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Signal Transduction and Targeted Therapy Aug 2023As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their... (Review)
Review
As a family of cationic host defense peptides, defensins are mainly synthesized by Paneth cells, neutrophils, and epithelial cells, contributing to host defense. Their biological functions in innate immunity, as well as their structure and activity relationships, along with their mechanisms of action and therapeutic potential, have been of great interest in recent years. To highlight the key research into the role of defensins in human and animal health, we first describe their research history, structural features, evolution, and antimicrobial mechanisms. Next, we cover the role of defensins in immune homeostasis, chemotaxis, mucosal barrier function, gut microbiota regulation, intestinal development and regulation of cell death. Further, we discuss their clinical relevance and therapeutic potential in various diseases, including infectious disease, inflammatory bowel disease, diabetes and obesity, chronic inflammatory lung disease, periodontitis and cancer. Finally, we summarize the current knowledge regarding the nutrient-dependent regulation of defensins, including fatty acids, amino acids, microelements, plant extracts, and probiotics, while considering the clinical application of such regulation. Together, the review summarizes the various biological functions, mechanism of actions and potential clinical significance of defensins, along with the challenges in developing defensins-based therapy, thus providing crucial insights into their biology and potential clinical utility.
Topics: Animals; Humans; Paneth Cells; Inflammatory Bowel Diseases; Defensins
PubMed: 37574471
DOI: 10.1038/s41392-023-01553-x -
Journal of the European Academy of... Oct 2023Guselkumab is an interleukin (IL)-23 inhibitor with demonstrated efficacy in patients with psoriasis. (Randomized Controlled Trial)
Randomized Controlled Trial
Early disease intervention with guselkumab in psoriasis leads to a higher rate of stable complete skin clearance ('clinical super response'): Week 28 results from the ongoing phase IIIb randomized, double-blind, parallel-group, GUIDE study.
BACKGROUND
Guselkumab is an interleukin (IL)-23 inhibitor with demonstrated efficacy in patients with psoriasis.
OBJECTIVES
Evaluate the impact of early disease intervention on clinical responses following 28 weeks of guselkumab treatment in patients with moderate-to-severe plaque psoriasis. Correlate clinical response and disease duration data with serum biomarker data.
METHODS
GUIDE is a phase IIIb randomized, double-blind, parallel-group, multicentre study of adults with moderate-to-severe plaque psoriasis. In study part 1, patients with a short disease duration (SDD [≤2 years]) or a long disease duration (LDD [>2 years]) received guselkumab 100 mg at Week (W) 0, 4, 12, and 20. Those achieving complete skin clearance at W20 and W28 were defined as a super responder (SRe). A multivariable logistic regression analysed the association between baseline factors and the likelihood of becoming an SRe. The relationship between clinical response, disease duration and serum biomarker data was assessed at W0 and 4.
RESULTS
In total, 880 patients were enrolled (SDD/LDD = 40.6%/59.4% of patients). More SDD than LDD patients achieved absolute Psoriasis Area and Severity Index (PASI) = 0 at W28 (51.8% vs. 39.4%) and were SRes (43.7% vs. 28.1% [overall 34.4%]). SDD patients also achieved PASI = 0 quicker than LDD patients (median 141 vs. 200 days). Disease duration and prior biologic use had the greatest impact on becoming an SRe, with no strong association among these independent variables. At baseline, there were no significant differences in the serum biomarker levels of IL-17A, IL-17F, IL-22 and β-defensin 2 between SDD and LDD patients, or between SRe and non-SRe patients. Guselkumab rapidly decreased these markers of systemic inflammation across all patient groups analysed at W4. Guselkumab was well tolerated.
CONCLUSIONS
Guselkumab efficacy was consistent across subpopulations, on the skin and systemically. The proportion of SRes was higher in SDD than LDD patients, indicating early treatment intervention may improve clinical outcomes.
Topics: Adult; Humans; Antibodies, Monoclonal; Treatment Outcome; Severity of Illness Index; Psoriasis; Biomarkers; Double-Blind Method
PubMed: 37262309
DOI: 10.1111/jdv.19236 -
Science Translational Medicine Mar 2024Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease...
Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including . IgA1 was deglycosylated by both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1-CD89) that underwent intestinal colonization by developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins-a risk locus for IgA nephropathy-inhibited growth of vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease.
Topics: Humans; Mice; Animals; Immunoglobulin A; Glomerulonephritis, IGA; Gastrointestinal Microbiome; Kidney; Immunoglobulin G
PubMed: 38536935
DOI: 10.1126/scitranslmed.adl6149 -
MedComm Dec 2023The diverse bacterial populations within the symbiotic microbiota play a pivotal role in both health and disease. Microbiota modulates critical aspects of tumor biology... (Review)
Review
The diverse bacterial populations within the symbiotic microbiota play a pivotal role in both health and disease. Microbiota modulates critical aspects of tumor biology including cell proliferation, invasion, and metastasis. This regulation occurs through mechanisms like enhancing genomic damage, hindering gene repair, activating aberrant cell signaling pathways, influencing tumor cell metabolism, promoting revascularization, and remodeling the tumor immune microenvironment. These microbiota-mediated effects significantly impact overall survival and the recurrence of tumors after surgery by affecting the efficacy of chemoradiotherapy. Moreover, leveraging the microbiota for the development of biovectors, probiotics, prebiotics, and synbiotics, in addition to utilizing antibiotics, dietary adjustments, defensins, oncolytic virotherapy, and fecal microbiota transplantation, offers promising alternatives for cancer treatment. Nonetheless, due to the extensive and diverse nature of the microbiota, along with tumor heterogeneity, the molecular mechanisms underlying the role of microbiota in cancer remain a subject of intense debate. In this context, we refocus on various cancers, delving into the molecular signaling pathways associated with the microbiota and its derivatives, the reshaping of the tumor microenvironmental matrix, and the impact on tolerance to tumor treatments such as chemotherapy and radiotherapy. This exploration aims to shed light on novel perspectives and potential applications in the field.
PubMed: 37937304
DOI: 10.1002/mco2.417 -
International Journal of Molecular... Sep 2023Periodontitis is one of the primary causes of tooth loss, and is also related to various systemic diseases. Early detection of this condition is crucial when it comes to... (Meta-Analysis)
Meta-Analysis Review
Periodontitis is one of the primary causes of tooth loss, and is also related to various systemic diseases. Early detection of this condition is crucial when it comes to preventing further oral damage and the associated health complications. This study offers a systematic review of the literature published up to April 2023, and aims to clearly explain the role of proteomics in identifying salivary biomarkers for periodontitis. Comprehensive searches were conducted on PubMed and Web of Science to shortlist pertinent studies. The inclusion criterion was those that reported on mass spectrometry-driven proteomic analyses of saliva samples from periodontitis cohorts, while those on gingivitis or other oral diseases were excluded. An assessment for risk of bias was carried out using the Newcastle-Ottawa Scale and Quality Assessment of Diagnostic Accuracy Studies or the NIH quality assessment tool, and a meta-analysis was performed for replicable candidate biomarkers, i.e., consistently reported candidate biomarkers (in specific saliva samples, and periodontitis subgroups, reported in ≥2 independent cohorts/reports) were identified. A Gene Ontology enrichment analysis was conducted using the Database for Annotation, Visualization, and Integrated Discovery bioinformatics resources, which consistently expressed candidate biomarkers, to explore the predominant pathway wherein salivary biomarkers consistently manifested. Of the 15 studies included, 13 were case-control studies targeting diagnostic biomarkers for periodontitis participants (periodontally healthy/diseased, = 342/432), while two focused on biomarkers responsive to periodontal treatment ( = 26 participants). The case-control studies were considered to have a low risk of bias, while the periodontitis treatment studies were deemed fair. Summary estimate and confidence/credible interval, etc. determination for the identified putative salivary biomarkers could not be ascertained due to the low number of studies in each case. The results from the included case-control studies identified nine consistently expressed candidate biomarkers (from nine studies with 230/297 periodontally healthy/diseased participants): (i) those that were upregulated: alpha-amylase, serum albumin, complement C3, neutrophil defensin, profilin-1, and S100-P; and (ii) those that were downregulated: carbonic anhydrase 6, immunoglobulin J chain, and lactoferrin. All putative biomarkers exhibited consistent regulation patterns. The implications of the current putative marker proteins identified were reviewed, with a focus on their potential roles in periodontitis diagnosis and pathogenesis, and as putative therapeutic targets. Although in its early stages, mass spectrometry-based salivary periodontal disease biomarker proteomics detection appeared promising. More mass spectrometry-based proteomics studies, with or without the aid of already available clinical biochemical approaches, are warranted to aid the discovery, identification, and validation of periodontal health/disease indicator molecule(s). Protocol registration number: CRD42023447722; supported by RD-02-202410 and GRF17119917.
Topics: Humans; Proteomics; Periodontitis; Mass Spectrometry; Biomarkers; Proteins; Periodontal Diseases; Saliva
PubMed: 37834046
DOI: 10.3390/ijms241914599 -
Frontiers in Immunology 2023COPD is characterized by chronic airway inflammation, small airways changes, with disappearance and obstruction, and also distal/alveolar destruction (emphysema). The...
RATIONALE
COPD is characterized by chronic airway inflammation, small airways changes, with disappearance and obstruction, and also distal/alveolar destruction (emphysema). The chronology by which these three features evolve with altered mucosal immunity remains elusive. This study assessed the mucosal immune defense in human control and end-stage COPD lungs, by detailed microCT and RNA transcriptomic analysis of diversely affected zones.
METHODS
In 11 control (non-used donors) and 11 COPD (end-stage) explant frozen lungs, 4 cylinders/cores were processed per lung for microCT and tissue transcriptomics. MicroCT was used to quantify tissue percentage and alveolar surface density to classify the COPD cores in mild, moderate and severe alveolar destruction groups, as well as to quantify terminal bronchioles in each group. Transcriptomics of each core assessed fold changes in innate and adaptive cells and pathway enrichment score between control and COPD cores. Immunostainings of immune cells were performed for validation.
RESULTS
In mildly affected zones, decreased defensins and increased mucus production were observed, along CD8+ T cell accumulation and activation of the IgA pathway. In more severely affected zones, CD68+ myeloid antigen-presenting cells, CD4+ T cells and B cells, as well as MHCII and IgA pathway genes were upregulated. In contrast, terminal bronchioles were decreased in all COPD cores.
CONCLUSION
Spatial investigation of end-stage COPD lungs show that mucosal defense dysregulation with decreased defensins and increased mucus and IgA responses, start concomitantly with CD8+ T-cell accumulation in mild emphysema zones, where terminal bronchioles are already decreased. In contrast, adaptive Th and B cell activation is observed in areas with more advanced tissue destruction. This study suggests that in COPD innate immune alterations occur early in the tissue destruction process, which affects both the alveoli and the terminal bronchioles, before the onset of an adaptive immune response.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Inflammation; Emphysema; Defensins; Immunoglobulin A
PubMed: 37915582
DOI: 10.3389/fimmu.2023.1275845 -
Frontiers in Cellular and Infection... 2023Identifying novel biomarkers that are both specific and sensitive to periprosthetic joint infection (PJI) has the potential to improve diagnostic accuracy and ultimately... (Review)
Review
BACKGROUND
Identifying novel biomarkers that are both specific and sensitive to periprosthetic joint infection (PJI) has the potential to improve diagnostic accuracy and ultimately enhance patient outcomes. Therefore, the aim of this systematic review is to identify and evaluate the effectiveness of novel biomarkers for the diagnosis of PJI.
METHODS
We searched the MEDLINE, EMBASE, PubMed, and Cochrane Library databases from January 1, 2018, to September 30, 2022, using the search terms "periprosthetic joint infection," "prosthetic joint infection," or "periprosthetic infection" as the diagnosis of interest and the target index, combined with the term "marker." We excluded articles that mentioned established biomarkers such as CRP, ESR, Interleukin 6, Alpha defensin, PCT (procalcitonin), and LC (leucocyte cell count). We used the MSIS, ICM, or EBJS criteria for PJI as the reference standard during quality assessment.
RESULTS
We collected 19 studies that analyzed fourteen different novel biomarkers. Proteins were the most commonly analyzed biomarkers (nine studies), followed by molecules (three studies), exosomes (two studies), DNA (two studies), interleukins (one study), and lysosomes (one study). Calprotectin was a frequently analyzed and promising marker. In the scenario where the threshold was set at ≥50-mg/mL, the calprotectin point-of-care (POC) performance showed a high sensitivity of 98.1% and a specificity of 95.7%.
CONCLUSION
None of the analyzed biomarkers demonstrated outstanding performance compared to the established parameters used for standardized treatment based on established PJI definitions. Further studies are needed to determine the benefit and usefulness of implementing new biomarkers in diagnostic PJI settings.
Topics: Humans; Prosthesis-Related Infections; Arthritis, Infectious; Biomarkers; Procalcitonin; Leukocyte Count; alpha-Defensins; Sensitivity and Specificity
PubMed: 37529352
DOI: 10.3389/fcimb.2023.1210345 -
Transgenic Research Oct 2023Insecticidal transgenes, when incorporated and expressed in plants, confer resistance against insects by producing several products having insecticidal properties.... (Review)
Review
Insecticidal transgenes, when incorporated and expressed in plants, confer resistance against insects by producing several products having insecticidal properties. Protease inhibitors, lectins, amylase inhibitors, and chitinase genes are associated with the natural defenses developed by plants to counter insect attacks. Several toxin genes are also derived from spiders and scorpions for protection against insects. Bacillus thuringiensis Berliner is a microbial source of insecticidal toxins. Several methods have facilitated the large-scale production of transgenic plants. Bt-derived cry, cyt, vip, and sip genes, plant-derived genes such as lectins, protease inhibitors, and alpha-amylase inhibitors, insect cell wall-degrading enzymes like chitinase and some proteins like arcelins, plant defensins, and ribosome-inactivating proteins have been successfully utilized to impart resistance to insects. Besides, transgenic plants expressing double-stranded RNA have been developed with enhanced resistance. However, the long-term effects of transgenes on insect resistance, the environment, and human health must be thoroughly investigated before they are made available for commercial planting. In this chapter, the present status, prospects, and future scope of transgenes for insect pest management have been summarized and discussed.
Topics: Animals; Humans; Insecta; Insecticides; Transgenes; Plants, Genetically Modified; Bacillus thuringiensis; Protease Inhibitors; Lectins; Chitinases; Bacterial Proteins; Endotoxins; Hemolysin Proteins; Pest Control, Biological
PubMed: 37573273
DOI: 10.1007/s11248-023-00362-w -
International Immunopharmacology Jan 2024Tuberculosis (TB) is a serious airborne communicable disease caused by organisms of the Mycobacterium tuberculosis (Mtb) complex. Although the standard treatment... (Review)
Review
Tuberculosis (TB) is a serious airborne communicable disease caused by organisms of the Mycobacterium tuberculosis (Mtb) complex. Although the standard treatment antimicrobials, including isoniazid, rifampicin, pyrazinamide, and ethambutol, have made great progress in the treatment of TB, problems including the rising incidence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the severe toxicity and side effects of antimicrobials, and the low immunity of TB patients have become the bottlenecks of the current TB treatments. Therefore, both safe and effective new strategies to prevent and treat TB have become a top priority. As a subfamily of cationic antimicrobial peptides, defensins are rich in cysteine and play a vital role in resisting the invasion of microorganisms and regulating the immune response. Inspired by studies on the roles of defensins in host defence, we describe their research history and then review their structural features and antimicrobial mechanisms, specifically for fighting Mtb in detail. Finally, we discuss the clinical relevance, therapeutic potential, and potential challenges of defensins in anti-TB therapy. We further debate the possible solutions of the current application of defensins to provide new insights for eliminating Mtb.
Topics: Humans; Mycobacterium tuberculosis; Antitubercular Agents; Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis; Defensins
PubMed: 38118315
DOI: 10.1016/j.intimp.2023.111383 -
Seminars in Cell & Developmental Biology Feb 2024Atopic dermatitis (AD), also known as atopic eczema, is a common but also complex chronic, itchy skin condition with underlying inflammation of the skin. This skin... (Review)
Review
Atopic dermatitis (AD), also known as atopic eczema, is a common but also complex chronic, itchy skin condition with underlying inflammation of the skin. This skin ailment is prevalent worldwide and affects people of all ages, particularly children below five years of age. The itching and resulting rashes in AD patients are often the result of inflammatory signals, thus necessitating a closer look at the inflammation-regulating mechanisms for putative relief, care and therapy. Several chemical- as well as genetically-induced animal models have established the importance of targeting pro-inflammatory AD microenvironment. Epigenetic mechanisms are gaining attention towards a better understanding of the onset as well as the progression of inflammation. Several physiological processes with implications in pathophysiology of AD, such as, barrier dysfunction either due to reduced filaggrin / human β-defensins or altered microbiome, reprograming of Fc receptors with resulting overexpression of high affinity IgE receptors, elevated eosinophil numbers or the elevated IL-22 production by CD4 + T cells have underlying epigenetic mechanisms that include differential promoter methylation and/or regulation by non-coding RNAs. Reversing these epigenetic changes has been verified to reduce inflammatory burden through altered secretion of cytokines IL-6, IL-4, IL-13, IL-17, IL-22 etc, with benefit against AD progression in experimental models. A thorough understanding of epigenetic remodeling of inflammation in AD has the potential of opening avenues for novel diagnostic, prognostic and therapeutic options.
PubMed: 37120405
DOI: 10.1016/j.semcdb.2023.04.005