Journal Description
International Journal of Molecular Sciences
International Journal of Molecular Sciences
is an international, peer-reviewed, open access journal providing an advanced forum for biochemistry, molecular and cell biology, molecular biophysics, molecular medicine, and all aspects of molecular research in chemistry, and is published semimonthly online by MDPI. The Australian Society of Plant Scientists (ASPS), Epigenetics Society, European Calcium Society (ECS), European Chitin Society (EUCHIS), Spanish Society for Cell Biology (SEBC) and others are affiliated with IJMS and their members receive a discount on the article processing charges.
- Open Access— free for readers, with article processing charges (APC) paid by authors or their institutions.
- High Visibility: indexed within Scopus, SCIE (Web of Science), PubMed, PMC, MEDLINE, Embase, CAPlus / SciFinder, and other databases.
- Journal Rank: JCR - Q1 (Biochemistry & Molecular Biology) / CiteScore - Q1 (Inorganic Chemistry)
- Rapid Publication: manuscripts are peer-reviewed and a first decision is provided to authors approximately 16.3 days after submission; acceptance to publication is undertaken in 2.6 days (median values for papers published in this journal in the second half of 2023).
- Recognition of Reviewers: reviewers who provide timely, thorough peer-review reports receive vouchers entitling them to a discount on the APC of their next publication in any MDPI journal, in appreciation of the work done.
- Testimonials: See what our editors and authors say about the IJMS.
- Companion journals for IJMS include: Biophysica, Obesities, Stresses and Lymphatics.
Impact Factor:
5.6 (2022);
5-Year Impact Factor:
6.2 (2022)
Latest Articles
Applications of Flow Cytometry in Drug Discovery and Translational Research
Int. J. Mol. Sci. 2024, 25(7), 3851; https://doi.org/10.3390/ijms25073851 (registering DOI) - 29 Mar 2024
Abstract
Flow cytometry is a mainstay technique in cell biology research, where it is used for phenotypic analysis of mixed cell populations. Quantitative approaches have unlocked a deeper value of flow cytometry in drug discovery research. As the number of drug modalities and druggable
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Flow cytometry is a mainstay technique in cell biology research, where it is used for phenotypic analysis of mixed cell populations. Quantitative approaches have unlocked a deeper value of flow cytometry in drug discovery research. As the number of drug modalities and druggable mechanisms increases, there is an increasing drive to identify meaningful biomarkers, evaluate the relationship between pharmacokinetics and pharmacodynamics (PK/PD), and translate these insights into the evaluation of patients enrolled in early clinical trials. In this review, we discuss emerging roles for flow cytometry in the translational setting that supports the transition and evaluation of novel compounds in the clinic.
Full article
(This article belongs to the Special Issue Trends and Prospects of Flow Cytometry in Cell and Molecular Biology)
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High-Resolution Frequency-Domain Spectroscopic and Modeling Studies of Photosystem I (PSI), PSI Mutants and PSI Supercomplexes
by
Valter Zazubovich and Ryszard Jankowiak
Int. J. Mol. Sci. 2024, 25(7), 3850; https://doi.org/10.3390/ijms25073850 (registering DOI) - 29 Mar 2024
Abstract
Photosystem I (PSI) is one of the two main pigment–protein complexes where the primary steps of oxygenic photosynthesis take place. This review describes low-temperature frequency-domain experiments (absorption, emission, circular dichroism, resonant and non-resonant hole-burned spectra) and modeling efforts reported for PSI in recent
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Photosystem I (PSI) is one of the two main pigment–protein complexes where the primary steps of oxygenic photosynthesis take place. This review describes low-temperature frequency-domain experiments (absorption, emission, circular dichroism, resonant and non-resonant hole-burned spectra) and modeling efforts reported for PSI in recent years. In particular, we focus on the spectral hole-burning studies, which are not as common in photosynthesis research as the time-domain spectroscopies. Experimental and modeling data obtained for trimeric cyanobacterial Photosystem I (PSI3), PSI3 mutants, and PSI3–IsiA18 supercomplexes are analyzed to provide a more comprehensive understanding of their excitonic structure and excitation energy transfer (EET) processes. Detailed information on the excitonic structure of photosynthetic complexes is essential to determine the structure–function relationship. We will focus on the so-called “red antenna states” of cyanobacterial PSI, as these states play an important role in photochemical processes and EET pathways. The high-resolution data and modeling studies presented here provide additional information on the energetics of the lowest energy states and their chlorophyll (Chl) compositions, as well as the EET pathways and how they are altered by mutations. We present evidence that the low-energy traps observed in PSI are excitonically coupled states with significant charge-transfer (CT) character. The analysis presented for various optical spectra of PSI3 and PSI3-IsiA18 supercomplexes allowed us to make inferences about EET from the IsiA18 ring to the PSI3 core and demonstrate that the number of entry points varies between sample preparations studied by different groups. In our most recent samples, there most likely are three entry points for EET from the IsiA18 ring per the PSI core monomer, with two of these entry points likely being located next to each other. Therefore, there are nine entry points from the IsiA18 ring to the PSI3 trimer. We anticipate that the data discussed below will stimulate further research in this area, providing even more insight into the structure-based models of these important cyanobacterial photosystems.
Full article
(This article belongs to the Special Issue New Insights into Photosystem I)
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Advancements in Regenerative Hydrogels in Skin Wound Treatment: A Comprehensive Review
by
Gabriel Olteanu, Sorinel Marius Neacșu, Florin Alexandru Joița, Adina Magdalena Musuc, Elena Carmen Lupu, Corina-Bianca Ioniță-Mîndrican, Dumitru Lupuliasa and Magdalena Mititelu
Int. J. Mol. Sci. 2024, 25(7), 3849; https://doi.org/10.3390/ijms25073849 (registering DOI) - 29 Mar 2024
Abstract
This state-of-the-art review explores the emerging field of regenerative hydrogels and their profound impact on the treatment of skin wounds. Regenerative hydrogels, composed mainly of water-absorbing polymers, have garnered attention in wound healing, particularly for skin wounds. Their unique properties make them well
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This state-of-the-art review explores the emerging field of regenerative hydrogels and their profound impact on the treatment of skin wounds. Regenerative hydrogels, composed mainly of water-absorbing polymers, have garnered attention in wound healing, particularly for skin wounds. Their unique properties make them well suited for tissue regeneration. Notable benefits include excellent water retention, creating a crucially moist wound environment for optimal healing, and facilitating cell migration, and proliferation. Biocompatibility is a key feature, minimizing adverse reactions and promoting the natural healing process. Acting as a supportive scaffold for cell growth, hydrogels mimic the extracellular matrix, aiding the attachment and proliferation of cells like fibroblasts and keratinocytes. Engineered for controlled drug release, hydrogels enhance wound healing by promoting angiogenesis, reducing inflammation, and preventing infection. The demonstrated acceleration of the wound healing process, particularly beneficial for chronic or impaired healing wounds, adds to their appeal. Easy application and conformity to various wound shapes make hydrogels practical, including in irregular or challenging areas. Scar minimization through tissue regeneration is crucial, especially in cosmetic and functional regions. Hydrogels contribute to pain management by creating a protective barrier, reducing friction, and fostering a soothing environment. Some hydrogels, with inherent antimicrobial properties, aid in infection prevention, which is a crucial aspect of successful wound healing. Their flexibility and ability to conform to wound contours ensure optimal tissue contact, enhancing overall treatment effectiveness. In summary, regenerative hydrogels present a promising approach for improving skin wound healing outcomes across diverse clinical scenarios. This review provides a comprehensive analysis of the benefits, mechanisms, and challenges associated with the use of regenerative hydrogels in the treatment of skin wounds. In this review, the authors likely delve into the application of rational design principles to enhance the efficacy and performance of hydrogels in promoting wound healing. Through an exploration of various methodologies and approaches, this paper is poised to highlight how these principles have been instrumental in refining the design of hydrogels, potentially revolutionizing their therapeutic potential in addressing skin wounds. By synthesizing current knowledge and highlighting potential avenues for future research, this review aims to contribute to the advancement of regenerative medicine and ultimately improve clinical outcomes for patients with skin wounds.
Full article
(This article belongs to the Special Issue Rational Design and Application of Functional Hydrogels)
Open AccessReview
Autoimmune Liver Diseases and Rheumatoid Arthritis—Is There an Etiopathogenic Link?
by
Ioana Ruxandra Mihai, Ciprian Rezus, Maria Alexandra Burlui, Anca Cardoneanu, Luana Andreea Macovei, Patricia Richter, Ioana Bratoiu and Elena Rezus
Int. J. Mol. Sci. 2024, 25(7), 3848; https://doi.org/10.3390/ijms25073848 (registering DOI) - 29 Mar 2024
Abstract
Rheumatoid arthritis (RA) is a systemic immune-mediated disease that, in addition to the articular involvement, can have extra-articular manifestations. Even though liver damage in RA is not very common, associated autoimmune liver diseases (AILDs) may occur. The most common AILD associated with RA
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Rheumatoid arthritis (RA) is a systemic immune-mediated disease that, in addition to the articular involvement, can have extra-articular manifestations. Even though liver damage in RA is not very common, associated autoimmune liver diseases (AILDs) may occur. The most common AILD associated with RA is primary biliary cirrhosis (PBC), followed by autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). There are common underlying mechanisms that play a role in the emergence of autoimmunity and inflammation in both rheumatic and autoimmune liver diseases. Genetic studies have revealed the existence of several common disease-associated genes shared between RA and AILDs, and infectious triggers, particularly those associated with recurrent or complicated urinary tract infections, are also speculated to be potential triggers for these conditions. Moreover, these diseases share common serologic patterns characterized by the presence of specific autoantibodies and hyper-gammaglobulinemia. In this study, we focus on reviewing the association between RA and AILDs regarding the prevalence and possible etiopathogenic link.
Full article
(This article belongs to the Special Issue From Pathogenesis to Treatment—New Perspectives in Rheumatology 2.0)
Open AccessArticle
Establishment of a Mouse Degenerative Model of Patellar Tendinopathy with Upregulation of Inflammation
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Pauline Po Yee Lui, Zuru Liang, Ri Min Tan and Patrick Shu Hang Yung
Int. J. Mol. Sci. 2024, 25(7), 3847; https://doi.org/10.3390/ijms25073847 (registering DOI) - 29 Mar 2024
Abstract
There is no mouse model of patellar tendinopathy. This study aimed to establish a mouse inflammatory and degenerative patellar tendon injury model, which will facilitate research on patellar tendinopathy using advanced molecular tools including transgenic models. Collagenase at different doses (low dose (LD),
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There is no mouse model of patellar tendinopathy. This study aimed to establish a mouse inflammatory and degenerative patellar tendon injury model, which will facilitate research on patellar tendinopathy using advanced molecular tools including transgenic models. Collagenase at different doses (low dose (LD), medium dose (MD), high dose (HD)) or saline was injected over the mouse patellar tendon. At weeks 1, 2, 4, and 8 post-injection, the tendons were harvested for histology and further examined by micro-computed tomography (microCT) imaging at week 8. The optimal dose group and the saline group were further evaluated by immunohistochemical staining, gait pattern, and biomechanical properties. The histopathological score increased dose-dependently post-collagenase injection. Ectopic mineralization was observed and increased with collagenase dose. The LD group was selected for further analysis. The expression of IL-10, TNF-α, and MMP-1 significantly increased post-injection. The changes of limb idleness index (ΔLII) compared to preinjury state were significantly higher, while the ultimate load, stiffness, ultimate stress, and maximum Young’s modulus were significantly lower in the LD group compared to the saline group. A mouse inflammatory degenerative model of patellar tendon injury resembling tendinopathy was established as indicated by the dose-dependent increase in tendon histopathology, ectopic calcification, decrease in biomechanical properties, and pain-associated gait changes.
Full article
(This article belongs to the Special Issue Molecular Mechanisms of Tendinopathy: Unraveling the Pathogenesis of Tendon Diseases)
Open AccessReview
What Is the “Hydrogen Bond”? A QFT-QED Perspective
by
Paolo Renati and Pierre Madl
Int. J. Mol. Sci. 2024, 25(7), 3846; https://doi.org/10.3390/ijms25073846 (registering DOI) - 29 Mar 2024
Abstract
In this paper we would like to highlight the problems of conceiving the “Hydrogen Bond” (HB) as a real short-range, directional, electrostatic, attractive interaction and to reframe its nature through the non-approximated view of condensed matter offered by a Quantum Electro-Dynamic (QED) perspective.
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In this paper we would like to highlight the problems of conceiving the “Hydrogen Bond” (HB) as a real short-range, directional, electrostatic, attractive interaction and to reframe its nature through the non-approximated view of condensed matter offered by a Quantum Electro-Dynamic (QED) perspective. We focus our attention on water, as the paramount case to show the effectiveness of this 40-year-old theoretical background, which represents water as a two-fluid system (where one of the two phases is coherent). The HB turns out to be the result of the electromagnetic field gradient in the coherent phase of water, whose vacuum level is lower than in the non-coherent (gas-like) fraction. In this way, the HB can be properly considered, i.e., no longer as a “dipolar force” between molecules, but as the phenomenological effect of their collective thermodynamic tendency to occupy a lower ground state, compatible with temperature and pressure. This perspective allows to explain many “anomalous” behaviours of water and to understand why the calculated energy associated with the HB should change when considering two molecules (water-dimer), or the liquid state, or the different types of ice. The appearance of a condensed, liquid, phase at room temperature is indeed the consequence of the boson condensation as described in the context of spontaneous symmetry breaking (SSB). For a more realistic and authentic description of water, condensed matter and living systems, the transition from a still semi-classical Quantum Mechanical (QM) view in the first quantization to a Quantum Field Theory (QFT) view embedded in the second quantization is advocated.
Full article
(This article belongs to the Special Issue The Emerging Role of Quantum Sciences and Radiation Biology in Biomedical Applications)
Open AccessReview
Huntington’s Disease: Complex Pathogenesis and Therapeutic Strategies
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Huichun Tong, Tianqi Yang, Shuying Xu, Xinhui Li, Li Liu, Gongke Zhou, Sitong Yang, Shurui Yin, Xiao-Jiang Li and Shihua Li
Int. J. Mol. Sci. 2024, 25(7), 3845; https://doi.org/10.3390/ijms25073845 (registering DOI) - 29 Mar 2024
Abstract
Huntington’s disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (HTT), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and
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Huntington’s disease (HD) arises from the abnormal expansion of CAG repeats in the huntingtin gene (HTT), resulting in the production of the mutant huntingtin protein (mHTT) with a polyglutamine stretch in its N-terminus. The pathogenic mechanisms underlying HD are complex and not yet fully elucidated. However, mHTT forms aggregates and accumulates abnormally in neuronal nuclei and processes, leading to disruptions in multiple cellular functions. Although there is currently no effective curative treatment for HD, significant progress has been made in developing various therapeutic strategies to treat HD. In addition to drugs targeting the neuronal toxicity of mHTT, gene therapy approaches that aim to reduce the expression of the mutant HTT gene hold great promise for effective HD therapy. This review provides an overview of current HD treatments, discusses different therapeutic strategies, and aims to facilitate future therapeutic advancements in the field.
Full article
(This article belongs to the Special Issue Trends in Neuroscience: From Molecular Mechanisms to Innovative Therapeutics)
Open AccessArticle
Predicting Cellular Rejection of Renal Allograft Based on the Serum Proteomic Fingerprint
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Luís Ramalhete, Miguel Bigotte Vieira, Rúben Araújo, Emanuel Vigia, Inês Aires, Aníbal Ferreira and Cecília R. C. Calado
Int. J. Mol. Sci. 2024, 25(7), 3844; https://doi.org/10.3390/ijms25073844 (registering DOI) - 29 Mar 2024
Abstract
Kidney transplantation is an essential medical procedure that significantly enhances the survival rates and quality of life for patients with end-stage kidney disease. However, despite advancements in immunosuppressive therapies, allograft rejection remains a leading cause of organ loss. Notably, predictions of cellular rejection
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Kidney transplantation is an essential medical procedure that significantly enhances the survival rates and quality of life for patients with end-stage kidney disease. However, despite advancements in immunosuppressive therapies, allograft rejection remains a leading cause of organ loss. Notably, predictions of cellular rejection processes primarily rely on biopsy analysis, which is not routinely performed due to its invasive nature. The present work evaluates if the serum proteomic fingerprint, as acquired by Fourier Transform Infrared (FTIR) spectroscopy, can predict cellular rejection processes. We analyzed 28 serum samples, corresponding to 17 without cellular rejection processes and 11 associated with cellular rejection processes, as based on biopsy analyses. The leave-one-out-cross validation procedure of a Naïve Bayes model enabled the prediction of cellular rejection processes with high sensitivity and specificity (AUC > 0.984). The serum proteomic profile was obtained in a high-throughput mode and based on a simple, rapid, and economical procedure, making it suitable for routine analyses and large-scale studies. Consequently, the current method presents a high potential to predict cellular rejection processes translatable to clinical scenarios, and that should continue to be explored.
Full article
(This article belongs to the Special Issue Proteomic Analysis of Kidney Diseases)
Open AccessArticle
A Stem-like Patient-Derived Ovarian Cancer Model of Platinum Resistance Reveals Dissociation of Stemness and Resistance
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Tise Suzuki, Ashlyn Conant, Yeonkyu Jung, Ryan Bax, Ashley Antonissen, Wanqiu Chen, Gary Yu, Yevgeniya J. Ioffe, Charles Wang and Juli J. Unternaehrer
Int. J. Mol. Sci. 2024, 25(7), 3843; https://doi.org/10.3390/ijms25073843 (registering DOI) - 29 Mar 2024
Abstract
To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its
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To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its histopathological and BRCA2 mutation status, and exposed to cisplatin in vitro. In the cisplatin-resistant cells, transcriptomics were carried out, and cell morphology, protein expression, and functional status were characterized. Additionally, potential signaling pathways involved in cisplatin resistance were explored. Our findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin-resistant PDX4 compared to their sensitive counterparts. Surprisingly, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic–features indicative of an underlying complex mechanism for cell survival. Furthermore, DNA damage tolerance and cellular stress management pathways were enriched. This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapies tailored to combat resistance in stem-like ovarian cancer.
Full article
(This article belongs to the Special Issue Drug Resistance in Cancer: Molecular Mechanisms and Tackling Strategies 2.0)
Open AccessArticle
Different Kynurenine Pathway Dysregulation in Systemic Sclerosis in Men and Women
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Monika Turska-Kozłowska, Bruno Pedraz-Petrozzi, Piotr Paluszkiewicz and Jolanta Parada-Turska
Int. J. Mol. Sci. 2024, 25(7), 3842; https://doi.org/10.3390/ijms25073842 (registering DOI) - 29 Mar 2024
Abstract
Systemic sclerosis (SSc), a predominantly female-affected systemic autoimmune disease, requires tailored treatment strategies contingent on organ involvement and symptom severity. Given SSc’s inflammatory nature, the involvement of the kynurenine pathway (KP) in its pathophysiology is underexplored. Our study aimed to investigate sex-related differences
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Systemic sclerosis (SSc), a predominantly female-affected systemic autoimmune disease, requires tailored treatment strategies contingent on organ involvement and symptom severity. Given SSc’s inflammatory nature, the involvement of the kynurenine pathway (KP) in its pathophysiology is underexplored. Our study aimed to investigate sex-related differences in KP activation among SSc patients and assess the impact of angiotensin-converting enzyme (ACE) inhibitors and estimated glomerular filtration rate (eGFR) on KP metabolite concentrations. We enrolled 48 SSc patients and 53 healthy controls, quantifying KP metabolites (tryptophan (TRP), kynurenine (KYN), and kynurenic acid (KYNA)) in serum via high-performance liquid chromatography. Separate multivariate analyses of covariance (MANCOVAs) for women and men were performed to ascertain mean differences between patients and healthy controls while correcting for age. For our secondary objective, we conducted a MANCOVA to explore disparities in ACE inhibitor users and non-users among patients, with BMI correction. Our findings revealed decreased TRP concentrations but increased KYNA/TRP ratio and KYN/TRP ratio in both male and female SSc patients compared to their respective controls. Unlike women, SSc males exhibited higher KYN concentrations and decreased KYNA/KYN ratio relative to their controls. Additionally, SSc patients using ACE inhibitors had higher serum KYNA levels than non-users. Notably, we established a significant correlation between eGFR and KYNA in SSc patients. These results indicate differential KP activation in male and female SSc patients, with males demonstrating heightened KP activation. While ACE inhibitors may influence the KP in SSc patients, further research is necessary to comprehensively understand their impact on symptoms and prognosis in the context of these KP alterations.
Full article
(This article belongs to the Special Issue Kynurenic Acid: Emerging Research Advances and Therapeutic Implications)
Open AccessArticle
Multi-Omics Profiling Reveals Phenotypic and Functional Heterogeneity of Neutrophils in COVID-19
by
Lin Zhang, Hafumi Nishi and Kengo Kinoshita
Int. J. Mol. Sci. 2024, 25(7), 3841; https://doi.org/10.3390/ijms25073841 (registering DOI) - 29 Mar 2024
Abstract
Accumulating evidence has revealed unexpected phenotypic heterogeneity and diverse functions of neutrophils in several diseases. Coronavirus disease (COVID-19) can alter the leukocyte phenotype based on disease severity, including neutrophil activation in severe cases. However, the plasticity of neutrophil phenotypes and their relative impact
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Accumulating evidence has revealed unexpected phenotypic heterogeneity and diverse functions of neutrophils in several diseases. Coronavirus disease (COVID-19) can alter the leukocyte phenotype based on disease severity, including neutrophil activation in severe cases. However, the plasticity of neutrophil phenotypes and their relative impact on COVID-19 pathogenesis has not been well addressed. This study aimed to identify and validate the heterogeneity of neutrophils in COVID-19 and evaluate the functions of each subpopulation. We analyzed public single-cell RNA-seq, bulk RNA-seq, and proteome data from healthy donors and patients with COVID-19 to investigate neutrophil subpopulations and their response to disease pathogenesis. We identified eight neutrophil subtypes: pro-neutrophil, pre-neutrophil, immature neutrophil, and five mature neutrophil subpopulations. The subtypes exhibited distinct features, including diverse activation signatures and multiple enriched pathways. The pro-neutrophil subtype was associated with severe and fatal disease, while the pre-neutrophil subtype was particularly abundant in mild/moderate disease. One of the mature neutrophil subtypes showed consistently large fractions in patients with different disease severity. Bulk RNA-seq dataset analyses using a cellular deconvolution approach validated the relative abundances of neutrophil subtypes and the expansion of pro-neutrophils in severe COVID-19 patients. Cell–cell communication analysis revealed representative ligand–receptor interactions among the identified neutrophil subtypes. Further investigation into transcription factors and differential protein abundance revealed the regulatory network differences between healthy donors and patients with severe COVID-19. Overall, we demonstrated the complex interactions among heterogeneous neutrophil subtypes and other blood cell types during COVID-19 disease. Our work has great value in terms of both clinical and public health as it furthers our understanding of the phenotypic and functional heterogeneity of neutrophils and other cell populations in multiple diseases.
Full article
(This article belongs to the Section Molecular Genetics and Genomics)
Open AccessReview
Chagas Disease: A Silent Threat for Dogs and Humans
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João Durães-Oliveira, Joana Palma-Marques, Cláudia Moreno, Armanda Rodrigues, Marta Monteiro, Graça Alexandre-Pires, Isabel Pereira da Fonseca and Gabriela Santos-Gomes
Int. J. Mol. Sci. 2024, 25(7), 3840; https://doi.org/10.3390/ijms25073840 (registering DOI) - 29 Mar 2024
Abstract
Chagas disease (CD) is a vector-borne Neglected Zoonotic Disease (NZD) caused by a flagellate protozoan, Trypanosoma cruzi, that affects various mammalian species across America, including humans and domestic animals. However, due to an increase in population movements and new routes of transmission,
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Chagas disease (CD) is a vector-borne Neglected Zoonotic Disease (NZD) caused by a flagellate protozoan, Trypanosoma cruzi, that affects various mammalian species across America, including humans and domestic animals. However, due to an increase in population movements and new routes of transmission, T. cruzi infection is presently considered a worldwide health concern, no longer restricted to endemic countries. Dogs play a major role in the domestic cycle by acting very efficiently as reservoirs and allowing the perpetuation of parasite transmission in endemic areas. Despite the significant progress made in recent years, still there is no vaccine against human and animal disease, there are few drugs available for the treatment of human CD, and there is no standard protocol for the treatment of canine CD. In this review, we highlight human and canine Chagas Disease in its different dimensions and interconnections. Dogs, which are considered to be the most important peridomestic reservoir and sentinel for the transmission of T. cruzi infection in a community, develop CD that is clinically similar to human CD. Therefore, an integrative approach, based on the One Health concept, bringing together the advances in genomics, immunology, and epidemiology can lead to the effective development of vaccines, new treatments, and innovative control strategies to tackle CD.
Full article
(This article belongs to the Section Molecular Immunology)
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Open AccessArticle
Non-Thermal Plasma Reduces HSV-1 Infection of and Replication in HaCaT Keratinocytes In Vitro
by
Julia Sutter, Jascha Brettschneider, Brian Wigdahl, Peter J. Bruggeman, Fred C. Krebs and Vandana Miller
Int. J. Mol. Sci. 2024, 25(7), 3839; https://doi.org/10.3390/ijms25073839 (registering DOI) - 29 Mar 2024
Abstract
Herpes simplex virus type 1 (HSV-1) is a lifelong pathogen characterized by asymptomatic latent infection in the trigeminal ganglia (TG), with periodic outbreaks of cold sores caused by virus reactivation in the TG and subsequent replication in the oral mucosa. While antiviral therapies
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Herpes simplex virus type 1 (HSV-1) is a lifelong pathogen characterized by asymptomatic latent infection in the trigeminal ganglia (TG), with periodic outbreaks of cold sores caused by virus reactivation in the TG and subsequent replication in the oral mucosa. While antiviral therapies can provide relief from cold sores, they are unable to eliminate HSV-1. We provide experimental results that highlight non-thermal plasma (NTP) as a new alternative therapy for HSV-1 infection that would resolve cold sores faster and reduce the establishment of latent infection in the TG. Additionally, this study is the first to explore the use of NTP as a therapy that can both treat and prevent human viral infections. The antiviral effect of NTP was investigated using an in vitro model of HSV-1 epithelial infection that involved the application of NTP from two separate devices to cell-free HSV-1, HSV-1-infected cells, and uninfected cells. It was found that NTP reduced the infectivity of cell-free HSV-1, reduced viral replication in HSV-1-infected cells, and diminished the susceptibility of uninfected cells to HSV-1 infection. This triad of antiviral mechanisms of action suggests the potential of NTP as a therapeutic agent effective against HSV-1 infection.
Full article
(This article belongs to the Section Molecular Biophysics)
Open AccessArticle
Circadian Gene Variants: Effects in Overweight and Obese Pregnant Women
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Marica Franzago, Paola Borrelli, Pierluigi Cavallo, Luciano Di Tizio, Diego Gazzolo, Marta Di Nicola, Liborio Stuppia and Ester Vitacolonna
Int. J. Mol. Sci. 2024, 25(7), 3838; https://doi.org/10.3390/ijms25073838 (registering DOI) - 29 Mar 2024
Abstract
Obesity and overweight are common and complex conditions influenced by multiple genetic and environmental factors. Several genetic variants located in the genes involved in clock systems and fat taste perception can affect metabolic health. In particular, the polymorphisms in CLOCK and BMAL1 genes
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Obesity and overweight are common and complex conditions influenced by multiple genetic and environmental factors. Several genetic variants located in the genes involved in clock systems and fat taste perception can affect metabolic health. In particular, the polymorphisms in CLOCK and BMAL1 genes were reported to be significantly related to cardiovascular disease, metabolic syndrome, sleep reduction, and evening preference. Moreover, genetic variants in the CD36 gene have been shown to be involved in lipid metabolism, regulation of fat intake, and body weight regulation. The aim of this study is to evaluate, for the first time, the association between variants in some candidate genes (namely, BMAL1 rs7950226 (G>A), CLOCK rs1801260 (A>G), CLOCK rs4864548 (G>A), CLOCK rs3736544 (G>A), CD36 rs1984112 (A>G), CD36 rs1761667 (G>A)) and overweight/obesity (OB) in pregnant women. A total of 163 normal-weight (NW) and 128 OB participants were included. A significant correlation was observed between A-allele in CLOCK rs4864548 and an increased risk of obesity (OR: 1.97; 95% CI 1.22–3.10, p = 0.005). In addition, we found that subjects carrying the haplotype of rs1801260-A, rs4864548-A, and rs3736544-G are likely to be overweight or obese (OR 1.47, 95% CI 1.03–2.09, p = 0.030), compared with those with other haplotypes. Moreover, a significant relation was observed between third-trimester lipid parameters and genetic variants—namely, CD36 rs1984112, CD36 rs1761667, BMAL1 rs7950226, and CLOCK rs1801260. A multivariate logistic regression model revealed that CLOCK rs4864548 A-allele carriage was a strong risk factor for obesity (OR 2.05, 95% CI 1.07–3.93, p = 0.029); on the other hand, greater adherence to Mediterranean diet (OR 0.80, 95% CI 0.65–0.98, p = 0.038) and higher HDL levels (OR 0.96, 95% CI 0.94–0.99, p = 0.021) were related to a reduced risk of obesity. Interestingly, an association between maternal CLOCK rs4864548 and neonatal birthweight was detected (p = 0.025). These data suggest a potential role of the polymorphisms in clock systems and in fat taste perception in both susceptibility to overweight/obesity and influencing the related metabolic traits in pregnant women.
Full article
(This article belongs to the Special Issue Molecular Advances in Circadian Rhythm and Metabolism)
Open AccessReview
Assessing Animal Models to Study Impaired and Chronic Wounds
by
Shayan Saeed and Manuela Martins-Green
Int. J. Mol. Sci. 2024, 25(7), 3837; https://doi.org/10.3390/ijms25073837 (registering DOI) - 29 Mar 2024
Abstract
Impaired healing wounds do not proceed through the normal healing processes in a timely and orderly manner, and while they do eventually heal, their healing is not optimal. Chronic wounds, on the other hand, remain unhealed for weeks or months. In the US
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Impaired healing wounds do not proceed through the normal healing processes in a timely and orderly manner, and while they do eventually heal, their healing is not optimal. Chronic wounds, on the other hand, remain unhealed for weeks or months. In the US alone, chronic wounds impact ~8.5 million people and cost ~USD 28–90 billion per year, not accounting for the psychological and physical pain and emotional suffering that patients endure. These numbers are only expected to rise in the future as the elderly populations and the incidence of comorbidities such as diabetes, hypertension, and obesity increase. Over the last few decades, scientists have used a variety of approaches to treat chronic wounds, but unfortunately, to date, there is no effective treatment. Indeed, while there are thousands of drugs to combat cancer, there is only one single drug approved for the treatment of chronic wounds. This is in part because wound healing is a very complex process involving many phases that must occur sequentially and in a timely manner. Furthermore, models that fully mimic human chronic wounds have not been developed. In this review, we assess various models currently being used to study the biology of impaired healing and chronic non-healing wounds. Among them, this paper also highlights one model which shows significant promise; this model uses aged and obese db/db−/− mice and the chronic wounds that develop show characteristics of human chronic wounds that include increased oxidative stress, chronic inflammation, damaged microvasculature, abnormal collagen matrix deposition, a lack of re-epithelialization, and the spontaneous development of multi-bacterial biofilm. We also discuss how important it is that we continue to develop chronic wound models that more closely mimic those of humans and that can be used to test potential treatments to heal chronic wounds.
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(This article belongs to the Special Issue Cellular and Molecular Mechanisms on Wound Healing)
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An Overview on the Big Players in Bone Tissue Engineering: Biomaterials, Scaffolds and Cells
by
Maria Pia Ferraz
Int. J. Mol. Sci. 2024, 25(7), 3836; https://doi.org/10.3390/ijms25073836 (registering DOI) - 29 Mar 2024
Abstract
Presently, millions worldwide suffer from degenerative and inflammatory bone and joint issues, comprising roughly half of chronic ailments in those over 50, leading to prolonged discomfort and physical limitations. These conditions become more prevalent with age and lifestyle factors, escalating due to the
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Presently, millions worldwide suffer from degenerative and inflammatory bone and joint issues, comprising roughly half of chronic ailments in those over 50, leading to prolonged discomfort and physical limitations. These conditions become more prevalent with age and lifestyle factors, escalating due to the growing elderly populace. Addressing these challenges often entails surgical interventions utilizing implants or bone grafts, though these treatments may entail complications such as pain and tissue death at donor sites for grafts, along with immune rejection. To surmount these challenges, tissue engineering has emerged as a promising avenue for bone injury repair and reconstruction. It involves the use of different biomaterials and the development of three-dimensional porous matrices and scaffolds, alongside osteoprogenitor cells and growth factors to stimulate natural tissue regeneration. This review compiles methodologies that can be used to develop biomaterials that are important in bone tissue replacement and regeneration. Biomaterials for orthopedic implants, several scaffold types and production methods, as well as techniques to assess biomaterials’ suitability for human use—both in laboratory settings and within living organisms—are discussed. Even though researchers have had some success, there is still room for improvements in their processing techniques, especially the ones that make scaffolds mechanically stronger without weakening their biological characteristics. Bone tissue engineering is therefore a promising area due to the rise in bone-related injuries.
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(This article belongs to the Special Issue The Application of Biomaterials in Bone Tissue Repair and Regeneration)
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Insect Antimicrobial Peptides as Guardians of Immunity and Beyond: A Review
by
Lizhen Zhou, Guanliang Meng, Ling Zhu, Li Ma and Kangkang Chen
Int. J. Mol. Sci. 2024, 25(7), 3835; https://doi.org/10.3390/ijms25073835 (registering DOI) - 29 Mar 2024
Abstract
Antimicrobial peptides (AMPs), as immune effectors synthesized by a variety of organisms, not only constitute a robust defense mechanism against a broad spectrum of pathogens in the host but also show promising applications as effective antimicrobial agents. Notably, insects are significant reservoirs of
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Antimicrobial peptides (AMPs), as immune effectors synthesized by a variety of organisms, not only constitute a robust defense mechanism against a broad spectrum of pathogens in the host but also show promising applications as effective antimicrobial agents. Notably, insects are significant reservoirs of natural AMPs. However, the complex array of variations in types, quantities, antimicrobial activities, and production pathways of AMPs, as well as evolution of AMPs across insect species, presents a significant challenge for immunity system understanding and AMP applications. This review covers insect AMP discoveries, classification, common properties, and mechanisms of action. Additionally, the types, quantities, and activities of immune-related AMPs in each model insect are also summarized. We conducted the first comprehensive investigation into the diversity, distribution, and evolution of 20 types of AMPs in model insects, employing phylogenetic analysis to describe their evolutionary relationships and shed light on conserved and distinctive AMP families. Furthermore, we summarize the regulatory pathways of AMP production through classical signaling pathways and additional pathways associated with Nitric Oxide, insulin-like signaling, and hormones. This review advances our understanding of AMPs as guardians in insect immunity systems and unlocks a gateway to insect AMP resources, facilitating the use of AMPs to address food safety concerns.
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(This article belongs to the Special Issue Antimicrobial Peptides and Immunology 2.0)
Open AccessReview
The Clinical Relevance of the EPH/Ephrin Signaling Pathway in Pediatric Solid and Hematologic Malignancies
by
Elena Chatzikalil, Ioanna E. Stergiou, Stavros P. Papadakos, Ippokratis Konstantinidis and Stamatios Theocharis
Int. J. Mol. Sci. 2024, 25(7), 3834; https://doi.org/10.3390/ijms25073834 (registering DOI) - 29 Mar 2024
Abstract
Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance
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Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell–cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell–cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway’s intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges.
Full article
(This article belongs to the Special Issue Navigating Precision Oncology: Integrating Biomarkers into Clinical Practice)
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The Role of NRF2 in Cerebrovascular Protection: Implications for Vascular Cognitive Impairment and Dementia (VCID)
by
Yizhou Hu, Feng Zhang, Milos Ikonomovic and Tuo Yang
Int. J. Mol. Sci. 2024, 25(7), 3833; https://doi.org/10.3390/ijms25073833 (registering DOI) - 29 Mar 2024
Abstract
Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most common type of dementia, and the prevalence continues to increase. Nuclear factor erythroid 2-related factor 2 (NRF2) is
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Vascular cognitive impairment and dementia (VCID) represents a broad spectrum of cognitive decline secondary to cerebral vascular aging and injury. It is the second most common type of dementia, and the prevalence continues to increase. Nuclear factor erythroid 2-related factor 2 (NRF2) is enriched in the cerebral vasculature and has diverse roles in metabolic balance, mitochondrial stabilization, redox balance, and anti-inflammation. In this review, we first briefly introduce cerebrovascular aging in VCID and the NRF2 pathway. We then extensively discuss the effects of NRF2 activation in cerebrovascular components such as endothelial cells, vascular smooth muscle cells, pericytes, and perivascular macrophages. Finally, we summarize the clinical potential of NRF2 activators in VCID.
Full article
(This article belongs to the Special Issue Vascular, Oxidative and Inflammatory Dysregulation in Neurodegenerative Diseases: Current Status and Future Therapeutic Perspectives)
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Glucagon-like Peptide 1, Glucose-Dependent Insulinotropic Polypeptide, and Glucagon Receptor Agonists in Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Medication in New Liver Disease Nomenclature
by
Lampros G. Chrysavgis, Spyridon Kazanas, Konstantina Bafa, Sophia Rozani, Maria-Evangelia Koloutsou and Evangelos Cholongitas
Int. J. Mol. Sci. 2024, 25(7), 3832; https://doi.org/10.3390/ijms25073832 (registering DOI) - 29 Mar 2024
Abstract
Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that regulate postprandial glucose regulation, stimulating insulin secretion from pancreatic β-cells in response to food ingestion. Modified GLP-1 receptor agonists (GLP-1RAs) are being administered for the treatment of obesity and type 2
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Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretins that regulate postprandial glucose regulation, stimulating insulin secretion from pancreatic β-cells in response to food ingestion. Modified GLP-1 receptor agonists (GLP-1RAs) are being administered for the treatment of obesity and type 2 diabetes mellitus (T2DM). Strongly related to those disorders, metabolic dysfunction-associated steatotic liver disease (MASLD), especially its aggressive form, defined as metabolic dysfunction-associated steatohepatitis (MASH), is a major healthcare burden associated with high morbidity and extrahepatic complications. GLP-1RAs have been explored in MASH patients with evident improvement in liver dysfunction enzymes, glycemic control, and weight loss. Importantly, the combination of GLP-1RAs with GIP and/or glucagon RAs may be even more effective via synergistic mechanisms in amelioration of metabolic, biochemical, and histological parameters of MASLD but also has a beneficial impact on MASLD-related complications. In this current review, we aim to provide an overview of incretins’ physiology, action, and signaling. Furthermore, we provide insight into the key pathophysiological mechanisms through which they impact MASLD aspects, as well as we analyze clinical data from human interventional studies. Finally, we discuss the current challenges and future perspectives pertinent to this growing area of research and clinical medicine.
Full article
(This article belongs to the Special Issue Molecular Targets for the Formation and Treatment of Nonalcoholic Fatty Liver Disease)
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