International Journal of Molecular Sciences

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23 pages, 2030 KiB

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Challenges in Humoral Immune Response to Adeno-Associated Viruses Determination

by Daria A. Naumova, Tatyana Krokunova, Denis Maksimov, Olga N. Mityaeva, Ekaterina A. Astakhova and Pavel Yu Volchkov

Int. J. Mol. Sci. 2025, 26(2), 816; https://doi.org/10.3390/ijms26020816 - 19 Jan 2025

Viewed by 1002

Abstract

Adeno-associated viruses (AAVs) are non-pathogenic, replication-deficient viruses that have gained widespread attention for their application as gene therapy vectors. While these vectors offer high transduction efficiency and long-term gene expression, the host immune response poses a significant challenge to their clinical success. This [...] Read more.

Adeno-associated viruses (AAVs) are non-pathogenic, replication-deficient viruses that have gained widespread attention for their application as gene therapy vectors. While these vectors offer high transduction efficiency and long-term gene expression, the host immune response poses a significant challenge to their clinical success. This review focuses on the obstacles to evaluating the humoral response to AAVs. We discuss the problems with the validation of in vitro tests and the possible approaches to overcome them. Using published data on neutralizing titers of AAV serotypes, we built the first antigenic maps of AAVs in order to visualize the antigenic relationships between varying serotypes. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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33 pages, 2075 KiB

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Inflammatory Effects and Regulatory Mechanisms of Chitinase-3-like-1 in Multiple Human Body Systems: A Comprehensive Review

by Dong Liu, Xin Hu, Xiao Ding, Ming Li and Lei Ding

Int. J. Mol. Sci. 2024, 25(24), 13437; https://doi.org/10.3390/ijms252413437 - 15 Dec 2024

Cited by 4 | Viewed by 1524

Abstract

Chitinase-3-like-1 (Chi3l1), also known as YKL-40 or BRP-39, is a highly conserved mammalian chitinase with a chitin-binding ability but no chitinase enzymatic activity. Chi3l1 is secreted by various cell types and induced by several inflammatory cytokines. It can mediate a series of cell [...] Read more.

Chitinase-3-like-1 (Chi3l1), also known as YKL-40 or BRP-39, is a highly conserved mammalian chitinase with a chitin-binding ability but no chitinase enzymatic activity. Chi3l1 is secreted by various cell types and induced by several inflammatory cytokines. It can mediate a series of cell biological processes, such as proliferation, apoptosis, migration, differentiation, and polarization. Accumulating evidence has verified that Chi3l1 is involved in diverse inflammatory conditions; however, a systematic and comprehensive understanding of the roles and mechanisms of Chi3l1 in almost all human body system-related inflammatory diseases is still lacking. The human body consists of ten organ systems, which are combinations of multiple organs that perform one or more physiological functions. Abnormalities in these human systems can trigger a series of inflammatory environments, posing serious threats to the quality of life and lifespan of humans. Therefore, exploring novel and reliable biomarkers for these diseases is highly important, with Chi3l1 being one such parameter because of its physiological and pathophysiological roles in the development of multiple inflammatory diseases. Reportedly, Chi3l1 plays an important role in diagnosing and determining disease activity/severity/prognosis related to multiple human body system inflammation disorders. Additionally, many studies have revealed the influencing factors and regulatory mechanisms (e.g., the ERK and MAPK pathways) of Chi3l1 in these inflammatory conditions, identifying potential novel therapeutic targets for these diseases. In this review, we comprehensively summarize the potential roles and underlying mechanisms of Chi3l1 in inflammatory disorders of the respiratory, digestive, circulatory, nervous, urinary, endocrine, skeletal, muscular, and reproductive systems, which provides a more systematic understanding of Chi3l1 in multiple human body system-related inflammatory diseases. Moreover, this article summarizes potential therapeutic strategies for inflammatory diseases in these systems on the basis of the revealed roles and mechanisms mediated by Chi3l1. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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17 pages, 1012 KiB

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Secreted Phospholipases A2: Drivers of Inflammation and Cancer

by Ivan Hidalgo, Maria Alba Sorolla, Anabel Sorolla, Antonieta Salud and Eva Parisi

Int. J. Mol. Sci. 2024, 25(22), 12408; https://doi.org/10.3390/ijms252212408 - 19 Nov 2024

Cited by 1 | Viewed by 2208

Abstract

Secreted phospholipase 2 (sPLA2) is the largest family of phospholipase A2 (PLA2) enzymes with 11 mammalian isoforms. Each sPLA2 exhibits different localizations and specific properties, being involved in a very wide spectrum of biological processes. The enzymatic activity of sPLA2 has been well [...] Read more.

Secreted phospholipase 2 (sPLA2) is the largest family of phospholipase A2 (PLA2) enzymes with 11 mammalian isoforms. Each sPLA2 exhibits different localizations and specific properties, being involved in a very wide spectrum of biological processes. The enzymatic activity of sPLA2 has been well described; however, recent findings have shown that they could regulate different signaling pathways by acting directly as ligands. Arachidonic acid (AA) and its derivatives are produced by sPLA2 in collaboration with other molecules in the extracellular space, making important impacts on the cellular environment, being especially relevant in the contexts of immunity and cancer. For these reasons, this review focuses on sPLA2 functions in processes such as the promotion of EMT, angiogenesis, and immunomodulation in the context of tumor initiation and progression. Finally, we will also describe how this knowledge has been applied in the search for new sPLA2 inhibitory compounds that can be used for cancer treatment. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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27 pages, 1361 KiB

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The Importance of Phosphoinositide 3-Kinase in Neuroinflammation

by Brock Wright, Samuel King and Cenk Suphioglu

Int. J. Mol. Sci. 2024, 25(21), 11638; https://doi.org/10.3390/ijms252111638 - 30 Oct 2024

Cited by 9 | Viewed by 2385

Abstract

Neuroinflammation, characterised by the activation of immune cells in the central nervous system (CNS), plays a dual role in both protecting against and contributing to the progression of neurodegenerative diseases, such as Alzheimer’s disease (AD) and multiple sclerosis (MS). This review explores the [...] Read more.

Neuroinflammation, characterised by the activation of immune cells in the central nervous system (CNS), plays a dual role in both protecting against and contributing to the progression of neurodegenerative diseases, such as Alzheimer’s disease (AD) and multiple sclerosis (MS). This review explores the role of phosphoinositide 3-kinase (PI3K), a key enzyme involved in cellular survival, proliferation, and inflammatory responses, within the context of neuroinflammation. Two PI3K isoforms of interest, PI3Kγ and PI3Kδ, are specific to the regulation of CNS cells, such as microglia, astrocytes, neurons, and oligodendrocytes, influencing pathways, such as Akt, mTOR, and NF-κB, that control cytokine production, immune cell activation, and neuroprotection. The dysregulation of PI3K signalling is implicated in chronic neuroinflammation, contributing to the exacerbation of neurodegenerative diseases. Preclinical studies show promise in targeting neuronal disorders using PI3K inhibitors, such as AS605240 (PI3Kγ) and idelalisib (PI3Kδ), which have reduced inflammation, microglial activation, and neuronal death in in vivo models of AD. However, the clinical translation of these inhibitors faces challenges, including blood–brain barrier (BBB) permeability, isoform specificity, and long-term safety concerns. This review highlights the therapeutic potential of PI3K modulation in neuroinflammatory diseases, identifying key gaps in the current research, particularly in the need for brain-penetrating and isoform-specific inhibitors. These findings underscore the importance of future research to develop targeted therapies that can effectively modulate PI3K activity and provide neuroprotection in chronic neurodegenerative disorders. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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17 pages, 1669 KiB

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Post-Meningitic Syndrome: Pathophysiology and Consequences of Streptococcal Infections on the Central Nervous System

by Rachid Kaddoura, Karim Abdalbari, Mhmod Kadom, Beshr Abdulaziz Badla, Amin Abu Hijleh, Mohamed Hanifa, Masa AlAshkar, Mohamed Asbaita, Deema Othman, Hanan Faraji, Orjwan AlBakri, Sara Tahlak, Amir Abu Hijleh, Raneem Kabbani, Murtadha Resen, Helmi Abdalbari, Stefan S. Du Plessis and Temidayo S. Omolaoye

Int. J. Mol. Sci. 2024, 25(20), 11053; https://doi.org/10.3390/ijms252011053 - 15 Oct 2024

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Abstract

Streptococcus species represent a significant global cause of meningitis, leading to brain damage through bacterial virulence factors and the host inflammatory response. Upon entering the central nervous system (CNS), excessive inflammation leads to various neurological and psychological complications. This review explores the pathophysiological [...] Read more.

Streptococcus species represent a significant global cause of meningitis, leading to brain damage through bacterial virulence factors and the host inflammatory response. Upon entering the central nervous system (CNS), excessive inflammation leads to various neurological and psychological complications. This review explores the pathophysiological mechanisms and associated outcomes of streptococcal meningitis, particularly its short- and long-term neurological sequelae. Neurological symptoms, such as cognitive impairment, motor deficits, and sensory loss, are shown to vary in severity, with children being particularly susceptible to lasting complications. Among survivors, hearing loss, cognitive decline, and cranial nerve palsies emerge as the most frequently reported complications. The findings highlight the need for timely intervention, including neurorehabilitation strategies that focus on optimizing recovery and mitigating long-term disabilities. Future recommendations emphasize improving early diagnosis, expanding vaccine access, and personalizing rehabilitation protocols to enhance patient outcomes. As a novel contribution, this review proposes the term “post-meningitic syndrome” to showcase the broad spectrum of CNS complications that persist following streptococcal meningitis, providing a framework for a future clinical and research focus. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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17 pages, 948 KiB

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Molecular Mechanisms Affecting Statin Pharmacokinetics after Bariatric Surgery

by Matea Petrinović, Domagoj Majetić, Miro Bakula, Ivan Pećin, Daniela Fabris-Vitković, Marin Deškin, Deša Tešanović Perković, Maja Bakula, Marina Gradišer, Ines Bilić Ćurčić and Silvija Canecki-Varžić

Int. J. Mol. Sci. 2024, 25(19), 10375; https://doi.org/10.3390/ijms251910375 - 26 Sep 2024

Cited by 2 | Viewed by 1701

Abstract

According to recent data, one in eight people in the world struggle with obesity. Obesity management is increasingly dependent on bariatric surgical interventions, as the combination of lifestyle modifications and pharmacotherapy could have a modest long-term effect. Surgery is recommended only for individuals [...] Read more.

According to recent data, one in eight people in the world struggle with obesity. Obesity management is increasingly dependent on bariatric surgical interventions, as the combination of lifestyle modifications and pharmacotherapy could have a modest long-term effect. Surgery is recommended only for individuals whose body mass index (BMI) ≥ 40 kg/m² and ≥ 35 kg/m² in the presence of weight-related comorbidities. The most commonly performed procedures are sleeve gastrectomy and roux-en-Y gastric bypass. Pharmacokinetic and pharmacodynamic alterations occur as a result of the anatomical and physiological changes caused by surgery, which further differ depending on physicochemical drug factors and factors related to the dosage form. The following modifications are distinguished based on the type of bariatric surgery performed. Most bariatric patients have accompanying comorbidities, including dyslipidemia treated with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins. Significant improvements in the lipid profile are observed early in the postoperative period. The data reported in this review on statin pharmacokinetic alterations have demonstrated substantial inter- and intravariability, making it difficult to adopt clear guidelines. Based on the current literature review, reducing the statin dose to the lowest effective with continuous monitoring is considered an optimal approach in clinical practice. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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16 pages, 1357 KiB

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Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review

by Marino Paroli, Chiara Gioia, Daniele Accapezzato and Rosalba Caccavale

Int. J. Mol. Sci. 2024, 25(11), 5922; https://doi.org/10.3390/ijms25115922 - 29 May 2024

Cited by 10 | Viewed by 5013

Abstract

Fibromyalgia (FM) is a chronic disease characterized by widespread musculoskeletal pain of unknown etiology. The condition is commonly associated with other symptoms, including fatigue, sleep disturbances, cognitive impairment, and depression. For this reason, FM is also referred to as FM syndrome. The nature [...] Read more.

Fibromyalgia (FM) is a chronic disease characterized by widespread musculoskeletal pain of unknown etiology. The condition is commonly associated with other symptoms, including fatigue, sleep disturbances, cognitive impairment, and depression. For this reason, FM is also referred to as FM syndrome. The nature of the pain is defined as nociplastic according to the latest international classification and is characterized by altered nervous sensitization both centrally and peripherally. Psychosocial conditions have traditionally been considered critical in the genesis of FM. However, recent studies in animal models and humans have provided new evidence in favor of an inflammatory and/or autoimmune pathogenesis. In support of this hypothesis are epidemiological data of an increased female prevalence, similar to that of autoimmune diseases, and the frequent association with immune-mediated inflammatory disorders. In addition, the observation of an increased incidence of this condition during long COVID revived the hypothesis of an infectious pathogenesis. This narrative review will, therefore, discuss the evidence supporting the immune-mediated pathogenesis of FM in light of the most current data available in the literature. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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14 pages, 1378 KiB

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New Insight into Intestinal Mast Cells Revealed by Single-Cell RNA Sequencing

by Erisa Putro, Alessia Carnevale, Caterina Marangio, Valerio Fulci, Rossella Paolini and Rosa Molfetta

Int. J. Mol. Sci. 2024, 25(11), 5594; https://doi.org/10.3390/ijms25115594 - 21 May 2024

Cited by 2 | Viewed by 2665

Abstract

Mast cells (MCs) are tissue-resident immune cells distributed in all tissues and strategically located close to blood and lymphatic vessels and nerves. Thanks to the expression of a wide array of receptors, MCs act as tissue sentinels, able to detect the presence of [...] Read more.

Mast cells (MCs) are tissue-resident immune cells distributed in all tissues and strategically located close to blood and lymphatic vessels and nerves. Thanks to the expression of a wide array of receptors, MCs act as tissue sentinels, able to detect the presence of bacteria and parasites and to respond to different environmental stimuli. MCs originate from bone marrow (BM) progenitors that enter the circulation and mature in peripheral organs under the influence of microenvironment factors, thus differentiating into heterogeneous tissue-specific subsets. Even though MC activation has been traditionally linked to IgE-mediated allergic reactions, a role for these cells in other pathological conditions including tumor progression has recently emerged. However, several aspects of MC biology remain to be clarified. The advent of single-cell RNA sequencing platforms has provided the opportunity to understand MCs’ origin and differentiation as well as their phenotype and functions within different tissues, including the gut. This review recapitulates how single-cell transcriptomic studies provided insight into MC development as well as into the functional role of intestinal MC subsets in health and disease. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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18 pages, 2942 KiB

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The Functional Roles of the Src Homology 2 Domain-Containing Inositol 5-Phosphatases SHIP1 and SHIP2 in the Pathogenesis of Human Diseases

by Spike Murphy Müller and Manfred Jücker

Int. J. Mol. Sci. 2024, 25(10), 5254; https://doi.org/10.3390/ijms25105254 - 11 May 2024

Cited by 4 | Viewed by 2765

Abstract

The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds [...] Read more.

The src homology 2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 are two proteins involved in intracellular signaling pathways and have been linked to the pathogenesis of several diseases. Both protein paralogs are well known for their involvement in the formation of various kinds of cancer. SHIP1, which is expressed predominantly in hematopoietic cells, has been implicated as a tumor suppressor in leukemogenesis especially in myeloid leukemia, whereas SHIP2, which is expressed ubiquitously, has been implicated as an oncogene in a wider variety of cancer types and is suggested to be involved in the process of metastasis of carcinoma cells. However, there are numerous other diseases, such as inflammatory diseases as well as allergic responses, Alzheimer’s disease, and stroke, in which SHIP1 can play a role. Moreover, SHIP2 overexpression was shown to correlate with opsismodysplasia and Alzheimer’s disease, as well as metabolic diseases. The SHIP1-inhibitor 3-α-aminocholestane (3AC), and SHIP1-activators, such as AQX-435 and AQX-1125, and SHIP2-inhibitors, such as K161 and AS1949490, have been developed and partly tested in clinical trials, which indicates the importance of the SHIP-paralogs as possible targets in the therapy of those diseases. The aim of this article is to provide an overview of the current knowledge about the involvement of SHIP proteins in the pathogenesis of cancer and other human diseases and to create awareness that SHIP1 and SHIP2 are more than just tumor suppressors and oncogenes. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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15 pages, 1102 KiB

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The Golgi Apparatus: A Key Player in Innate Immunity

by Ion Mărunţelu, Alexandra-Elena Constantinescu, Razvan-Adrian Covache-Busuioc and Ileana Constantinescu

Int. J. Mol. Sci. 2024, 25(7), 4120; https://doi.org/10.3390/ijms25074120 - 8 Apr 2024

Cited by 9 | Viewed by 3945

Abstract

The Golgi apparatus, long recognized for its roles in protein processing and vesicular trafficking, has recently been identified as a crucial contributor to innate immune signaling pathways. This review discusses our expanding understanding of the Golgi apparatus’s involvement in initiating and activating these [...] Read more.

The Golgi apparatus, long recognized for its roles in protein processing and vesicular trafficking, has recently been identified as a crucial contributor to innate immune signaling pathways. This review discusses our expanding understanding of the Golgi apparatus’s involvement in initiating and activating these pathways. It highlights the significance of membrane connections between the Golgi and other organelles, such as the endoplasmic reticulum, mitochondria, endosomes, and autophagosomes. These connections are vital for the efficient transmission of innate immune signals and the activation of effector responses. Furthermore, the article delves into the Golgi apparatus’s roles in key immune pathways, including the inflammasome-mediated activation of caspase-1, the cGAS-STING pathway, and TLR/RLR signaling. Overall, this review aims to provide insights into the multifunctional nature of the Golgi apparatus and its impact on innate immunity. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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23 pages, 370 KiB

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Role of CARD9 in Cell- and Organ-Specific Immune Responses in Various Infections

by Ji Seok Lee and Chaekyun Kim

Int. J. Mol. Sci. 2024, 25(5), 2598; https://doi.org/10.3390/ijms25052598 - 23 Feb 2024

Cited by 2 | Viewed by 2008

Abstract

The caspase recruitment domain-containing protein 9 (CARD9) is an intracellular adaptor protein that is abundantly expressed in cells of the myeloid lineage, such as neutrophils, macrophages, and dendritic cells. CARD9 plays a critical role in host immunity against infections caused by fungi, bacteria, [...] Read more.

The caspase recruitment domain-containing protein 9 (CARD9) is an intracellular adaptor protein that is abundantly expressed in cells of the myeloid lineage, such as neutrophils, macrophages, and dendritic cells. CARD9 plays a critical role in host immunity against infections caused by fungi, bacteria, and viruses. A CARD9 deficiency impairs the production of inflammatory cytokines and chemokines as well as migration and infiltration, thereby increasing susceptibility to infections. However, CARD9 signaling varies depending on the pathogen causing the infection. Furthermore, different studies have reported altered CARD9-mediated signaling even with the same pathogen. Therefore, this review focuses on and elucidates the current literature on varied CARD9 signaling in response to various infectious stimuli in humans and experimental mice models. Full article

(This article belongs to the Special Issue Latest Review Papers in Molecular Immunology 2024)

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