteria including Escherichia coli share a common structure, other Gram-negative bacteria belonging to various classes of the phylum Proteobacteria and other taxonomical groups show wide variety of lipid A structure with relatively decreased endotoxic activity compared to that of E. coli. The structural diversity is produced from the difference of chain length of 3-hydroxy fatty acids and non-hydroxy fatty acids linked to their hydroxyl groups. In some bacteria, glucosamine in the backbone is substituted by another amino sugar, or phosphate groups bound to the backbone are modified. The variation of structure is also introduced by the enzymes that can modify electrostatic charges or acylation profiles of lipid A during or after its synthesis. Furthermore, lipid A structure can be artificially modified or engineered by the disruption and introduction of biosynthetic genes especially those of acyltransferases. These technologies may produce novel vaccine adjuvants or antagonistic drugs derived from endotoxin in the future. Full article
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Review
Therapeutic Rationale for Endotoxin Removal with Polymyxin B Immobilized Fiber Column (PMX) for Septic Shock
Int. J. Mol. Sci. 2021, 22(4), 2228; https://doi.org/10.3390/ijms22042228 - 23 Feb 2021
Cited by 9 | Viewed by 1871
Abstract
Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented [...] Read more.
Endotoxin removal therapy with polymyxin B immobilized fiber column (PMX) has been clinically applied for sepsis and septic shock patients since 1994. The effectiveness and usefulness of this therapy have been demonstrated for more than a quarter of a century. However, a documented survival benefit has not yet been demonstrable in a large, multicenter, randomized and controlled trial. Following the findings derived from a large sepsis clinical trial with PMX in North America, a new trial is ongoing to determine if PMX has a long-term survival benefit when administered to septic patients. Another approach to support a survival benefit from intervention with PMX is to utilize a detailed analysis available from a large clinical data base. The endotoxin adsorption capacity of PMX columns in vitro and the effectiveness of PMX columns can be further demonstrable in animal models. The capability of PMX and details of its mechanism of action to intervene in the sepsis cascade and impede organ dysfunction in septic patients is not fully understood. The surface antigen expression in monocytes and neutrophils are improved after PMX therapy. Immunomodulatory effects as a result of endotoxin removal and/or other mechanisms of action have been suggested. These effects and other potential immune effects may explain some of the improved effects upon organ dysfunction of sepsis and septic shock patients. Endotoxemia may be involved in the pathophysiology of other diseases than sepsis. A rapid diagnostic method to detect and target endotoxemia could allow us to practice precision medicine and expand the clinical indications of endotoxin removal therapy. Full article
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Review
Transglutaminase 2 as a Marker for Inflammation and Therapeutic Target in Sepsis
Int. J. Mol. Sci. 2021, 22(4), 1897; https://doi.org/10.3390/ijms22041897 - 14 Feb 2021
Cited by 6 | Viewed by 1483
Abstract
Sepsis results in lethal organ malfunction due to dysregulated host response to infection, which is a condition with increasing prevalence worldwide. Transglutaminase 2 (TG2) is a crosslinking enzyme that forms a covalent bond between lysine and glutamine. TG2 plays important roles in diverse [...] Read more.
Sepsis results in lethal organ malfunction due to dysregulated host response to infection, which is a condition with increasing prevalence worldwide. Transglutaminase 2 (TG2) is a crosslinking enzyme that forms a covalent bond between lysine and glutamine. TG2 plays important roles in diverse cellular processes, including extracellular matrix stabilization, cytoskeletal function, cell motility, adhesion, signal transduction, apoptosis, and cell survival. We have shown that the co-culture of Candida albicans and hepatocytes activates and induces the translocation of TG2 into the nucleus. In addition, the expression and activation of TG2 in liver macrophages was dramatically induced in the lipopolysaccharide-injected and cecal ligation puncture-operated mouse models of sepsis. Based on these findings and recently published research, we have reviewed the current understanding of the relationship between TG2 and sepsis. Following the genetic and pharmacological inhibition of TG2, we also assessed the evidence regarding the use of TG2 as a potential marker and therapeutic target in inflammation and sepsis. Full article
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Review
3D Structural Insights into β-Glucans and Their Binding Proteins
Int. J. Mol. Sci. 2021, 22(4), 1578; https://doi.org/10.3390/ijms22041578 - 04 Feb 2021
Cited by 7 | Viewed by 1181
Abstract
β(1,3)-glucans are a component of fungal and plant cell walls. The β-glucan of pathogens is recognized as a non-self-component in the host defense system. Long β-glucan chains are capable of forming a triple helix structure, and the tertiary structure may profoundly affect the [...] Read more.
β(1,3)-glucans are a component of fungal and plant cell walls. The β-glucan of pathogens is recognized as a non-self-component in the host defense system. Long β-glucan chains are capable of forming a triple helix structure, and the tertiary structure may profoundly affect the interaction with β-glucan-binding proteins. Although the atomic details of β-glucan binding and signaling of cognate receptors remain mostly unclear, X-ray crystallography and NMR analyses have revealed some aspects of β-glucan structure and interaction. Here, we will review three-dimensional (3D) structural characteristics of β-glucans and the modes of interaction with β-glucan-binding proteins. Full article
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Review
Role of Antimicrobial Peptides in Skin Barrier Repair in Individuals with Atopic Dermatitis
Int. J. Mol. Sci. 2020, 21(20), 7607; https://doi.org/10.3390/ijms21207607 - 14 Oct 2020
Cited by 22 | Viewed by 2922
Abstract
Atopic dermatitis (AD) is a common chronic inflammatory skin disease that exhibits a complex interplay of skin barrier disruption and immune dysregulation. Patients with AD are susceptible to cutaneous infections that may progress to complications, including staphylococcal septicemia. Although most studies have focused [...] Read more.
Atopic dermatitis (AD) is a common chronic inflammatory skin disease that exhibits a complex interplay of skin barrier disruption and immune dysregulation. Patients with AD are susceptible to cutaneous infections that may progress to complications, including staphylococcal septicemia. Although most studies have focused on filaggrin mutations, the physical barrier and antimicrobial barrier also play critical roles in the pathogenesis of AD. Within the physical barrier, the stratum corneum and tight junctions play the most important roles. The tight junction barrier is involved in the pathogenesis of AD, as structural and functional defects in tight junctions not only disrupt the physical barrier but also contribute to immunological impairments. Furthermore, antimicrobial peptides, such as LL-37, human β-defensins, and S100A7, improve tight junction barrier function. Recent studies elucidating the pathogenesis of AD have led to the development of barrier repair therapy for skin barrier defects in patients with this disease. This review analyzes the association between skin barrier disruption in patients with AD and antimicrobial peptides to determine the effect of these peptides on skin barrier repair and to consider employing antimicrobial peptides in barrier repair strategies as an additional approach for AD management. Full article
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Review
Therapeutic Potential of Cathelicidin Peptide LL-37, an Antimicrobial Agent, in a Murine Sepsis Model
Int. J. Mol. Sci. 2020, 21(17), 5973; https://doi.org/10.3390/ijms21175973 - 19 Aug 2020
Cited by 20 | Viewed by 2593
Abstract
Among the mechanisms put-up by the host to defend against invading microorganisms, antimicrobial peptides represent the first line. In different species of mammals, the cathelicidin family of antimicrobial peptides AMPs has been identified, and in humans, LL-37 is the only type of cathelicidin [...] Read more.
Among the mechanisms put-up by the host to defend against invading microorganisms, antimicrobial peptides represent the first line. In different species of mammals, the cathelicidin family of antimicrobial peptides AMPs has been identified, and in humans, LL-37 is the only type of cathelicidin identified. LL-37 has many different biological activities, such as regulation of responses to inflammation, besides its lipopolysaccharide (LPS)-neutralizing and antimicrobial and activities. Recently, employing a murine septic model that involves cecal ligation and puncture (CLP), we examined the effect of LL-37. The results indicated that LL-37 exhibits multiple protective actions on septic mice; firstly, the survival of CLP mice was found to be improved by LL-37 by the suppression of the macrophage pyroptosis that induces the release of pro-inflammatory cytokines (such as IL-1β) and augments inflammatory reactions in sepsis; secondly, the release of neutrophil extracellular traps (NETs), which have potent bactericidal activity, is enhanced by LL-37, and protects mice from CLP-induced sepsis; thirdly, LL-37 stimulates neutrophils to release antimicrobial microvesicles (ectosomes), which improve the pathological condition of sepsis. These findings indicate that LL-37 protects CLP septic mice through at least three mechanisms, i.e., the suppression of pro-inflammatory macrophage pyroptosis and the release of antimicrobial NETs (induction of NETosis) and ectosomes from neutrophils. Thus, LL-37 can be a potential therapeutic candidate for sepsis due to its multiple properties, including the modulation of cell death (pyroptosis and NETosis) and the release of antimicrobial NETs and ectosomes as well as its own bactericidal and LPS-neutralizing activities. Full article
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