International Journal of Molecular Sciences

2025

Jump to: 2024, 2023, 2022

21 pages, 3126 KB

Open AccessArticle

Phage–Antibiotic Synergy Enhances Biofilm Eradication and Survival in a Zebrafish Model of Pseudomonas aeruginosa Infection

by Ling-Chun Lin, Yu-Chuan Tsai and Nien-Tsung Lin

Int. J. Mol. Sci. 2025, 26(11), 5337; https://doi.org/10.3390/ijms26115337 - 1 Jun 2025

Cited by 2 | Viewed by 1830

Abstract

Pseudomonas aeruginosa is a gram-negative opportunistic pathogen that poses a significant threat due to its increasing multidrug resistance, particularly in clinical settings. This study aimed to isolate and characterize a novel bacteriophage, phiLCL12, from hospital wastewater and evaluate its potential in combination with [...] Read more.

Pseudomonas aeruginosa is a gram-negative opportunistic pathogen that poses a significant threat due to its increasing multidrug resistance, particularly in clinical settings. This study aimed to isolate and characterize a novel bacteriophage, phiLCL12, from hospital wastewater and evaluate its potential in combination with antibiotics to combat P. aeruginosa infections and biofilm formation. Transmission electron microscopy revealed that phiLCL12 possesses a long contractile tail. The isolated phage exhibited a broad host range of 82.22% and could adsorb up to 98% of its target within 4 min. It was effective against multidrug-resistant strains at both high and low multiplicities of infection (MOIs) levels in lysis tests. Taxonomic classification was determined using PhaGCN2 and Whole genomic analysis, and the results identified phiLCL12 as a member of the Pbunavirus. In vitro experiments demonstrated that phiLCL12 significantly enhanced biofilm clearance and inhibited biofilm formation when combined with sub-inhibitory concentrations of imipenem. Furthermore, in vivo experiments using a zebrafish model showed that phage–antibiotic synergy (PAS) improved survival rate compared to antibiotic treatment alone. This study demonstrates that phiLCL12 is effective in both eradicating and preventing P. aeruginosa biofilm formation. The combination of phiLCL12 and imipenem provides a synergistic effect, significantly enhancing survival outcomes in a zebrafish model. These findings highlight the potential of phage–antibiotic synergy as a promising therapeutic strategy against biofilm-associated infections. Full article

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17 pages, 762 KB

Open AccessReview

Promising Vaccine Formulations for Emerging Infectious Diseases

by Pil-Gu Park, Seok-Yong Lee, Hyewon Youn and Kee-Jong Hong

Int. J. Mol. Sci. 2025, 26(10), 4893; https://doi.org/10.3390/ijms26104893 - 20 May 2025

Viewed by 1427

Abstract

Emerging infectious diseases (EIDs) are one of the greatest threats to human health today, thus requiring an urgent response. Vaccines are one of the most effective means of preventing the spread of infectious diseases, and their usefulness in responding to EIDs has been [...] Read more.

Emerging infectious diseases (EIDs) are one of the greatest threats to human health today, thus requiring an urgent response. Vaccines are one of the most effective means of preventing the spread of infectious diseases, and their usefulness in responding to EIDs has been clearly proven through the process of overcoming the global COVID-19 pandemic. As the characteristics of various vaccine formulations differ, it is necessary to apply the most appropriate one according to the EID response strategy. In this review, we first consider which vaccine formulation is the most suitable for EID vaccines by comparing the pros and cons of different vaccine formulations, and then we discuss the utility of mRNA vaccine formulations, which are considered the most promising for EID vaccines. Full article

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19 pages, 3097 KB

Open AccessArticle

Natural Killer Cells in Graves’ Disease: Increased Frequency but Impaired Degranulation Ability Compared to Healthy Controls

by Daniela Gallo, Eliana Piantanida, Raffaella Bombelli, Silvia Lepanto, Antonino Bruno, Matteo Gallazzi, Giorgia Bilato, Marina Borgese, Denisa Baci, Lorenzo Mortara and Maria Laura Tanda

Int. J. Mol. Sci. 2025, 26(3), 977; https://doi.org/10.3390/ijms26030977 - 24 Jan 2025

Viewed by 1595

Abstract

Graves’ disease (GD) is an autoimmune disorder, driven by the appearance of circulating autoantibodies (Ab) against the thyroid stimulating hormone (TSH) receptor, thus causing hyperthyroidism. While antithyroid drugs, the only available treatment for GD, carry a significant risk of relapse, advances in immunology [...] Read more.

Graves’ disease (GD) is an autoimmune disorder, driven by the appearance of circulating autoantibodies (Ab) against the thyroid stimulating hormone (TSH) receptor, thus causing hyperthyroidism. While antithyroid drugs, the only available treatment for GD, carry a significant risk of relapse, advances in immunology could pave the way for more effective therapies. Natural killer (NK) cells, divided into cytotoxic CD56^dim and cytokine-secreting CD56^bright subsets, regulate immune responses through cytokine production and cell lysis and may play a role in the pathogenesis of GD. To investigate their involvement, we conducted flow cytometry on peripheral blood samples from 131 GD patients at various stages (disease onset, on antithyroid drugs, and in remission) and 97 age- and sex-matched healthy controls (HC). We analyzed NK cell subsets, activating (CD16, CD69, NKG2D, NKp30) and inhibitory receptors (CD161, NKG2A), degranulation (CD107a), and intracellular cytokines expression (interferon γ, tumor necrosis factor α). Statistical comparisons were made between GD patients and HC and across disease stages. GD patients had a higher frequency of total NK cells (p < 0.028) and CD56^bright NK cells (p < 0.01) but a lower frequency of CD56^dim NK cells (p = 0.005) compared to HC. NK cells in GD patients expressed activating receptors more frequently, except for NKG2D, but had decreased cytokine expression and degranulation ability. At GD onset, patients had higher frequencies of total NK cells, CD56^bright NK cells, and NK cells expressing activating receptors compared to patients receiving ATD treatment and those in remission. CD161⁺ NK cells were lower at GD onset and returned to levels of HC following treatment. Correlation analysis revealed that free thyroxine (FT4) levels were inversely correlated with CD107a⁺ NK cells (p < 0.05) and positively correlated with CD69⁺ NK cells (p < 0.01). These findings suggest that hyperthyroidism impairs NK cell degranulation, with the increased frequency of NK cells potentially compensating for their reduced function. This dysfunction may contribute to the unregulated immune response in GD, highlighting NK cells as a potential target for novel therapeutic strategies. Full article

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19 pages, 3313 KB

Open AccessArticle

ProBDNF as a Myokine in Skeletal Muscle Injury: Role in Inflammation and Potential for Therapeutic Modulation of p75^NTR

by Katherine Aby, Ryan Antony, Tao Yang, Frank M. Longo and Yifan Li

Int. J. Mol. Sci. 2025, 26(1), 401; https://doi.org/10.3390/ijms26010401 - 5 Jan 2025

Viewed by 1421

Abstract

Brain-derived neurotropic factor (BDNF) is expressed by skeletal muscle as a myokine. Our previous work showed that the active precursor, proBDNF, is the predominant form of BDNF expressed in skeletal muscle, and that following skeletal muscle injury, proBDNF levels are significantly increased. However, [...] Read more.

Brain-derived neurotropic factor (BDNF) is expressed by skeletal muscle as a myokine. Our previous work showed that the active precursor, proBDNF, is the predominant form of BDNF expressed in skeletal muscle, and that following skeletal muscle injury, proBDNF levels are significantly increased. However, the function of the muscle-derived proBDNF in injury-induced inflammation has yet to be fully understood. Using a model of tourniquet-induced ischemia–reperfusion (IR) injury of the hindlimb, this study presents, for the first time, strong and novel evidence that following IR injury, proBDNF is released from skeletal muscle into circulation as an endocrine signaling molecule. Further, this study shows that 1 day post-IR injury, the proBDNF receptor, p75^NTR, is upregulated 12-fold in splenic monocytes, which are known to be quickly mobilized to the injury site. We demonstrate that p75^NTR plays a role in the activation of splenic monocytes, and that treatment with a p75^NTR small-molecule modulator, LM11A-31, significantly reduced monocyte inflammatory responses upon lipopolysaccharide stimulation. Overall, the present study establishes proBDNF as a myokine that plays a significant role in skeletal muscle injury-induced inflammation through its receptor, p75^NTR, which may be modulated using LM11A-31 as potential translational therapeutic against injury and inflammation. Full article

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2024

Jump to: 2025, 2023, 2022

11 pages, 1955 KB

Open AccessArticle

Intranasal Immunization with Nasal Immuno-Inducible Sequence-Fused Antigens Elicits Antigen-Specific Antibody Production

by Hiraku Sasaki, Yoshio Suzuki, Kodai Morimoto, Kazuyoshi Takeda, Koichiro Uchida, Masayuki Iyoda and Hiroki Ishikawa

Int. J. Mol. Sci. 2024, 25(23), 12828; https://doi.org/10.3390/ijms252312828 - 28 Nov 2024

Cited by 2 | Viewed by 1200

Abstract

Intranasal immunization is one of the most effective methods for eliciting lung mucosal immunity. Multiple intranasal immunization with bacterial polypeptide, termed as a modified PnxIIIA (MP3) protein, is known to elicit production of a specific antibody in mice. In this study, a nasal [...] Read more.

Intranasal immunization is one of the most effective methods for eliciting lung mucosal immunity. Multiple intranasal immunization with bacterial polypeptide, termed as a modified PnxIIIA (MP3) protein, is known to elicit production of a specific antibody in mice. In this study, a nasal immuno-inducible sequence (NAIS) was designed to remove the antigenicity of the MP3 protein that can induce mucosal immunity by intranasal immunization, and was examined to induce antigen-specific antibodies against the fused bacterial thioredoxin (Trx) as a model antigen. A NAIS was modified and generated to remove a large number of predicted MHC (Major Histocompatibility Complex)-I and MHC-II binding sites in parent protein PnxIIIA and MP3 in order to reduce the number of antigen epitope sites. For comparative analysis, full-length NAIS291, NAIS230, and NAIS61 fused with Trx and 6× His tag and Trx-fused 6× His tag were used as antigen variants for the intranasal immunization of BALB/c mice every two weeks for three immunizations. Anti-Trx antibody titers in serum and bronchoalveolar lavage fluid (BALF) IgA obtained from NAIS291-fused Trx-immunized mice were significantly higher than those from Trx-immunized mice. The antibody titers against NAIS alone were significantly lower than those against Trx alone in the serum IgG, serum IgA, and BALF IgA. These results indicate that the NAIS contributes to antibody elicitation of the fused antigen as an immunostimulant in intranasal vaccination vaccines. The results indicate that the NAIS and target inactivated antigen fusions can be applied to intranasal vaccine systems. Full article

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14 pages, 1504 KB

Open AccessArticle

Cannabidiol, a Strategy in Aging to Improve Redox State and Immunity in Male Rats

by Mónica De la Fuente, Noelia Joyera, Judith Félix, Estefanía Díaz-Del Cerro, Beatriz Linillos-Pradillo, Lisa Rancan and Jesús A. F. Tresguerres

Int. J. Mol. Sci. 2024, 25(22), 12288; https://doi.org/10.3390/ijms252212288 - 15 Nov 2024

Cited by 2 | Viewed by 1426

Abstract

Aging is characterized by oxidative stress and immune function impairment, and is associated with increased morbidity. Cannabidiol (CBD) has anti-oxidant properties, but its role in aging has been scarcely studied. This work aims to test the effect of CBD on the redox state [...] Read more.

Aging is characterized by oxidative stress and immune function impairment, and is associated with increased morbidity. Cannabidiol (CBD) has anti-oxidant properties, but its role in aging has been scarcely studied. This work aims to test the effect of CBD on the redox state and immunity during aging in rats. In this study, 15-month-old male Long Evans rats received 10 mg/kg b.w/day of CBD in their diet for 10 weeks and were compared with same-age control and 2-month-old rats serving as a young control group, both following a standard diet. After treatment, they were sacrificed, and the spleen, thymus, and total blood cells were collected. Redox parameters such as glutathione reductase and peroxidase activities, reduced (GSH) and oxidized (GSSG) glutathione concentration, GSSG/GSH ratio, and lipid peroxidation were evaluated. Moreover, immune functions (chemotaxis, natural killer activity, and lymphoproliferation) were analyzed in the spleen. Results show that the 15-month-old control rats exhibited increased oxidative stress and immunosenescence compared to the 2-month-old rats. However, the CBD-treated animals showed higher anti-oxidant defenses, lower oxidants in the spleen, thymus, and blood cells, and better immunity in the spleen than the corresponding age-matched controls. Therefore, CBD administration neutralizes oxidative stress and improves immunity, suggesting it is a strategy for achieving healthy aging. Full article

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24 pages, 1008 KB

Open AccessArticle

Comprehensive Characterization of Anti-HLA and Non-HLA Antibodies in Patients on Kidney Transplant Waiting List and Evaluation of Their Impact on Alloimmunization Risk and Dialysis Treatment

by Aida Mujić Franić, Marko Lilić, Nataša Katalinić and Ljubica Glavaš-Obrovac

Int. J. Mol. Sci. 2024, 25(22), 12103; https://doi.org/10.3390/ijms252212103 - 11 Nov 2024

Cited by 2 | Viewed by 2278

Abstract

Alloimmunization remains a major obstacle to successful kidney transplantation, mainly due to the formation of anti-HLA antibodies. In recent years, non-HLA antibodies have emerged as additional immunologic factors that can potentially contribute to graft rejection. The aim of this study was to investigate [...] Read more.

Alloimmunization remains a major obstacle to successful kidney transplantation, mainly due to the formation of anti-HLA antibodies. In recent years, non-HLA antibodies have emerged as additional immunologic factors that can potentially contribute to graft rejection. The aim of this study was to investigate the prevalence and specificity of both anti-HLA and non-HLA antibodies in patients with end-stage renal disease on a waiting list for kidney transplantation. Serum samples from 74 patients were analyzed using complement-dependent cytotoxicity and solid-phase assays. IgG anti-HLA antibodies were identified in 43.2% of participants, while IgG non-HLA antibodies were detected in 91.9%. The most frequent non-HLA antibodies included anti-ENO1 (28.4%), anti-FIBR1 (23.0%) and anti-PRKCZ (23.0%). A significant difference was found between the number of distinct IgG anti-HLA and IgG non-HLA antibody specificities. However, no significant correlation was found between the number of IgG non-HLA antibody specificities and previous alloimmunization events or dialysis treatments. These results suggest that non-HLA antibodies, although often overlooked, can sometimes play a critical role in transplant outcomes. Routine testing for non-HLA antibodies, in addition to mandatory anti-HLA antibody screening and identification, could improve immunologic risk assessment in transplant patients and post-transplant care. Full article

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14 pages, 1870 KB

Open AccessArticle

Optimization of Basophil Activation Test in the Diagnosis and Qualification for Allergen-Specific Immunotherapy in Children with Respiratory Allergy to the House Dust Mite Dermatophagoides pteronyssinus

by Radoslaw Spiewak, Aleksandra Gregorius, Grzegorz Ostrowski and Ewa Czarnobilska

Int. J. Mol. Sci. 2024, 25(18), 9959; https://doi.org/10.3390/ijms25189959 - 15 Sep 2024

Cited by 2 | Viewed by 2001

Abstract

The aim of this study was to optimize a basophil activation test in the detection of allergy to the house dust mite Dermatophagoides pteronyssinus in children with allergic respiratory diseases. This study involved 32 cases, 13 girls and 19 boys aged 4–17 years, [...] Read more.

The aim of this study was to optimize a basophil activation test in the detection of allergy to the house dust mite Dermatophagoides pteronyssinus in children with allergic respiratory diseases. This study involved 32 cases, 13 girls and 19 boys aged 4–17 years, with perennial asthma or allergic rhinitis caused by D. pteronyssinus. The control group consisted of 13 girls and 19 boys aged 4–17 years with seasonal allergic asthma or rhinitis provoked by Timothy or birch pollen. House dust mite (HDM) allergy was excluded in the controls based on their medical history, skin prick test (SPT) results and sIgE determination. In all patients, a basophil activation test (BAT) was performed with five dilutions of D. pteronyssinus allergen (the dilution series ranged from 22.5 to 0.00225 ng/mL). The results were analyzed by using the receiver operating characteristics (ROC) to determine the optimal allergen concentrations, outcome measures and cut-off points that would differentiate most accurately between HDM-allergic and non-allergic patients. As a “gold standard”, criteria for allergen-specific immunotherapy with D. pteronyssinus or respective pollens were applied by an experienced pediatric allergist following the guidelines of the European Academy of Allergy and Clinical Immunology. The highest diagnostic efficiency was yielded by the protocol assuming a cut-off value of 9.76% activated basophils after activation with a single allergen concentration of 2.25 ng/mL (sensitivity 90.6%, specificity 100%). This protocol yielded 3 (4.7%) misclassifications, all false negative, when compared with the “gold standard”. There was a strong correlation with the BAT results at 22.5, 2.25 and 0.225 ng/mL (respectively r = 0.90 and r = 0.78, p < 0.001), as well as between the BAT at 2.25 ng/mL and SPT (r = 0.82, p < 0.001) and between the SPT and sIgE levels (r = 0.78, p < 0.001). High cross-reactivity between D. pteronyssinus and D. farinae was confirmed based on the BAT at 22.5 ng/mL (r = 0.82, p < 0.001). In conclusion, the BAT showed very good concordance with the result of a meticulous process of decision-making that combined validated allergy tests (SPT, sIgE) with expert guidelines, specialist knowledge and experience. Facing the risk of the incorrect qualification of patients for costly, long-lasting and potentially risky allergen-specific immunotherapy, the inclusion of a basophil activation test into diagnostic process seems fully justified. Full article

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18 pages, 2318 KB

Open AccessArticle

The Archetypal Gamma-Core Motif of Antimicrobial Cys-Rich Peptides Inhibits H⁺-ATPases in Target Pathogens

by María T. Andrés, Nannette Y. Yount, Maikel Acosta-Zaldívar, Michael R. Yeaman and José F. Fierro

Int. J. Mol. Sci. 2024, 25(17), 9672; https://doi.org/10.3390/ijms25179672 - 6 Sep 2024

Cited by 2 | Viewed by 1426

Abstract

Human lactoferrin (hLf) is an innate host defense protein that inhibits microbial H⁺-ATPases. This protein includes an ancestral structural motif (i.e., γ-core motif) intimately associated with the antimicrobial activity of many natural Cys-rich peptides. Peptides containing a complete γ-core motif from [...] Read more.

Human lactoferrin (hLf) is an innate host defense protein that inhibits microbial H⁺-ATPases. This protein includes an ancestral structural motif (i.e., γ-core motif) intimately associated with the antimicrobial activity of many natural Cys-rich peptides. Peptides containing a complete γ-core motif from hLf or other phylogenetically diverse antimicrobial peptides (i.e., afnA, SolyC, PA1b, PvD₁, thanatin) showed microbicidal activity with similar features to those previously reported for hLf and defensins. Common mechanistic characteristics included (1) cell death independent of plasma membrane (PM) lysis, (2) loss of intracellular K⁺ (mediated by Tok1p K⁺ channels in yeast), (3) inhibition of microbicidal activity by high extracellular K⁺, (4) influence of cellular respiration on microbicidal activity, (5) involvement of mitochondrial ATP synthase in yeast cell death processes, and (6) increment of intracellular ATP. Similar features were also observed with the BM2 peptide, a fungal PM H⁺-ATPase inhibitor. Collectively, these findings suggest host defense peptides containing a homologous γ-core motif inhibit PM H⁺-ATPases. Based on this discovery, we propose that the γ-core motif is an archetypal effector involved in the inhibition of PM H⁺-ATPases across kingdoms of life and contributes to the in vitro microbicidal activity of Cys-rich antimicrobial peptides. Full article

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21 pages, 1419 KB

Open AccessReview

Macrophages and Gut Barrier Function: Guardians of Gastrointestinal Health in Post-Inflammatory and Post-Infection Responses

by Edward Xiangtai Meng, George Nicholas Verne and Qiqi Zhou

Int. J. Mol. Sci. 2024, 25(17), 9422; https://doi.org/10.3390/ijms25179422 - 30 Aug 2024

Cited by 12 | Viewed by 3890

Abstract

The gut barrier is essential for protection against pathogens and maintaining homeostasis. Macrophages are key players in the immune system, are indispensable for intestinal health, and contribute to immune defense and repair mechanisms. Understanding the multifaceted roles of macrophages can provide critical insights [...] Read more.

The gut barrier is essential for protection against pathogens and maintaining homeostasis. Macrophages are key players in the immune system, are indispensable for intestinal health, and contribute to immune defense and repair mechanisms. Understanding the multifaceted roles of macrophages can provide critical insights into maintaining and restoring gastrointestinal (GI) health. This review explores the essential role of macrophages in maintaining the gut barrier function and their contribution to post-inflammatory and post-infectious responses in the gut. Macrophages significantly contribute to gut barrier integrity through epithelial repair, immune modulation, and interactions with gut microbiota. They demonstrate active plasticity by switching phenotypes to resolve inflammation, facilitate tissue repair, and regulate microbial populations following an infection or inflammation. In addition, tissue-resident (M2) and infiltration (M1) macrophages convert to each other in gut problems such as IBS and IBD via major signaling pathways mediated by NF-κB, JAK/STAT, PI3K/AKT, MAPK, Toll-like receptors, and specific microRNAs such as miR-155, miR-29, miR-146a, and miR-199, which may be good targets for new therapeutic approaches. Future research should focus on elucidating the detailed molecular mechanisms and developing personalized therapeutic approaches to fully harness the potential of macrophages to maintain and restore intestinal permeability and gut health. Full article

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17 pages, 4384 KB

Open AccessArticle

The Structural Characterization of a Polysaccharide from the Dried Root of Salvia miltiorrhiza and Its Use as a Vaccine Adjuvant to Induce Humoral and Cellular Immune Responses

by Yixuan Zhu, Xiaochen Yang, Pengfei Gu, Xiao Wang, Yongzhan Bao and Wanyu Shi

Int. J. Mol. Sci. 2024, 25(14), 7765; https://doi.org/10.3390/ijms25147765 - 16 Jul 2024

Cited by 4 | Viewed by 1412

Abstract

In order to supplement the research gap concerning Salvia miltiorrhiza polysaccharide extracted from Danshen in NMR analysis, and to clarify its immune enhancement effect as an adjuvant, we isolated and purified SMPD–2, which is composed of nine monosaccharides such as Ara, Gal, and [...] Read more.

In order to supplement the research gap concerning Salvia miltiorrhiza polysaccharide extracted from Danshen in NMR analysis, and to clarify its immune enhancement effect as an adjuvant, we isolated and purified SMPD–2, which is composed of nine monosaccharides such as Ara, Gal, and Glc from Danshen. Its weight average molecular weight was 37.30 ± 0.096 KDa. The main chain was mainly composed of →4)-α-D-Galp-(1→, →3,6)-β-D-Glcp-(1→ and a small amount of α-L-Araf-(1→. After the subcutaneous injection of SMPD–2 as an adjuvant to OVA in mice, we found that it enhanced the immune response by activating DCs from lymph nodes, increasing OVA-specific antibody secretion, stimulating spleen lymphocyte activation, and showing good biosafety. In conclusion, SMPD–2 could be a promising candidate for an adjuvant. Full article

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17 pages, 2165 KB

Open AccessArticle

Serum Vascular Adhesion Protein-1 and Endothelial Dysfunction in Hepatic Cirrhosis: Searching for New Prognostic Markers

by Silvano Fasolato, Emanuela Bonaiuto, Monica Rossetto, Paola Vanzani, Fabio Ceccato, Fabio Vittadello, Lucio Zennaro, Adelio Rigo, Enzo Mammano, Paolo Angeli, Patrizia Pontisso and Maria Luisa Di Paolo

Int. J. Mol. Sci. 2024, 25(13), 7309; https://doi.org/10.3390/ijms25137309 - 3 Jul 2024

Cited by 2 | Viewed by 1949

Abstract

Endothelial dysfunction plays a key role in the development of liver cirrhosis. Among the biomarkers of endothelial dysfunction, the soluble form of Vascular Adhesion Protein-1 (sVAP-1) is an unconventional and less known adhesion molecule endowed also with amine oxidase activity. The aim of [...] Read more.

Endothelial dysfunction plays a key role in the development of liver cirrhosis. Among the biomarkers of endothelial dysfunction, the soluble form of Vascular Adhesion Protein-1 (sVAP-1) is an unconventional and less known adhesion molecule endowed also with amine oxidase activity. The aim of this study was to explore and correlate the behavior of sVAP-1 with that of the soluble vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1) and with the severity of liver cirrhosis. A cross-sectional study was carried out by enrolling 28 controls, 59 cirrhotic patients without hepatocellular carcinoma, and 56 patients with hepatocellular carcinoma (HCC), mainly caused by alcohol abuse. The levels of adhesion molecules and of the pro-inflammatory cytokines (IL-6 and TNF-αα) were determined by immunoassay and the enzymatic activity of sVAP-1 by a fluorometric assay. In non-diabetic patients without HCC, a specific behavior of sVAP-1 was highlighted. Differently from sVCAM-1, sICAM-1, and cytokines, the sVAP-1 level was significantly increased only in the early stage of disease, and then, it decreased in the last stage (866 ± 390 ng/mL vs. 545 ± 316 ng/mL, in Child–Pugh class A vs. C, respectively, p < 0.05). Bivariate analysis correlates sVAP-1 to sVCAM-1, in the absence of HCC (Spearman’s rho = 0.403, p < 0.01). Multiple linear regression analysis revealed that sVCAM-1 appears to be a predictor of sVAP-1 (β coefficient = 0.374, p = 0.021). In conclusion, in non-diabetic and non-HCC cirrhotic patients, sVAP-1 may be a potential prognostic biomarker that, together with sVCAM-1 and pro-inflammatory cytokines, may provide information on the progression of sinusoidal liver endothelium damage. Full article

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17 pages, 919 KB

Open AccessReview

Deciphering Immune Responses to Immunization via Transcriptional Analysis: A Narrative Review of the Current Evidence towards Personalized Vaccination Strategies

by Ioanna Papadatou, Maria Geropeppa, Christina Piperi, Vana Spoulou, Christos Adamopoulos and Athanasios G. Papavassiliou

Int. J. Mol. Sci. 2024, 25(13), 7095; https://doi.org/10.3390/ijms25137095 - 28 Jun 2024

Cited by 1 | Viewed by 1771

Abstract

The development of vaccines has drastically reduced the mortality and morbidity of several diseases. Despite the great success of vaccines, the immunological processes involved in protective immunity are not fully understood and several issues remain to be elucidated. Recently, the advent of high-throughput [...] Read more.

The development of vaccines has drastically reduced the mortality and morbidity of several diseases. Despite the great success of vaccines, the immunological processes involved in protective immunity are not fully understood and several issues remain to be elucidated. Recently, the advent of high-throughput technologies has enabled a more in-depth investigation of the immune system as a whole and the characterization of the interactions of numerous components of immunity. In the field of vaccinology, these tools allow for the exploration of the molecular mechanisms by which vaccines can induce protective immune responses. In this review, we aim to describe current data on transcriptional responses to vaccination, focusing on similarities and differences of vaccine-induced transcriptional responses among vaccines mostly in healthy adults, but also in high-risk populations, such as the elderly and children. Moreover, the identification of potential predictive biomarkers of vaccine immunogenicity, the effect of age on transcriptional response and future perspectives for the utilization of transcriptomics in the field of vaccinology will be discussed. Full article

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14 pages, 4311 KB

Open AccessArticle

A High-Homology Region Provides the Possibility of Detecting β-Barrel Pore-Forming Toxins from Various Bacterial Species

by Alexey S. Nagel, Olesya S. Vetrova, Natalia V. Rudenko, Anna P. Karatovskaya, Anna V. Zamyatina, Zhanna I. Andreeva-Kovalevskaya, Vadim I. Salyamov, Nadezhda A. Egorova, Alexander V. Siunov, Tatiana D. Ivanova, Khanafi M. Boziev, Fedor A. Brovko and Alexander S. Solonin

Int. J. Mol. Sci. 2024, 25(10), 5327; https://doi.org/10.3390/ijms25105327 - 14 May 2024

Cited by 2 | Viewed by 1590

Abstract

The pathogenicity of many bacteria, including Bacillus cereus and Staphylococcus aureus, depends on pore-forming toxins (PFTs), which cause the lysis of host cells by forming pores in the membranes of eukaryotic cells. Bioinformatic analysis revealed a region homologous to the Lys171-Gly250 sequence [...] Read more.

The pathogenicity of many bacteria, including Bacillus cereus and Staphylococcus aureus, depends on pore-forming toxins (PFTs), which cause the lysis of host cells by forming pores in the membranes of eukaryotic cells. Bioinformatic analysis revealed a region homologous to the Lys171-Gly250 sequence in hemolysin II (HlyII) from B. cereus in over 600 PFTs, which we designated as a “homologous peptide”. Three β-barrel PFTs were used for a detailed comparative analysis. Two of them—HlyII and cytotoxin K2 (CytK2)—are synthesized in Bacillus cereus sensu lato; the third, S. aureus α-toxin (Hla), is the most investigated representative of the family. Protein modeling showed certain amino acids of the homologous peptide to be located on the surface of the monomeric forms of these β-barrel PFTs. We obtained monoclonal antibodies against both a cloned homologous peptide and a 14-membered synthetic peptide, DSFNTFYGNQLFMK, as part of the homologous peptide. The HlyII, CytK2, and Hla regions recognized by the obtained antibodies, as well as an antibody capable of suppressing the hemolytic activity of CytK2, were identified in the course of this work. Antibodies capable of recognizing PFTs of various origins can be useful tools for both identification and suppression of the cytolytic activity of PFTs. Full article

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18 pages, 3661 KB

Open AccessArticle

The Effects of Caloric Restriction on Inflammatory Targets in the Prostates of Aged Rats

by Vittoria Rago, Francesco Conforti, Daniele La Russa, Gemma Antonucci, Lidia Urlandini, Danilo Lofaro, Sabrina Bossio, Maurizio Mandalà, Daniela Pellegrino, Antonio Aversa, Silvia Di Agostino and Anna Perri

Int. J. Mol. Sci. 2024, 25(10), 5236; https://doi.org/10.3390/ijms25105236 - 11 May 2024

Cited by 2 | Viewed by 2267

Abstract

Numerous animal models have demonstrated that caloric restriction (CR) is an excellent tool to delay aging and increase the quality of life, likely because it counteracts age-induced oxidative stress and inflammation. The aging process can affect the prostate in three ways: the onset [...] Read more.

Numerous animal models have demonstrated that caloric restriction (CR) is an excellent tool to delay aging and increase the quality of life, likely because it counteracts age-induced oxidative stress and inflammation. The aging process can affect the prostate in three ways: the onset of benign prostatic hyperplasia, prostatitis, and prostate cancer. In this study, we used 14 aged male Sprague Dawley rats, which were allocated into two groups, at the age of 18 months old. One group was fed ad libitum (a normal diet (ND)), and the other group followed a caloric restriction diet with a 60% decrease in intake. The rats were sacrificed at the age of 24 months. By immunohistochemical (IHC) and Western blot (WB) analyses, we studied the variations between the two groups in immune inflammation and fibrosis-related markers in aged prostate tissues. Morphological examinations showed lower levels of prostatic hyperplasia and fibrosis in the CR rats vs. the ND rats. The IHC results revealed that the prostates of the CR rats exhibited a lower immune proinflammatory infiltrate level and a reduced expression of the NLRP3 inflammasome pathway, together with significantly reduced expressions of mesenchymal markers and the profibrotic factor TGFβ1. Finally, by WB analysis, we observed a reduced expression of ERα, which is notoriously implicated in prostate stromal proliferation, and increased expressions of SOD1 and Hsp70, both exerting protective effects against oxidative stress. Overall, these data suggest that CR brings potential benefits to prostatic tissues as it reduces the physiological immune–inflammatory processes and the tissue remodeling caused by aging. Full article

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16 pages, 528 KB

Open AccessArticle

Insight into the Interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in IgA Vasculitis (IgAV)

by Martina Held, Ana Kozmar, Mario Sestan, Daniel Turudic, Nastasia Kifer, Sasa Srsen, Alenka Gagro, Marijan Frkovic and Marija Jelusic

Int. J. Mol. Sci. 2024, 25(8), 4383; https://doi.org/10.3390/ijms25084383 - 16 Apr 2024

Cited by 5 | Viewed by 1814

Abstract

The pathogenesis of IgAV, the most common systemic vasculitis in childhood, appears to be complex and requires further elucidation. We aimed to investigate the potential role of galactose-deficient immunoglobulin A1 (Gd-IgA1), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE) [...] Read more.

The pathogenesis of IgAV, the most common systemic vasculitis in childhood, appears to be complex and requires further elucidation. We aimed to investigate the potential role of galactose-deficient immunoglobulin A1 (Gd-IgA1), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE) and protocadherin 1 (PCDH1) in the pathogenesis of IgAV. Our prospective study enrolled 86 patients with IgAV and 70 controls. HMGB1, RAGE, Gd-IgA1 and PCDH1 in serum and urine were determined by the enzyme-linked immunosorbent assay (ELISA) method at the onset of the disease and after a six-month interval in patients and once in the control group. Serum concentrations of HMGB1, RAGE and PCDH1 and urinary concentrations of HMGB1, RAGE, Gd-IgA1 and PCDH1 were significantly higher in patients with IgAV than in the control group (p < 0.001). Concentrations of HMGB1 (5573 pg/mL vs. 3477 pg/mL vs. 1088 pg/mL, p < 0.001) and RAGE (309 pg/mL vs. 302.4 pg/mL vs. 201.3 pg/mL, p = 0.012) in the serum of patients remained significantly elevated when the disease onset was compared with the six-month follow-up interval, and thus could be a potential marker of disease activity. Urinary concentration of HMGB1 measured in the follow-up period was higher in patients with nephritis compared to IgAV without nephritis (270.9 (146.7–542.7) ng/mmol vs. 133.2 (85.9–318.6) ng/mmol, p = 0.049) and significantly positively correlated with the urine albumine to creatinine ratio (τ = 0.184, p < 0.05), the number of erythrocytes in urine samples (τ = 0.193, p < 0.05) and with the outcome of nephritis (τ = 0.287, p < 0.05); therefore, HMGB1 could be a potential tool for monitoring patients with IgAV who develop nephritis. Taken together, our results imply a possible interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in the development of IgAV. The identification of sensitive biomarkers in IgAV may provide disease prevention and future therapeutics. Full article

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16 pages, 4395 KB

Open AccessArticle

Complement MASP-1 Modifies Endothelial Wound Healing

by Zsuzsanna Németh, Flóra Demeter, József Dobó, Péter Gál and László Cervenak

Int. J. Mol. Sci. 2024, 25(7), 4048; https://doi.org/10.3390/ijms25074048 - 5 Apr 2024

Cited by 3 | Viewed by 1652

Abstract

Endothelial wound-healing processes are fundamental for the maintenance and restoration of the circulatory system and are greatly affected by the factors present in the blood. We have previously shown that the complement protein mannan-binding lectin-associated serine protease-1 (MASP-1) induces the proinflammatory activation of [...] Read more.

Endothelial wound-healing processes are fundamental for the maintenance and restoration of the circulatory system and are greatly affected by the factors present in the blood. We have previously shown that the complement protein mannan-binding lectin-associated serine protease-1 (MASP-1) induces the proinflammatory activation of endothelial cells and is able to cooperate with other proinflammatory activators. Our aim was to investigate the combined effect of mechanical wounding and MASP-1 on endothelial cells. Transcriptomic analysis showed that MASP-1 alters the expression of wound-healing-related and angiogenesis-related genes. Both wounding and MASP-1 induced Ca²⁺ mobilization when applied individually. However, MASP-1-induced Ca²⁺ mobilization was inhibited when the treatment was preceded by wounding. Mechanical wounding promoted CREB phosphorylation, and the presence of MASP-1 enhanced this effect. Wounding induced ICAM-1 and VCAM-1 expression on endothelial cells, and MASP-1 pretreatment further increased VCAM-1 levels. MASP-1 played a role in the subsequent stages of angiogenesis, facilitating the breakdown of the endothelial capillary network on Matrigel^®. Our findings extend our general understanding of endothelial wound healing and highlight the importance of complement MASP-1 activation in wound-healing processes. Full article

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2023

Jump to: 2025, 2024, 2022

16 pages, 6432 KB

Open AccessArticle

Teleost Eye Is the Portal of IHNV Entry and Contributes to a Robust Mucosal Immune Response

by Xinyou Wang, Guangyi Ding, Peng Yang, Gaofeng Cheng, Weiguang Kong and Zhen Xu

Int. J. Mol. Sci. 2024, 25(1), 160; https://doi.org/10.3390/ijms25010160 - 21 Dec 2023

Cited by 2 | Viewed by 1788

Abstract

The ocular mucosa (OM) is an important and unique part of the vertebrate mucosal immune system. The OM plays an important role in maintaining visual function and defending against foreign antigens or microorganisms, while maintaining a balance between the two through complex regulatory [...] Read more.

The ocular mucosa (OM) is an important and unique part of the vertebrate mucosal immune system. The OM plays an important role in maintaining visual function and defending against foreign antigens or microorganisms, while maintaining a balance between the two through complex regulatory mechanisms. However, the function of ocular mucosal defense against foreign pathogens and mucosal immune response in bony fish are still less studied. To acquire deeper understanding into the mucosal immunity of the OM in teleost fish, we established a study of the immune response of rainbow trout (Oncorhynchus mykiss) infected with the infectious hematopoietic necrosis virus (IHNV). Our findings revealed that IHNV could successfully infiltrate the trout’s OM, indicating that the OM could be an important portal for the IHNV. Furthermore, qPCR and RNA-Seq analysis results showed that a large number of immune-related genes were significantly upregulated in the OM of trout with IHNV infection. Critically, the results of our RNA-Seq analysis demonstrated that viral infection triggered a robust immune response, as evidenced by the substantial induction of antiviral, innate, and adaptive immune-related genes in the OM of infected fish, which underscored the essential role of the OM in viral infection. Overall, our findings revealed a previously unknown function of teleost OM in antiviral defense, and provided a theoretical basis for the study of the mucosal immunity of fish. Full article

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15 pages, 1718 KB

Open AccessArticle

RNF138 Downregulates Antiviral Innate Immunity by Inhibiting IRF3 Activation

by Xianhuang Zeng, Chaozhi Liu, Jinhao Fan, Jiabin Zou, Mingxiong Guo and Guihong Sun

Int. J. Mol. Sci. 2023, 24(22), 16110; https://doi.org/10.3390/ijms242216110 - 9 Nov 2023

Cited by 4 | Viewed by 1966

Abstract

A viral infection activates the transcription factors IRF3 and NF-κB, which synergistically induces type I interferons (IFNs). Here, we identify the E3 ubiquitin ligase RNF138 as an important negative regulator of virus-triggered IRF3 activation and IFN-β induction. The overexpression of RNF138 inhibited the [...] Read more.

A viral infection activates the transcription factors IRF3 and NF-κB, which synergistically induces type I interferons (IFNs). Here, we identify the E3 ubiquitin ligase RNF138 as an important negative regulator of virus-triggered IRF3 activation and IFN-β induction. The overexpression of RNF138 inhibited the virus-induced activation of IRF3 and the transcription of the IFNB1 gene, whereas the knockout of RNF138 promoted the virus-induced activation of IRF3 and transcription of the IFNB1 gene. We further found that RNF138 promotes the ubiquitination of PTEN and subsequently inhibits PTEN interactions with IRF3, which is essential for the PTEN-mediated nuclear translocation of IRF3, thereby inhibiting IRF3 import into the nucleus. Our findings suggest that RNF138 negatively regulates virus-triggered signaling by inhibiting the interaction of PTEN with IRF3, and these data provide new insights into the molecular mechanisms of cellular antiviral responses. Full article

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18 pages, 1353 KB

Open AccessReview

Fecal Microbiota Transplantation in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

by Parnian Jamshidi, Yeganeh Farsi, Zahra Nariman, Mohammad Reza Hatamnejad, Benyamin Mohammadzadeh, Hossein Akbarialiabad, Mohammad Javad Nasiri and Leonardo A. Sechi

Int. J. Mol. Sci. 2023, 24(19), 14562; https://doi.org/10.3390/ijms241914562 - 26 Sep 2023

Cited by 16 | Viewed by 4721

Abstract

Irritable bowel syndrome (IBS) poses a significant challenge due to its poorly understood pathogenesis, substantial morbidity, and often inadequate treatment outcomes. The role of fecal microbiota transplantation (FMT) in managing IBS symptoms remains inconclusive. This systematic review and meta-analysis aimed to ascertain the [...] Read more.

Irritable bowel syndrome (IBS) poses a significant challenge due to its poorly understood pathogenesis, substantial morbidity, and often inadequate treatment outcomes. The role of fecal microbiota transplantation (FMT) in managing IBS symptoms remains inconclusive. This systematic review and meta-analysis aimed to ascertain the effectiveness of FMT in relieving symptoms in IBS patients. A thorough search was executed on PubMed/Medline and Embase databases until 14 June 2023, including all studies on FMT use in IBS patients. We examined the efficiency of FMT in reducing patients’ symptoms overall and in particular subgroups, classified by placebo preparation, FMT preparation, frequency, and route of administration. Among 1015 identified studies, seven met the inclusion criteria for the meta-analysis. The overall symptomatology of FMT-treated IBS patients did not significantly differ from the control group (Odds Ratio (OR) = 0.99, 95% Confidence Interval (CI) 0.39–2.5). Multiple doses of FMT compared with non-FMT placebo, or single-donor FMT therapy compared with autologous FMT placebo also showed no significant benefit (OR = 0.32, 95%CI (0.07–1.32), p = 0.11, and OR = 1.67, 95%CI (0.59–4.67), p = 0.32, respectively). However, a single dose of multiple-donor FMT administered via colonoscopy (lower gastrointestinal (GI) administration) significantly improved patient symptoms compared with autologous FMT placebo (OR = 2.54, 95%CI (1.20–5.37), p = 0.01, and OR = 2.2, 95%CI (1.20–4.03), p = 0.01, respectively). The studies included in the analysis showed a low risk of bias and no publication bias. In conclusion, lower GI administration of a single dose of multiple-donor FMT significantly alleviates patient complaints compared with the autologous FMT used as a placebo. The underlying mechanisms need to be better understood, and further experimental studies are desired to fill the current gaps. Full article

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16 pages, 10241 KB

Open AccessArticle

Immune Activation and Inflammatory Response Mediated by the NOD/Toll-like Receptor Signaling Pathway—The Potential Mechanism of Bullfrog (Lithobates catesbeiana) Meningitis Caused by Elizabethkingia miricola

by Fulong Li, Baipeng Chen, Ming Xu, Yang Feng, Yongqiang Deng, Xiaoli Huang, Yi Geng, Ping Ouyang and Defang Chen

Int. J. Mol. Sci. 2023, 24(19), 14554; https://doi.org/10.3390/ijms241914554 - 26 Sep 2023

Cited by 7 | Viewed by 2158

Abstract

Elizabethkingia miricola is an emerging opportunistic pathogen that is highly pathogenic in both immunocompromised humans and animals. Once the disease occurs, treatment can be very difficult. Therefore, a deep understanding of the pathological mechanism of Elizabethkingia miricola is the key to the prevention [...] Read more.

Elizabethkingia miricola is an emerging opportunistic pathogen that is highly pathogenic in both immunocompromised humans and animals. Once the disease occurs, treatment can be very difficult. Therefore, a deep understanding of the pathological mechanism of Elizabethkingia miricola is the key to the prevention and control of the disease. In this study, we isolated the pathogenic bacteria from bullfrogs with dark skin color, weak limbs, wryneck, and cataracts. Via subsequent morphological observations and a 16S rRNA gene sequence analysis, the pathogen was identified as Elizabethkingia miricola. The histopathological and transmission electron microscopy analysis revealed that the brain was the main target organ. Therefore, brain samples from diseased and healthy bullfrogs were used for the RNA-Seq analysis. The comparative transcriptome analysis revealed that the diseased bullfrog brain was characterized by the immune activation and inflammatory response, which were mediated by the “NOD-like receptor signaling pathway” and the “Toll-like receptor signaling pathway”. We also performed qRT-PCR to examine the expression profile of inflammation-related genes, which further verified the reliability of our transcriptome data. Based on the above results, it was concluded that the NOD/Toll-like receptor-related networks that dominate the immune activation and inflammatory response were activated in the brain of Elizabethkingia miricola-infected bullfrogs. This study contributes to the search for therapeutic targets for bullfrog meningitis and provides basic information for establishing effective measures to prevent and control bullfrog meningitis. Full article

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20 pages, 1491 KB

Open AccessReview

Lupus Nephritis Risk Factors and Biomarkers: An Update

by Yves Renaudineau, Wesley Brooks and Julie Belliere

Int. J. Mol. Sci. 2023, 24(19), 14526; https://doi.org/10.3390/ijms241914526 - 25 Sep 2023

Cited by 23 | Viewed by 8950

Abstract

Lupus nephritis (LN) represents the most severe organ manifestation of systemic lupus erythematosus (SLE) in terms of morbidity and mortality. To reduce these risks, tremendous efforts have been made in the last decade to characterize the different steps of the disease and to [...] Read more.

Lupus nephritis (LN) represents the most severe organ manifestation of systemic lupus erythematosus (SLE) in terms of morbidity and mortality. To reduce these risks, tremendous efforts have been made in the last decade to characterize the different steps of the disease and to develop biomarkers in order to better (i) unravel the pre-SLE stage (e.g., anti-nuclear antibodies and interferon signature); (ii) more timely initiation of therapy by improving early and accurate LN diagnosis (e.g., pathologic classification was revised); (iii) monitor disease activity and therapeutic response (e.g., recommendation to re-biopsy, new urinary biomarkers); (iv) prevent disease flares (e.g., serologic and urinary biomarkers); (v) mitigate the deterioration in the renal function; and (vi) reduce side effects with new therapeutic guidelines and novel therapies. However, progress is poor in terms of improvement with early death attributed to active SLE or infections, while later deaths are related to the chronicity of the disease and the use of toxic therapies. Consequently, an individualized treat-to-target strategy is mandatory, and for that, there is an unmet need to develop a set of accurate biomarkers to be used as the standard of care and adapted to each stage of the disease. Full article

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11 pages, 1512 KB

Open AccessArticle

A dePEGylated Lipopeptide-Based Pan-Coronavirus Fusion Inhibitor Exhibits Potent and Broad-Spectrum Anti-HIV-1 Activity without Eliciting Anti-PEG Antibodies

by Ling Xu, Chao Wang, Wei Xu, Lixiao Xing, Jie Zhou, Jing Pu, Mingming Fu, Lu Lu, Shibo Jiang and Qian Wang

Int. J. Mol. Sci. 2023, 24(11), 9779; https://doi.org/10.3390/ijms24119779 - 5 Jun 2023

Cited by 2 | Viewed by 2302

Abstract

We previously identified a lipopeptide, EK1C4, by linking cholesterol to EK1, a pan-CoV fusion inhibitory peptide via a polyethylene glycol (PEG) linker, which showed potent pan-CoV fusion inhibitory activity. However, PEG can elicit antibodies to PEG in vivo, which will attenuate its antiviral [...] Read more.

We previously identified a lipopeptide, EK1C4, by linking cholesterol to EK1, a pan-CoV fusion inhibitory peptide via a polyethylene glycol (PEG) linker, which showed potent pan-CoV fusion inhibitory activity. However, PEG can elicit antibodies to PEG in vivo, which will attenuate its antiviral activity. Therefore, we designed and synthesized a dePEGylated lipopeptide, EKL1C, by replacing the PEG linker in EK1C4 with a short peptide. Similar to EK1C4, EKL1C displayed potent inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses. In this study, we found that EKL1C also exhibited broad-spectrum fusion inhibitory activity against human immunodeficiency virus type 1 (HIV-1) infection by interacting with the N-terminal heptad repeat 1 (HR1) of viral gp41 to block six-helix bundle (6-HB) formation. These results suggest that HR1 is a common target for the development of broad-spectrum viral fusion inhibitors and EKL1C has potential clinical application as a candidate therapeutic or preventive agent against infection by coronavirus, HIV-1, and possibly other class I enveloped viruses. Full article

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20 pages, 12436 KB

Open AccessArticle

Repetitive Cerulein-Induced Chronic Pancreatitis in Growing Pigs—A Pilot Study

by Ewa Tomaszewska, Małgorzata Świątkiewicz, Siemowit Muszyński, Janine Donaldson, Katarzyna Ropka-Molik, Marcin B. Arciszewski, Maciej Murawski, Tomasz Schwarz, Piotr Dobrowolski, Sylwia Szymańczyk, Sławomir Dresler and Joanna Bonior

Int. J. Mol. Sci. 2023, 24(9), 7715; https://doi.org/10.3390/ijms24097715 - 23 Apr 2023

Cited by 7 | Viewed by 3299

Abstract

Chronic pancreatitis (CP) is an irreversible and progressive inflammatory disease. Knowledge on the development and progression of CP is limited. The goal of the study was to define the serum profile of pro-inflammatory cytokines and the cell antioxidant defense system (superoxidase dismutase—SOD, and [...] Read more.

Chronic pancreatitis (CP) is an irreversible and progressive inflammatory disease. Knowledge on the development and progression of CP is limited. The goal of the study was to define the serum profile of pro-inflammatory cytokines and the cell antioxidant defense system (superoxidase dismutase—SOD, and reduced glutathione—GSH) over time in a cerulein-induced CP model and explore the impact of these changes on selected cytokines in the intestinal mucosa and pancreatic tissue, as well as on selected serum biochemical parameters. The mRNA expression of CLDN1 and CDH1 genes, and levels of Claudin-1 and E-cadherin, proteins of gut barrier, in the intestinal mucosa were determined via western blot analysis. The study showed moderate pathomorphological changes in the pigs’ pancreas 43 days after the last cerulein injection. Blood serum levels of interleukin (IL)-1-beta, IL-6, tumor necrosis factor alpha (TNF-alpha), C-reactive protein (CRP), lactate dehydrogenase (LDH), gamma-glutamyl transpeptidase (GGTP), SOD and GSH were increased following cerulein injections. IL-1-beta, IL-6, TNF-alpha and GSH were also increased in jejunal mucosa and pancreatic tissue. In duodenum, decreased mRNA expression of CDH1 and level of E-cadherin and increased D-lactate, an indicator of leaky gut, indicating an inflammatory state, were observed. Based on the current results, we can conclude that repetitive cerulein injections in growing pigs not only led to CP over time, but also induced inflammation in the intestine. As a result of the inflammation, the intestinal barrier was impaired. Full article

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20 pages, 3941 KB

Open AccessArticle

Integrative Analysis of Single-Cell and Bulk Sequencing Data Depicting the Expression and Function of P2ry12 in Microglia Post Ischemia–Reperfusion Injury

by Chenglong Wang, Li Peng, Yuan Wang, Ying Xue, Tianyi Chen, Yanyan Ji, Yishan Li, Yong Zhao and Shanshan Yu

Int. J. Mol. Sci. 2023, 24(7), 6772; https://doi.org/10.3390/ijms24076772 - 5 Apr 2023

Cited by 2 | Viewed by 3216

Abstract

P2ry12 is a microglial marker gene. Recently, increasing evidence has demonstrated that its expression levels can vary in response to different CNS disorders and can affect microglial functions, such as polarization, plasticity, and migration. However, the expression and function of P2ry12 in microglia [...] Read more.

P2ry12 is a microglial marker gene. Recently, increasing evidence has demonstrated that its expression levels can vary in response to different CNS disorders and can affect microglial functions, such as polarization, plasticity, and migration. However, the expression and function of P2ry12 in microglia during ischemia–reperfusion injury (IRI) remain unclear. Here, we developed a computational method to obtain microglia-specific P2ry12 genes (MSPGs) using sequencing data associated with IRI. We evaluated the change in comprehensive expression levels of MSPGs during IRI and compared it to the expression of P2ry12 to determine similarity. Subsequently, the MSPGs were used to explore the P2ry12 functions in microglia through bioinformatics. Moreover, several animal experiments were also conducted to confirm the reliability of the results. The expression of P2ry12 was observed to decrease gradually within 24 h post injury. In response, microglia with reduced P2ry12 expression showed an increase in the expression of one receptor-encoding gene (Flt1) and three ligand-encoding genes (Nampt, Igf1, and Cxcl2). Furthermore, double-labeling immunofluorescence staining revealed that inhibition of P2ry12 blocked microglial migration towards vessels during IRI. Overall, we employ a combined computational and experimental approach to successfully explore P2ry12 expression and function in microglia during IRI. Full article

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17 pages, 2274 KB

Open AccessArticle

HED, a Human-Engineered Domain, Confers a Unique Fc-Binding Activity to Produce a New Class of Humanized Antibody-like Molecules

by Zhiqiang Zhu, Peeyush N. Goel, Cai Zheng, Yasuhiro Nagai, Lian Lam, Arabinda Samanta, Meiqing Ji, Hongtao Zhang and Mark I. Greene

Int. J. Mol. Sci. 2023, 24(7), 6477; https://doi.org/10.3390/ijms24076477 - 30 Mar 2023

Viewed by 2471

Abstract

Our laboratory has identified and developed a unique human-engineered domain (HED) structure that was obtained from the human Alpha-2-macroglobulin receptor-associated protein based on the three-dimensional structure of the Z-domain derived from Staphylococcal protein A. This HED retains µM binding activity to the human [...] Read more.

Our laboratory has identified and developed a unique human-engineered domain (HED) structure that was obtained from the human Alpha-2-macroglobulin receptor-associated protein based on the three-dimensional structure of the Z-domain derived from Staphylococcal protein A. This HED retains µM binding activity to the human IgG1CH2-CH3 elbow region. We determined the crystal structure of HED in association with IgG1’s Fc. This demonstrated that HED preserves the same three-bundle helix structure and Fc-interacting residues as the Z domain. HED was fused to the single chain variable fragment (scFv) of mAb 4D5 to produce an antibody-like protein capable of interacting with the p185Her2/neu ectodomain and the Fc of IgG. When further fused with murine IFN-γ (mIFN-γ) at the carboxy terminus, the novel species exhibited antitumor efficacy in vivo in a mouse model of human breast cancer. The HED is a novel platform for the therapeutic utilization of engineered proteins to alleviate human disease. Full article

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17 pages, 2512 KB

Open AccessReview

Inflammation and Organ Injury the Role of Substance P and Its Receptors

by Zhixing Zhu and Madhav Bhatia

Int. J. Mol. Sci. 2023, 24(7), 6140; https://doi.org/10.3390/ijms24076140 - 24 Mar 2023

Cited by 13 | Viewed by 4488

Abstract

Tightly controlled inflammation is an indispensable mechanism in the maintenance of cellular and organismal homeostasis in living organisms. However, aberrant inflammation is detrimental and has been suggested as a key contributor to organ injury with different etiologies. Substance P (SP) is a neuropeptide [...] Read more.

Tightly controlled inflammation is an indispensable mechanism in the maintenance of cellular and organismal homeostasis in living organisms. However, aberrant inflammation is detrimental and has been suggested as a key contributor to organ injury with different etiologies. Substance P (SP) is a neuropeptide with a robust effect on inflammation. The proinflammatory effects of SP are achieved by activating its functional receptors, namely the neurokinin 1 receptor (NK1R) receptor and mas-related G protein-coupled receptors X member 2 (MRGPRX2) and its murine homolog MRGPRB2. Upon activation, the receptors further signal to several cellular signaling pathways involved in the onset, development, and progression of inflammation. Therefore, excessive SP–NK1R or SP–MRGPRX2/B2 signals have been implicated in the pathogenesis of inflammation-associated organ injury. In this review, we summarize our current knowledge of SP and its receptors and the emerging roles of the SP–NK1R system and the SP–MRGPRX2/B2 system in inflammation and injury in multiple organs resulting from different pathologies. We also briefly discuss the prospect of developing a therapeutic strategy for inflammatory organ injury by disrupting the proinflammatory actions of SP via pharmacological intervention. Full article

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22 pages, 753 KB

Open AccessReview

How Does Vitamin D Affect Immune Cells Crosstalk in Autoimmune Diseases?

by Daniela Gallo, Denisa Baci, Natasa Kustrimovic, Nicola Lanzo, Bohdan Patera, Maria Laura Tanda, Eliana Piantanida and Lorenzo Mortara

Int. J. Mol. Sci. 2023, 24(5), 4689; https://doi.org/10.3390/ijms24054689 - 28 Feb 2023

Cited by 31 | Viewed by 10311

Abstract

Vitamin D is a secosteroid hormone that is highly involved in bone health. Mounting evidence revealed that, in addition to the regulation of mineral metabolism, vitamin D is implicated in cell proliferation and differentiation, vascular and muscular functions, and metabolic health. Since the [...] Read more.

Vitamin D is a secosteroid hormone that is highly involved in bone health. Mounting evidence revealed that, in addition to the regulation of mineral metabolism, vitamin D is implicated in cell proliferation and differentiation, vascular and muscular functions, and metabolic health. Since the discovery of vitamin D receptors in T cells, local production of active vitamin D was demonstrated in most immune cells, addressing the interest in the clinical implications of vitamin D status in immune surveillance against infections and autoimmune/inflammatory diseases. T cells, together with B cells, are seen as the main immune cells involved in autoimmune diseases; however, growing interest is currently focused on immune cells of the innate compartment, such as monocytes, macrophages, dendritic cells, and natural killer cells in the initiation phases of autoimmunity. Here we reviewed recent advances in the onset and regulation of Graves’ and Hashimoto’s thyroiditis, vitiligo, and multiple sclerosis in relation to the role of innate immune cells and their crosstalk with vitamin D and acquired immune cells. Full article

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18 pages, 3975 KB

Open AccessArticle

Zebrafish HERC7c Acts as an Inhibitor of Fish IFN Response

by Yi-Lin Li, Xiu-Ying Gong, Zi-Ling Qu, Xiang Zhao, Cheng Dan, Hao-Yu Sun, Li-Li An, Jian-Fang Gui and Yi-Bing Zhang

Int. J. Mol. Sci. 2023, 24(5), 4592; https://doi.org/10.3390/ijms24054592 - 27 Feb 2023

Cited by 4 | Viewed by 3019

Abstract

In humans, four small HERCs (HERC3-6) exhibit differential degrees of antiviral activity toward HIV-1. Recently we revealed a novel member HERC7 of small HERCs exclusively in non-mammalian vertebrates and varied copies of herc7 genes in distinct fish species, raising a question of what [...] Read more.

In humans, four small HERCs (HERC3-6) exhibit differential degrees of antiviral activity toward HIV-1. Recently we revealed a novel member HERC7 of small HERCs exclusively in non-mammalian vertebrates and varied copies of herc7 genes in distinct fish species, raising a question of what is the exact role for a certain fish herc7 gene. Here, a total of four herc7 genes (named HERC7a–d sequentially) are identified in the zebrafish genome. They are transcriptionally induced by a viral infection, and detailed promoter analyses indicate that zebrafish herc7c is a typical interferon (IFN)-stimulated gene. Overexpression of zebrafish HERC7c promotes SVCV (spring viremia of carp virus) replication in fish cells and concomitantly downregulates cellular IFN response. Mechanistically, zebrafish HERC7c targets STING, MAVS, and IRF7 for protein degradation, thus impairing cellular IFN response. Whereas the recently-identified crucian carp HERC7 has an E3 ligase activity for the conjugation of both ubiquitin and ISG15, zebrafish HERC7c only displays the potential to transfer ubiquitin. Considering the necessity for timely regulation of IFN expression during viral infection, these results together suggest that zebrafish HERC7c is a negative regulator of fish IFN antiviral response. Full article

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14 pages, 2495 KB

Open AccessArticle

Co-Transplantation of Barcoded Lymphoid-Primed Multipotent (LMPP) and Common Lymphocyte (CLP) Progenitors Reveals a Major Contribution of LMPP to the Lymphoid Lineage

by Victoria Michaels, Smahane Chalabi, Agnes Legrand, Julie Renard, Emmanuel Tejerina, Marina Daouya, Sylvie Fabrega, Jérôme Megret, Robert Olaso, Anne Boland, Jean-François Deleuze, Christophe Battail, Diana Tronik-Le Roux and Sophie Ezine

Int. J. Mol. Sci. 2023, 24(5), 4368; https://doi.org/10.3390/ijms24054368 - 22 Feb 2023

Viewed by 3057

Abstract

T cells have the potential to maintain immunological memory and self-tolerance by recognizing antigens from pathogens or tumors. In pathological situations, failure to generate de novo T cells causes immunodeficiency resulting in acute infections and complications. Hematopoietic stem cells (HSC) transplantation constitutes a [...] Read more.

T cells have the potential to maintain immunological memory and self-tolerance by recognizing antigens from pathogens or tumors. In pathological situations, failure to generate de novo T cells causes immunodeficiency resulting in acute infections and complications. Hematopoietic stem cells (HSC) transplantation constitutes a valuable option to restore proper immune function. However, delayed T cell reconstitution is observed compared to other lineages. To overcome this difficulty, we developed a new approach to identify populations with efficient lymphoid reconstitution properties. To this end, we use a DNA barcoding strategy based on the insertion into a cell chromosome of a lentivirus (LV) carrying a non-coding DNA fragment named barcode (BC). These will segregate through cell divisions and be present in cells’ progeny. The remarkable characteristic of the method is that different cell types can be tracked simultaneously in the same mouse. Thus, we in vivo barcoded LMPP and CLP progenitors to test their ability to reconstitute the lymphoid lineage. Barcoded progenitors were co-grafted in immuno-compromised mice and their fate analyzed by evaluating the BC composition in transplanted mice. The results highlight the predominant role of LMPP progenitors for lymphoid generation and reveal valuable novel insights to be reconsidered in clinical transplantation assays. Full article

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13 pages, 1403 KB

Open AccessReview

Alzheimer’s Disease: A Brief History of Immunotherapies Targeting Amyloid β

by Anne-Cathrine S. Vogt, Gary T. Jennings, Mona O. Mohsen, Monique Vogel and Martin F. Bachmann

Int. J. Mol. Sci. 2023, 24(4), 3895; https://doi.org/10.3390/ijms24043895 - 15 Feb 2023

Cited by 52 | Viewed by 13491

Abstract

Alzheimer’s disease (AD) is the most common form of dementia and may contribute to 60–70% of cases. Worldwide, around 50 million people suffer from dementia and the prediction is that the number will more than triple by 2050, as the population ages. Extracellular [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia and may contribute to 60–70% of cases. Worldwide, around 50 million people suffer from dementia and the prediction is that the number will more than triple by 2050, as the population ages. Extracellular protein aggregation and plaque deposition as well as accumulation of intracellular neurofibrillary tangles, all leading to neurodegeneration, are the hallmarks of brains with Alzheimer’s disease. Therapeutic strategies including active and passive immunizations have been widely explored in the last two decades. Several compounds have shown promising results in many AD animal models. To date, only symptomatic treatments are available and because of the alarming epidemiological data, novel therapeutic strategies to prevent, mitigate, or delay the onset of AD are required. In this mini-review, we focus on our understanding of AD pathobiology and discuss current active and passive immunomodulating therapies targeting amyloid-β protein. Full article

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19 pages, 2074 KB

Open AccessArticle

Hyperoxidized Species of Heme Have a Potent Capacity to Induce Autoreactivity of Human IgG Antibodies

by Marie Wiatr, Maya Hadzhieva, Maxime Lecerf, Rémi Noé, Sune Justesen, Sébastien Lacroix-Desmazes, Marie-Agnès Dragon-Durey and Jordan D. Dimitrov

Int. J. Mol. Sci. 2023, 24(4), 3416; https://doi.org/10.3390/ijms24043416 - 8 Feb 2023

Cited by 1 | Viewed by 2384

Abstract

The interaction of some human antibodies with heme results in posttranslational acquisition of binding to various self- and pathogen-derived antigens. The previous studies on this phenomenon were performed with oxidized heme (Fe³⁺). In the present study, we elucidated the effect of [...] Read more.

The interaction of some human antibodies with heme results in posttranslational acquisition of binding to various self- and pathogen-derived antigens. The previous studies on this phenomenon were performed with oxidized heme (Fe³⁺). In the present study, we elucidated the effect of other pathologically relevant species of heme, i.e., species that were formed after contact of heme with oxidizing agents such as hydrogen peroxide, situations in which heme’s iron could acquire higher oxidation states. Our data reveal that hyperoxidized species of heme have a superior capacity to heme (Fe³⁺) in triggering the autoreactivity of human IgG. Mechanistic studies demonstrated that oxidation status of iron was of critical importance for the heme’s effect on antibodies. We also demonstrated that hyperoxidized heme species interacted at higher affinities with IgG and that this binding occurred through a different mechanism as compared to heme (Fe³⁺). Regardless of their profound functional impact on the antigen-binding properties of antibodies, hyperoxidized species of heme did not affect Fc-mediated functions of IgG, such as binding to the neonatal Fc receptor. The obtained data contribute to a better understanding of the pathophysiological mechanism of hemolytic diseases and of the origin of elevated antibody autoreactivity in patients with some hemolytic disorders. Full article

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12 pages, 717 KB

Open AccessReview

Role of Protein Kinase A Activation in the Immune System with an Emphasis on Lipopolysaccharide-Responsive and Beige-like Anchor Protein in B Cells

by Daniela Pérez-Pérez, Leopoldo Santos-Argumedo, Juan Carlos Rodríguez-Alba and Gabriela López-Herrera

Int. J. Mol. Sci. 2023, 24(4), 3098; https://doi.org/10.3390/ijms24043098 - 4 Feb 2023

Cited by 8 | Viewed by 4616

Abstract

Cyclic AMP-dependent protein kinase A (PKA) is a ubiquitous enzymatic complex that is involved in a broad spectrum of intracellular receptor signaling. The activity of PKA depends on A-kinase anchoring proteins (AKAPs) that attach to PKAs close to their substrates to control signaling. [...] Read more.

Cyclic AMP-dependent protein kinase A (PKA) is a ubiquitous enzymatic complex that is involved in a broad spectrum of intracellular receptor signaling. The activity of PKA depends on A-kinase anchoring proteins (AKAPs) that attach to PKAs close to their substrates to control signaling. Although the relevance of PKA-AKAP signaling in the immune system is evident in T cells, its relevance in B and other immune cells remains relatively unclear. In the last decade, lipopolysaccharide-responsive and beige-like anchor protein (LRBA) has emerged as an AKAP that is ubiquitously expressed in B and T cells, specifically after activation. A deficiency of LRBA leads to immune dysregulation and immunodeficiency. The cellular mechanisms regulated by LRBA have not yet been investigated. Therefore, this review summarizes the functions of PKA in immunity and provides the most recent information regarding LRBA deficiency to deepen our understanding of immune regulation and immunological diseases. Full article

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20 pages, 903 KB

Open AccessArticle

The Search of Association of HLA Class I and Class II Alleles with COVID-19 Mortality in the Russian Cohort

by Valery Cheranev, Irina Bulusheva, Valery Vechorko, Dmitriy Korostin and Denis Rebrikov

Int. J. Mol. Sci. 2023, 24(4), 3068; https://doi.org/10.3390/ijms24043068 - 4 Feb 2023

Cited by 6 | Viewed by 3032

Abstract

HLA genes play a pivotal role in the immune response via presenting the pathogen peptides on the cell surface in a host organism. Here, we studied the association of HLA allele variants of class I (loci A, B, C) and class II (loci [...] Read more.

HLA genes play a pivotal role in the immune response via presenting the pathogen peptides on the cell surface in a host organism. Here, we studied the association of HLA allele variants of class I (loci A, B, C) and class II (loci DRB1, DQB1, DPB1) genes with the outcome of COVID-19 infection. We performed high-resolution sequencing of class HLA I and class II genes based on the sample population of 157 patients who died from COVID-19 and 76 patients who survived despite severe symptoms. The results were further compared with HLA genotype frequencies in the control population represented by 475 people from the Russian population. Although the obtained data revealed no significant differences between the samples at a locus level, they allowed one to uncover a set of notable alleles potentially contributing to the COVID-19 outcome. Our results did not only confirm the previously discovered fatal role of age or association of DRB1*01:01:01G and DRB1*01:02:01G alleles with severe symptoms and survival, but also allowed us to single out the DQB1*05:03:01G allele and B*14:02:01G~C*08:02:01G haplotype, which were associated with survival. Our findings showed that not only separate allele, but also their haplotype, could serve as potential markers of COVID-19 outcome and be used during triage for hospital admission. Full article

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34 pages, 1954 KB

Open AccessReview

Cytokine Imbalance as a Biomarker of Intervertebral Disk Degeneration

by Natalia A. Shnayder, Azamat V. Ashhotov, Vera V. Trefilova, Zaitun A. Nurgaliev, Maxim A. Novitsky, Elena E. Vaiman, Marina M. Petrova and Regina F. Nasyrova

Int. J. Mol. Sci. 2023, 24(3), 2360; https://doi.org/10.3390/ijms24032360 - 25 Jan 2023

Cited by 31 | Viewed by 5000

Abstract

The intervertebral disk degeneration (IDD) and its associated conditions are an important problem in modern medicine. The onset of IDD may be in childhood and adolescence in patients with a genetic predisposition. IDD progresses with age, leading to spondylosis, spondylarthrosis, intervertebral disk herniation, [...] Read more.

The intervertebral disk degeneration (IDD) and its associated conditions are an important problem in modern medicine. The onset of IDD may be in childhood and adolescence in patients with a genetic predisposition. IDD progresses with age, leading to spondylosis, spondylarthrosis, intervertebral disk herniation, and spinal stenosis. The purpose of this review is an attempt to summarize the data characterizing the patterns of production of pro-inflammatory and anti-inflammatory cytokines in IDD and to appreciate the prognostic value of cytokine imbalance as its biomarker. This narrative review demonstrates that the problem of evaluating the contribution of pro-inflammatory and anti-inflammatory cytokines to the maintenance or alteration of cytokine balance may be a new key to unlocking the mystery of IDD development and new therapeutic strategies for the treatment of IDD in the setting of acute and chronic inflammation. The presented data support the hypothesis that cytokine imbalance is one of the most important biomarkers of IDD. Full article

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17 pages, 1022 KB

Open AccessReview

Diagnostic and Prognostic Role of Extracellular Vesicles in Pancreatic Cancer: Current Evidence and Future Perspectives

by Alberto Nicoletti, Marcantonio Negri, Mattia Paratore, Federica Vitale, Maria Elena Ainora, Enrico Celestino Nista, Antonio Gasbarrini, Maria Assunta Zocco and Lorenzo Zileri Dal Verme

Int. J. Mol. Sci. 2023, 24(1), 885; https://doi.org/10.3390/ijms24010885 - 3 Jan 2023

Cited by 23 | Viewed by 5748

Abstract

Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately [...] Read more.

Pancreatic cancer is one of the most aggressive tumors, with a dismal prognosis due to poor detection rates at early stages, rapid progression, post-surgical complications, and limited effectiveness of conventional oncologic therapies. There are no consistently reliable biomarkers or imaging modalities to accurately diagnose, classify, and predict the biological behavior of this tumor. Therefore, it is imperative to develop new and improved strategies to detect pancreatic lesions in the early stages of cancerization with greater sensitivity and specificity. Extracellular vesicles, including exosome and microvesicles, are membrane-coated cellular products that are released in the outer environment. All cells produce extracellular vesicles; however, this process is enhanced by inflammation and tumorigenesis. Based on accumulating evidence, extracellular vesicles play a crucial role in pancreatic cancer progression and chemoresistance. Moreover, they may represent potential biomarkers and promising therapy targets. The aim of the present review is to review the current evidence on the role of extracellular vesicles in pancreatic cancer. Full article

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2022

Jump to: 2025, 2024, 2023

12 pages, 1532 KB

Open AccessArticle

IL-20 Activates ERK1/2 and Suppresses Splicing of X-Box Protein-1 in Intestinal Epithelial Cells but Does Not Improve Pathology in Acute or Chronic Models of Colitis

by Md. Moniruzzaman, Kuan Yau Wong, Ran Wang, Hamish Symon, Alexandra Mueller, M. Arifur Rahman and Sumaira Z. Hasnain

Int. J. Mol. Sci. 2023, 24(1), 174; https://doi.org/10.3390/ijms24010174 - 22 Dec 2022

Cited by 5 | Viewed by 2928

Abstract

The cytokine Interleukin (IL)-20 belongs to the IL-10 superfamily. IL-20 levels are reported to increase in the intestines of Ulcerative Colitis (UC) patients, however not much is known about its effects on intestinal epithelial cells. Here, we investigated the influence of IL-20 on [...] Read more.

The cytokine Interleukin (IL)-20 belongs to the IL-10 superfamily. IL-20 levels are reported to increase in the intestines of Ulcerative Colitis (UC) patients, however not much is known about its effects on intestinal epithelial cells. Here, we investigated the influence of IL-20 on intestinal epithelial cell lines and primary intestinal organoid cultures. By using chemical-induced (dextran sodium sulphate; DSS) colitis and a spontaneous model of colitis (Winnie mice), we assess whether recombinant IL-20 treatment is beneficial in reducing/improving pathology. Following stimulation with IL-20, intestinal primary organoids from wild-type and Winnie mice increased the expression of ERK1/2. However, this was lost when cells were differentiated into secretory goblet cells. Importantly, IL-20 treatment significantly reduced endoplasmic reticulum (ER) stress, as measured by spliced-XBP1 in epithelial cells, and this effect was lost in the goblet cells. IL-20 treatment in vivo in the DSS and Winnie models had minimal effects on pathology, but a decrease in macrophage activation was noted. Taken together, these data suggest a possible, but subtle role of IL-20 on epithelial cells in vivo. The therapeutic potential of IL-20 could be harnessed by the development of a targeted therapy or combination therapy to improve the healing of the mucosal barrier. Full article

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36 pages, 2669 KB

Open AccessReview

Old and New Facts and Speculations on the Role of the B Cell Receptor in the Origin of Chronic Lymphocytic Leukemia

by Davide Bagnara, Andrea Nicola Mazzarello, Fabio Ghiotto, Monica Colombo, Giovanna Cutrona, Franco Fais and Manlio Ferrarini

Int. J. Mol. Sci. 2022, 23(22), 14249; https://doi.org/10.3390/ijms232214249 - 17 Nov 2022

Cited by 10 | Viewed by 3874

Abstract

The engagement of the B cell receptor (BcR) on the surface of leukemic cells represents a key event in chronic lymphocytic leukemia (CLL) since it can lead to the maintenance and expansion of the neoplastic clone. This notion was initially suggested by observations [...] Read more.

The engagement of the B cell receptor (BcR) on the surface of leukemic cells represents a key event in chronic lymphocytic leukemia (CLL) since it can lead to the maintenance and expansion of the neoplastic clone. This notion was initially suggested by observations of the CLL BcR repertoire and of correlations existing between certain BcR features and the clinical outcomes of single patients. Based on these observations, tyrosine kinase inhibitors (TKIs), which block BcR signaling, have been introduced in therapy with the aim of inhibiting CLL cell clonal expansion and of controlling the disease. Indeed, the impressive results obtained with these compounds provided further proof of the role of BcR in CLL. In this article, the key steps that led to the determination of the role of BcR are reviewed, including the features of the CLL cell repertoire and the fine mechanisms causing BcR engagement and cell signaling. Furthermore, we discuss the biological effects of the engagement, which can lead to cell survival/proliferation or apoptosis depending on certain intrinsic cell characteristics and on signals that the micro-environment can deliver to the leukemic cells. In addition, consideration is given to alternative mechanisms promoting cell proliferation in the absence of BcR signaling, which can explain in part the incomplete effectiveness of TKI therapies. The role of the BcR in determining clonal evolution and disease progression is also described. Finally, we discuss possible models to explain the selection of a special BcR set during leukemogenesis. The BcR may deliver activation signals to the cells, which lead to their uncontrolled growth, with the possible collaboration of other still-undefined events which are capable of deregulating the normal physiological response of B cells to BcR-delivered stimuli. Full article

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16 pages, 1855 KB

Open AccessArticle

Differential Expression of Endogenous Retroviruses and Inflammatory Mediators in Female and Male Offspring in a Mouse Model of Maternal Immune Activation

by Chiara Cipriani, Anna Maria Tartaglione, Martina Giudice, Erica D’Avorio, Vita Petrone, Nicola Toschi, Flavia Chiarotti, Martino Tony Miele, Gemma Calamandrei, Enrico Garaci, Claudia Matteucci, Paola Sinibaldi-Vallebona, Laura Ricceri and Emanuela Balestrieri

Int. J. Mol. Sci. 2022, 23(22), 13930; https://doi.org/10.3390/ijms232213930 - 11 Nov 2022

Cited by 5 | Viewed by 3242

Abstract

Maternal infections during pregnancy and the consequent maternal immune activation (MIA) are the major risk factors for autism spectrum disorder (ASD). Epidemiological evidence is corroborated by the preclinical models in which MIA leads to ASD-like behavioral abnormalities and altered neuroinflammatory profiles, with an [...] Read more.

Maternal infections during pregnancy and the consequent maternal immune activation (MIA) are the major risk factors for autism spectrum disorder (ASD). Epidemiological evidence is corroborated by the preclinical models in which MIA leads to ASD-like behavioral abnormalities and altered neuroinflammatory profiles, with an increase in pro-inflammatory cytokines and microglial markers. In addition to neuroinflammatory response, an abnormal expression of endogenous retroviruses (ERVs) has been identified in neurodevelopmental disorders and have been found to correlate with disease severity. Our aim was to evaluate the transcriptional profile of several ERV families, ERV-related genes, and inflammatory mediators (by RT real-time PCR) in mouse offspring of both sexes, prenatally exposed to polyinosinic:polycytidylic acid (Poly I:C), a synthetic double-stranded RNA molecule targeting TLR-3 that mimics viral maternal infection during pregnancy. We found that prenatal exposure to Poly I:C deregulated the expression of some ERVs and ERV-related genes both in the prefrontal cortex (PFC) and hippocampus, while no changes were detected in the blood. Interestingly, sex-related differences in the expression levels of some ERVs, ERV-related genes, and inflammatory mediators that were higher in females than in males emerged only in PFC. Our findings support the tissue specificity of ERV and ERV-related transcriptional profiles in MIA mice. Full article

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12 pages, 1587 KB

Open AccessArticle

Conservation of Importin α Function in Apicomplexans: Ivermectin and GW5074 Target Plasmodium falciparum Importin α and Inhibit Parasite Growth in Culture

by Sujata B. Walunj, Chunxiao Wang, Kylie M. Wagstaff, Swati Patankar and David A. Jans

Int. J. Mol. Sci. 2022, 23(22), 13899; https://doi.org/10.3390/ijms232213899 - 11 Nov 2022

Cited by 4 | Viewed by 2676

Abstract

Signal-dependent transport into and out of the nucleus mediated by members of the importin (IMP) superfamily of nuclear transporters is critical to the eukaryotic function and a point of therapeutic intervention with the potential to limit disease progression and pathogenic outcomes. Although the [...] Read more.

Signal-dependent transport into and out of the nucleus mediated by members of the importin (IMP) superfamily of nuclear transporters is critical to the eukaryotic function and a point of therapeutic intervention with the potential to limit disease progression and pathogenic outcomes. Although the apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii both retain unique IMPα genes that are essential, a detailed analysis of their properties has not been performed. As a first step to validate apicomplexan IMPα as a target, we set out to compare the properties of P. falciparum and T. gondii IMPα (PfIMPα and TgIMPα, respectively) to those of mammalian IMPα, as exemplified by Mus musculus IMPα (MmIMPα). Close similarities were evident, with all three showing high-affinity binding to modular nuclear localisation signals (NLSs) from apicomplexans as well as Simian virus SV40 large tumour antigen (T-ag). PfIMPα and TgIMPα were also capable of binding to mammalian IMPβ1 (MmIMPβ1) with high affinity; strikingly, NLS binding by PfIMPα and TgIMPα could be inhibited by the mammalian IMPα targeting small molecules ivermectin and GW5074 through direct binding to PfIMPα and TgIMPα to perturb the α-helical structure. Importantly, GW5074 could be shown for the first time to resemble ivermectin in being able to limit growth of P. falciparum. The results confirm apicomplexan IMPα as a viable target for the development of therapeutics, with agents targeting it worthy of further consideration as an antimalarial. Full article

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16 pages, 5090 KB

Open AccessArticle

SARS-CoV-2 Spike Protein (RBD) Subunit Adsorption at Abiotic Surfaces and Corona Formation at Polymer Particles

by Paulina Żeliszewska, Monika Wasilewska, Piotr Batys, Katarzyna Pogoda, Piotr Deptuła, Robert Bucki and Zbigniew Adamczyk

Int. J. Mol. Sci. 2022, 23(20), 12374; https://doi.org/10.3390/ijms232012374 - 15 Oct 2022

Cited by 3 | Viewed by 3436

Abstract

The adsorption kinetics of the SARS-CoV-2 spike protein subunit with the receptor binding domain at abiotic surfaces was investigated. A combination of sensitive methods was used such as atomic force microscopy yielding a molecular resolution, a quartz microbalance, and optical waveguide lightmode spectroscopy. [...] Read more.

The adsorption kinetics of the SARS-CoV-2 spike protein subunit with the receptor binding domain at abiotic surfaces was investigated. A combination of sensitive methods was used such as atomic force microscopy yielding a molecular resolution, a quartz microbalance, and optical waveguide lightmode spectroscopy. The two latter methods yielded in situ information about the protein adsorption kinetics under flow conditions. It was established that at pH 3.5–4 the protein adsorbed on mica and silica surfaces in the form of compact quasi-spherical aggregates with an average size of 14 nm. The maximum coverage of the layers was equal to 3 and 1 mg m⁻² at pH 4 and 7.4, respectively. The experimental data were successfully interpreted in terms of theoretical results derived from modeling. The experiments performed for flat substrates were complemented by investigations of the protein corona formation at polymer particles carried out using in situ laser Doppler velocimetry technique. In this way, the zeta potential of the protein layers was acquired as a function of the coverage. Applying the electrokinetic model, these primary data were converted to the dependence of the subunit zeta potential on pH. It was shown that a complete acid-base characteristic of the layer can be acquired only using nanomolar quantities of the protein. Full article

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16 pages, 1299 KB

Open AccessReview

Cytokines and Immune Cells Profile in Different Tissues of Rodents Induced by Environmental Enrichment: Systematic Review

by Matheus Santos de Sousa Fernandes, Gabriela Carvalho Jurema Santos, Tayrine Ordonio Filgueira, Dayane Aparecida Gomes, Elias Almeida Silva Barbosa, Tony Meireles dos Santos, Niels Olsen Saraiva Câmara, Angela Castoldi and Fabricio Oliveira Souto

Int. J. Mol. Sci. 2022, 23(19), 11986; https://doi.org/10.3390/ijms231911986 - 9 Oct 2022

Cited by 10 | Viewed by 3173

Abstract

Environmental Enrichment (EE) is based on the promotion of socio-environmental stimuli, which mimic favorable environmental conditions for the practice of physical activity and health. The objective of the present systematic review was to evaluate the influence of EE on pro-and anti-inflammatory immune parameters, [...] Read more.

Environmental Enrichment (EE) is based on the promotion of socio-environmental stimuli, which mimic favorable environmental conditions for the practice of physical activity and health. The objective of the present systematic review was to evaluate the influence of EE on pro-and anti-inflammatory immune parameters, but also in cell activation related to the innate and acquired immune responses in the brain and peripheral tissues in rodents. Three databases [PubMed (2209 articles), Scopus (1154 articles), and Science Direct (1040 articles)] were researched. After applying the eligibility criteria, articles were selected for peer review, independently, as they were identified by September 2021. The protocol for this systematic review was registered in the PROSPERO. Of the 4417 articles found, 16 were selected for this systematic review. In the brain, EE promoted a reduction in proinflammatory cytokines and chemokines. In the blood, EE promoted a higher percentage of leukocytes, an increase in CD19+ B lymphocytes, and the proliferation of Natura Killer (NK cells). In the bone marrow, there was an increase in the number of CD27− and CD11b+ mature NK cells and a reduction in CD27− and CD11b+ immature Natural Killer cells. In conclusion, EE can be an immune modulation approach and plays a key role in the prevention of numerous chronic diseases, including cancer, that have a pro-inflammatory response and immunosuppressive condition as part of their pathophysiology. Full article

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14 pages, 1858 KB

Open AccessArticle

A Temporal Comparative RNA Transcriptome Profile of the Annexin Gene Family in the Salivary versus Lacrimal Glands of the Sjögren’s Syndrome-Susceptible C57BL/6.NOD-Aec1Aec2 Mouse

by Ammon B. Peck and Julian L. Ambrus, Jr.

Int. J. Mol. Sci. 2022, 23(19), 11709; https://doi.org/10.3390/ijms231911709 - 3 Oct 2022

Cited by 4 | Viewed by 2896

Abstract

A generally accepted hypothesis for the initial activation of an immune or autoimmune response argues that alarmins are released from injured, dying and/or activated immune cells, and these products complex with receptors that activate signal transduction pathways and recruit immune cells to the [...] Read more.

A generally accepted hypothesis for the initial activation of an immune or autoimmune response argues that alarmins are released from injured, dying and/or activated immune cells, and these products complex with receptors that activate signal transduction pathways and recruit immune cells to the site of injury where the recruited cells are stimulated to initiate immune and/or cellular repair responses. While there are multiple diverse families of alarmins such as interleukins (IL), heat-shock proteins (HSP), Toll-like receptors (TLR), plus individual molecular entities such as Galectin-3, Calreticulin, Thymosin, alpha-Defensin-1, RAGE, and Interferon-1, one phylogenetically conserved family are the Annexin proteins known to promote an extensive range of biomolecular and cellular products that can directly and indirectly regulate inflammation and immune activities. For the present report, we examined the temporal expression profiles of the 12 mammalian annexin genes (Anxa1-11 and Anxa13), applying our temporal genome-wide transcriptome analyses of ex vivo salivary and lacrimal glands from our C57BL/6.NOD-Aec1Aec2 mouse model of Sjögren’s Syndrome (SS), a human autoimmune disease characterized primarily by severe dry mouth and dry eye symptoms. Results indicate that annexin genes Anax1-7 and -11 exhibited upregulated expressions and the initial timing for these upregulations occurred as early as 8 weeks of age and prior to any covert signs of a SS-like disease. While the profiles of the two glands were similar, they were not identical, suggesting the possibility that the SS-like disease may not be uniform in the two glands. Nevertheless, this early pre-clinical and concomitant upregulated expression of this specific set of alarmins within the immune-targeted organs represents a potential target for identifying the pre-clinical stage in human SS as well, a fact that would clearly impact future interventions and therapeutic strategies. Full article

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18 pages, 4387 KB

Open AccessArticle

Therapeutic Potential of Mesenchymal Stem Cell-Secreted Factors on Delay in Corneal Wound Healing by Nitrogen Mustard

by Seungwon An, Xiang Shen, Khandaker Anwar, Mohammadjavad Ashraf, Hyungjo Lee, Raghuram Koganti, Mahmood Ghassemi and Ali R. Djalilian

Int. J. Mol. Sci. 2022, 23(19), 11510; https://doi.org/10.3390/ijms231911510 - 29 Sep 2022

Cited by 13 | Viewed by 3107

Abstract

Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial cells, cell death, and severe loss of tissue function. No definitive treatment for mustard gas-induced ocular surface disorders is [...] Read more.

Ocular surface exposure to nitrogen mustard (NM) leads to severe ocular toxicity which includes the separation of epithelial and stromal layers, loss of endothelial cells, cell death, and severe loss of tissue function. No definitive treatment for mustard gas-induced ocular surface disorders is currently available. The research was conducted to investigate the therapeutic potential of mesenchymal stem cell-conditioned media (MSC-CM) in NM-induced corneal wounds. NM was added to different types of corneal cells, the ocular surface of porcine, and the ocular surface of mice, followed by MSC-CM treatment. NM significantly induced apoptotic cell death, cellular ROS (Reactive oxygen species), and reduced cell viability, metabolic gene expression, and mitochondrial function, and, in turn, delayed wound healing. The application of MSC-CM post NM exposure partially restored mitochondrial function and decreased intracellular ROS generation which promoted cell survival. MSC-CM therapy enhanced wound healing process. MSC-CM inhibited NM-induced apoptotic cell death in murine and porcine corneal tissue. The application of MSC-CM following a chemical insult led to significant improvements in the preservation of corneal structure and wound healing. In vitro, ex vivo, and in vivo results suggest that MSC-CM can potentially provide targeted therapy for the treatment of chemical eye injuries, including mustard gas keratopathy (MGK) which presents with significant loss of vision alongside numerous corneal pathologies. Full article

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23 pages, 779 KB

Open AccessReview

Homo sapiens May Incorporate Daily Acute Cycles of “Conditioning–Deconditioning” to Maintain Musculoskeletal Integrity: Need to Integrate with Biological Clocks and Circadian Rhythm Mediators

by David A. Hart, Ronald F. Zernicke and Nigel G. Shrive

Int. J. Mol. Sci. 2022, 23(17), 9949; https://doi.org/10.3390/ijms23179949 - 1 Sep 2022

Cited by 5 | Viewed by 3474

Abstract

Human evolution required adaptation to the boundary conditions of Earth, including 1 g gravity. The bipedal mobility of Homo sapiens in that gravitational field causes ground reaction force (GRF) loading of their lower extremities, influencing the integrity of the tissues of those extremities. [...] Read more.

Human evolution required adaptation to the boundary conditions of Earth, including 1 g gravity. The bipedal mobility of Homo sapiens in that gravitational field causes ground reaction force (GRF) loading of their lower extremities, influencing the integrity of the tissues of those extremities. However, humans usually experience such loading during the day and then a period of relative unloading at night. Many studies have indicated that loading of tissues and cells of the musculoskeletal (MSK) system can inhibit their responses to biological mediators such as cytokines and growth factors. Such findings raise the possibility that humans use such cycles of acute conditioning and deconditioning of the cells and tissues of the MSK system to elaborate critical mediators and responsiveness in parallel with these cycles, particularly involving GRF loading. However, humans also experience circadian rhythms with the levels of a number of mediators influenced by day/night cycles, as well as various levels of biological clocks. Thus, if responsiveness to MSK-generated mediators also occurs during the unloaded part of the daily cycle, that response must be integrated with circadian variations as well. Furthermore, it is also possible that responsiveness to circadian rhythm mediators may be regulated by MSK tissue loading. This review will examine evidence for the above scenario and postulate how interactions could be both regulated and studied, and how extension of the acute cycles biased towards deconditioning could lead to loss of tissue integrity. Full article

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20 pages, 1812 KB

Open AccessReview

Probing the Skin–Brain Axis: New Vistas Using Mouse Models

by Aliće Weiglein, Evelyn Gaffal and Anne Albrecht

Int. J. Mol. Sci. 2022, 23(13), 7484; https://doi.org/10.3390/ijms23137484 - 5 Jul 2022

Cited by 13 | Viewed by 6636

Abstract

Inflammatory diseases of the skin, including atopic dermatitis and psoriasis, have gained increasing attention with rising incidences in developed countries over the past decades. While bodily properties, such as immunological responses of the skin, have been described in some detail, interactions with the [...] Read more.

Inflammatory diseases of the skin, including atopic dermatitis and psoriasis, have gained increasing attention with rising incidences in developed countries over the past decades. While bodily properties, such as immunological responses of the skin, have been described in some detail, interactions with the brain via different routes are less well studied. The suggested routes of the skin–brain axis comprise the immune system, HPA axis, and the peripheral and central nervous system, including microglia responses and structural changes. They provide starting points to investigate the molecular mechanisms of neuropsychiatric comorbidities in AD and psoriasis. To this end, mouse models exist for AD and psoriasis that could be tested for relevant behavioral entities. In this review, we provide an overview of the current mouse models and assays. By combining an extensive behavioral characterization and state-of-the-art genetic interventions with the investigation of underlying molecular pathways, insights into the mechanisms of the skin–brain axis in inflammatory cutaneous diseases are examined, which will spark further research in humans and drive the development of novel therapeutic strategies. Full article

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