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19 pages, 1584 KiB

Open AccessEditor’s ChoiceReview

TNF Superfamily and ILC2 Activation in Asthma

by Takahiro Matsuyama, Brittany Marie Salter, Nahal Emami Fard, Kentaro Machida and Roma Sehmi

Biomolecules 2024, 14(3), 294; https://doi.org/10.3390/biom14030294 - 29 Feb 2024

Viewed by 1825

Eosinophilic asthma is the most prevalent and well-defined phenotype of asthma. Despite a majority of patients responding to corticosteroid therapy and T2 biologics, there remains a subset that have recurrent asthma exacerbations, highlighting a need for additional therapies to fully ameliorate airway eosinophilia. [...] Read more.

Eosinophilic asthma is the most prevalent and well-defined phenotype of asthma. Despite a majority of patients responding to corticosteroid therapy and T2 biologics, there remains a subset that have recurrent asthma exacerbations, highlighting a need for additional therapies to fully ameliorate airway eosinophilia. Group 2 innate lymphoid cells (ILC2) are considered key players in the pathogenesis of eosinophilic asthma through the production of copious amounts of type 2 cytokines, namely IL-5 and IL-13. ILC2 numbers are increased in the airways of asthmatics and with the greatest numbers of activated ILC2 detected in sputa from severe prednisone-dependent asthma with uncontrolled eosinophilia. Although epithelial-derived cytokines are important mediators of ILC2 activation, emerging evidence suggests that additional pathways stimulate ILC2 function. The tumor necrosis factor super family (TNFSF) and its receptors (TNFRSF) promote ILC2 activity. In this review, we discuss evidence supporting a relationship between ILC2 and TNFSF/TNFRSF axis in eosinophilic asthma and the role of this relationship in severe asthma with airway autoimmune responses. Full article

(This article belongs to the Special Issue Biomarkers of Severe Asthma: From Pathogenetic Mechanisms to Clinical Application)

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15 pages, 2511 KiB

Open AccessEditor’s ChoiceArticle

Menthol Pretreatment Alleviates Campylobacter jejuni-Induced Enterocolitis in Human Gut Microbiota-Associated IL-10^−/− Mice

by Markus M. Heimesaat, Luis Q. Langfeld, Niklas Schabbel, Nizar W. Shayya, Soraya Mousavi and Stefan Bereswill

Biomolecules 2024, 14(3), 290; https://doi.org/10.3390/biom14030290 - 29 Feb 2024

Cited by 1 | Viewed by 1329

Abstract

Human Campylobacter jejuni infections are of worldwide importance and represent the most commonly reported bacterial enteritis cases in middle- and high-income countries. Since antibiotics are usually not indicated and the severity of campylobacteriosis is directly linked to the risk of developing post-infectious complications, [...] Read more.

Human Campylobacter jejuni infections are of worldwide importance and represent the most commonly reported bacterial enteritis cases in middle- and high-income countries. Since antibiotics are usually not indicated and the severity of campylobacteriosis is directly linked to the risk of developing post-infectious complications, non-toxic antibiotic-independent treatment approaches are highly desirable. Given its health-promoting properties, including anti-microbial and anti-inflammatory activities, we tested the disease-alleviating effects of oral menthol in murine campylobacteriosis. Therefore, human gut microbiota-associated IL-10^−/− mice were orally subjected to synthetic menthol starting a week before C. jejuni infection and followed up until day 6 post-infection. Whereas menthol pretreatment did not improve campylobacteriosis symptoms, it resulted in reduced colonic C. jejuni numbers and alleviated both macroscopic and microscopic aspects of C. jejuni infection in pretreated mice vs. controls. Menthol pretreatment dampened the recruitment of macrophages, monocytes, and T lymphocytes to colonic sites of infection, which was accompanied by mitigated intestinal nitric oxide secretion. Furthermore, menthol pretreatment had only marginal effects on the human fecal gut microbiota composition during the C. jejuni infection. In conclusion, the results of this preclinical placebo-controlled intervention study provide evidence that menthol application constitutes a promising way to tackle acute campylobacteriosis, thereby reducing the risk for post-infectious complications. Full article

(This article belongs to the Special Issue The Value of Natural Compounds as Therapeutic Agents: 2nd Edition)

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18 pages, 2267 KiB

Open AccessEditor’s ChoiceArticle

Alterations of the Adipo–Myokine Irisin in Sepsis and Septic Shock: Diagnostic and Prognostic Implications

by Irene Karampela, Natalia G. Vallianou, Dimitrios Tsilingiris, Gerasimos Socrates Christodoulatos, Sotiria Psallida, Dimitris Kounatidis, Theodora Stratigou, Ioanna Marinou, Evaggelos Vogiatzakis and Maria Dalamaga

Biomolecules 2024, 14(3), 291; https://doi.org/10.3390/biom14030291 - 29 Feb 2024

Cited by 2 | Viewed by 1272

Abstract

Irisin, a novel adipo-myokine with metabolic regulatory functions, exerts anti-inflammatory, antioxidant, and anti-apoptotic actions that may confer protection against sepsis-induced organ injury in experimental studies. Until now, only one human study has explored circulating irisin at sepsis onset. We aimed to examine serum [...] Read more.

Irisin, a novel adipo-myokine with metabolic regulatory functions, exerts anti-inflammatory, antioxidant, and anti-apoptotic actions that may confer protection against sepsis-induced organ injury in experimental studies. Until now, only one human study has explored circulating irisin at sepsis onset. We aimed to examine serum irisin and its kinetics in critically ill patients with sepsis and septic shock with regard to sepsis severity and outcome. We enrolled 102 critically ill patients with sepsis or septic shock within 48 h of diagnosis and 102 age- and gender-matched healthy controls. Irisin was determined in serum upon enrollment in all participants and one week later in patients using an immunoenzymatic method. The outcome of sepsis was recorded 28 days after enrollment. At enrollment, circulating irisin was significantly lower in patients than controls (22.3 ± 6.8 μg/L vs. 28.1 ± 6.7 μg/L, p < 0.001), and increased significantly one week later (22.3 ± 6.8 μg/L vs. 26.6 ± 9.5 μg/L, p < 0.001). Irisin was significantly lower in patients who presented with septic shock than those with sepsis, and in non-survivors than survivors both at enrollment and one week later. However, kinetics of irisin did not differ between the groups (p > 0.05). Patients with higher circulating irisin during the first week of sepsis had a better outcome (p < 0.001). Lower irisin was independently associated with 28-day mortality (sepsis onset: HR 0.44, 95% C.I. 0.26–0.77, p = 0.004 and one week after: HR 0.37, 95% C.I. 0.23–0.58, p < 0.001). Irisin was negatively correlated with severity scores, metabolic, and inflammatory biomarkers. Circulating irisin decreases early in sepsis and is an independent predictor of 28-day mortality. Irisin may be a promising diagnostic and prognostic sepsis biomarker; nevertheless, larger studies are needed to explore its role in sepsis. Full article

(This article belongs to the Collection Feature Papers in Section Molecular Medicine)

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22 pages, 2181 KiB

Open AccessEditor’s ChoiceReview

Astrocytes: The Stars in Neurodegeneration?

by Katarina Stoklund Dittlau and Kristine Freude

Biomolecules 2024, 14(3), 289; https://doi.org/10.3390/biom14030289 - 28 Feb 2024

Cited by 6 | Viewed by 2570

Abstract

Today, neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline [...] Read more.

Today, neurodegenerative disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline has been explained by the very apparent deterioration of neurons in various regions of the brain and spinal cord. However, more recent studies show that disease progression is greatly influenced by the vast population of glial cells. Astrocytes are traditionally considered star-shaped cells on which neurons rely heavily for their optimal homeostasis and survival. Increasing amounts of evidence depict how astrocytes lose their supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many of these changes are similar across various neurodegenerative diseases, and in this review, we highlight these commonalities. We discuss how astrocyte dysfunction drives neuronal demise across a wide range of neurodegenerative diseases, but rather than categorizing based on disease, we aim to provide an overview based on currently known mechanisms. As such, this review delivers a different perspective on the disease causes of neurodegeneration in the hope to encourage further cross-disease studies into shared disease mechanisms, which might ultimately disclose potentially common therapeutic entry points across a wide panel of neurodegenerative diseases. Full article

(This article belongs to the Special Issue The Contribution of Astrocytes to Neuropathology)

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27 pages, 2833 KiB

Open AccessEditor’s ChoiceReview

N-Glycosylation as a Modulator of Protein Conformation and Assembly in Disease

by Chiranjeevi Pasala, Sahil Sharma, Tanaya Roychowdhury, Elisabetta Moroni, Giorgio Colombo and Gabriela Chiosis

Biomolecules 2024, 14(3), 282; https://doi.org/10.3390/biom14030282 - 27 Feb 2024

Cited by 1 | Viewed by 4889

Abstract

Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the [...] Read more.

Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations characterized by distinct interactomes—namely, protein assemblies—under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation’s influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly, and disease. Full article

(This article belongs to the Special Issue Protein Glycosylation and Human Diseases)

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17 pages, 3659 KiB

Open AccessEditor’s ChoiceArticle

Bis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands

by Srijana Upadhyay, Amanuel Esayas Hailemariam, Fuada Mariyam, Zahin Hafiz, Gregory Martin, Jainish Kothari, Evan Farkas, Gargi Sivaram, Logan Bell, Ronald Tjalkens and Stephen Safe

Biomolecules 2024, 14(3), 284; https://doi.org/10.3390/biom14030284 - 27 Feb 2024

Viewed by 1944

Abstract

Bis-indole derived compounds such as 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl) methane (DIM-3,5) and the corresponding 4-hydroxyl analogs (DIM8-3,5) are NR4A1 ligands that act as inverse NR4A1 agonists and are potent inhibitors of tumor growth. The high potency of several DIM-3,5 analogs (IC₅₀ < 1 mg/kg/day), coupled [...] Read more.

Bis-indole derived compounds such as 1,1-bis(3′-indolyl)-1-(3,5-disubstitutedphenyl) methane (DIM-3,5) and the corresponding 4-hydroxyl analogs (DIM8-3,5) are NR4A1 ligands that act as inverse NR4A1 agonists and are potent inhibitors of tumor growth. The high potency of several DIM-3,5 analogs (IC₅₀ < 1 mg/kg/day), coupled with the >60% similarity of the ligand-binding domains (LBDs) of NR4A1 and NR4A2 and the pro-oncogenic activities of both receptors lead us to hypothesize that these compounds may act as dual NR4A1 and NR4A2 ligands. Using a fluorescence binding assay, it was shown that 22 synthetic DIM8-3,5 and DIM-3,5 analogs bound the LBD of NR4A1 and NR4A2 with most K_D values in the low µM range. Moreover, the DIM-3,5 and DIM8-3,5 analogs also decreased NR4A1- and NR4A2-dependent transactivation in U87G glioblastoma cells transfected with GAL4-NR4A1 or GAL4-NR4A2 chimeras and a UAS-luciferase reporter gene construct. The DIM-3,5 and DIM8-3,5 analogs were cytotoxic to U87 glioblastoma and RKO colon cancer cells and the DIM-3,5 compounds were more cytotoxic than the DIM8-3,5 compounds. These studies show that both DIM-3,5 and DIM8-3,5 compounds previously identified as NR4A1 ligands bind both NR4A1 and NR4A2 and are dual NR4A1/2 ligands. Full article

(This article belongs to the Special Issue Feature Papers in the Natural and Bio-Derived Molecules Section)

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21 pages, 795 KiB

Open AccessEditor’s ChoiceReview

Vascular Calcification: Molecular Networking, Pathological Implications and Translational Opportunities

by Miguel A. Ortega, Diego De Leon-Oliva, Maria José Gimeno-Longas, Diego Liviu Boaru, Oscar Fraile-Martinez, Cielo García-Montero, Amador Velazquez de Castro, Silvestra Barrena-Blázquez, Laura López-González, Silvia Amor, Natalio García-Honduvilla, Julia Buján, Luis G. Guijarro, Elisa Castillo-Ruiz, Miguel Ángel Álvarez-Mon, Agustin Albillos, Melchor Álvarez-Mon, Raul Diaz and Miguel A. Saez

Biomolecules 2024, 14(3), 275; https://doi.org/10.3390/biom14030275 - 25 Feb 2024

Viewed by 1941

Abstract

Calcification is a process of accumulation of calcium in tissues and deposition of calcium salts by the crystallization of PO₄³⁻ and ionized calcium (Ca²⁺). It is a crucial process in the development of bones and teeth. However, pathological calcification [...] Read more.

Calcification is a process of accumulation of calcium in tissues and deposition of calcium salts by the crystallization of PO₄³⁻ and ionized calcium (Ca²⁺). It is a crucial process in the development of bones and teeth. However, pathological calcification can occur in almost any soft tissue of the organism. The better studied is vascular calcification, where calcium salts can accumulate in the intima or medial layer or in aortic valves, and it is associated with higher mortality and cardiovascular events, including myocardial infarction, stroke, aortic and peripheral artery disease (PAD), and diabetes or chronic kidney disease (CKD), among others. The process involves an intricate interplay of different cellular components, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), fibroblasts, and pericytes, concurrent with the activation of several signaling pathways, calcium, Wnt, BMP/Smad, and Notch, and the regulation by different molecular mediators, growth factors (GFs), osteogenic factors and matrix vesicles (MVs). In the present review, we aim to explore the cellular players, molecular pathways, biomarkers, and clinical treatment strategies associated with vascular calcification to provide a current and comprehensive overview of the topic. Full article

(This article belongs to the Special Issue Tissue Calcification in Normal and Pathological Environments)

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18 pages, 6004 KiB

Open AccessEditor’s ChoiceArticle

Neuroprotective Effects of the Nutraceutical Dehydrozingerone and Its C₂-Symmetric Dimer in a Drosophila Model of Parkinson’s Disease

by Maria Dolores Setzu, Ignazia Mocci, Davide Fabbri, Paola Carta, Patrizia Muroni, Andrea Diana, Maria Antonietta Dettori and Maria Antonietta Casu

Biomolecules 2024, 14(3), 273; https://doi.org/10.3390/biom14030273 - 24 Feb 2024

Viewed by 2121

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons responsible for unintended or uncontrollable movements. Mutations in the leucine-rich repeat kinase 2 locus contribute to genetic forms of PD. The fruit fly Drosophila melanogaster carrying this mutation (LRRK2-Dm) [...] Read more.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons responsible for unintended or uncontrollable movements. Mutations in the leucine-rich repeat kinase 2 locus contribute to genetic forms of PD. The fruit fly Drosophila melanogaster carrying this mutation (LRRK2-Dm) is an in vivo model of PD that develops motor impairment and stands for an eligible non-mammalian paradigm to test novel therapeutic approaches. Dehydrozingerone (DHZ) is a natural phenolic compound isolated from ginger and presents anti-inflammatory, antioxidant and neuroprotective properties, making it a potential therapeutic target for PD. We administered DHZ and its C₂-symmetric dimer (DHZ-DIM) at 0.5 and 1 mM for 14 and 21 days in the LRRK2-Dm, with the aim of assessing changes in rescuing motor behavior, brain dopaminergic neurons, mitochondria and synapses (T-bars). The shorter treatment with both molecules revealed efficacy at the higher dose, improving climbing behavior with a prevention of dopaminergic neuronal demise. After 21 days, a recovery of the motor disability, dopaminergic neuron loss, mitochondrial damage and T-bars failure was observed with the DHZ-DIM. Our data indicate that the DHZ-DIM exerts a more potent neuroprotective effect with respect to the monomer in LRRK2-Dm, prompting further investigation of these compounds in rodent models of PD. Full article

(This article belongs to the Special Issue Biomolecular Approaches and Drugs for Neurodegeneration)

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19 pages, 2445 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Early Life Stress Is Associated with Alterations in Lymphocyte Subsets Independent of Increased Inflammation in Adolescents

by Brie M. Reid, Christopher Desjardins, Bharat Thyagarajan, Michael A. Linden and Megan Gunnar

Biomolecules 2024, 14(3), 262; https://doi.org/10.3390/biom14030262 - 22 Feb 2024

Cited by 2 | Viewed by 1503

Abstract

Early life stress (ELS) is linked to an elevated risk of poor health and early mortality, with emerging evidence pointing to the pivotal role of the immune system in long-term health outcomes. While recent research has focused on the impact of ELS on [...] Read more.

Early life stress (ELS) is linked to an elevated risk of poor health and early mortality, with emerging evidence pointing to the pivotal role of the immune system in long-term health outcomes. While recent research has focused on the impact of ELS on inflammation, this study examined the impact of ELS on immune function, including CMV seropositivity, inflammatory cytokines, and lymphocyte cell subsets in an adolescent cohort. This study used data from the Early Life Stress and Cardiometabolic Health in Adolescence Study (N = 191, aged 12 to 21 years, N = 95 exposed to ELS). We employed multiple regression to investigate the association between ELS, characterized by early institutional care, cytomegalovirus (CMV) seropositivity (determined by chemiluminescent immunoassay), inflammation (CRP, IL-6, and TNF-a determined by ELISA), and twenty-one immune cell subsets characterized by flow cytometry (sixteen T cell subsets and five B cell subsets). Results reveal a significant association between ELS and lymphocytes that was independent of the association between ELS and inflammation: ELS was associated with increased effector memory helper T cells, effector memory cytotoxic T cells, senescent T cells, senescent B cells, and IgD− memory B cells compared to non-adopted youth. ELS was also associated with reduced percentages of helper T cells and naive cytotoxic T cells. Exploratory analyses found that the association between ELS and fewer helper T cells and increased cytotoxic T cells remained even in cytomegalovirus (CMV) seronegative youth. These findings suggest that ELS is associated with cell subsets that are linked to early mortality risk in older populations and markers of replicative senescence, separate from inflammation, in adolescents. Full article

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

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25 pages, 2696 KiB

Open AccessEditor’s ChoiceReview

Tricarboxylic Acid Cycle Intermediates and Individual Ageing

by Natalia Kurhaluk

Biomolecules 2024, 14(3), 260; https://doi.org/10.3390/biom14030260 - 22 Feb 2024

Cited by 2 | Viewed by 2350

Abstract

Anti-ageing biology and medicine programmes are a focus of genetics, molecular biology, immunology, endocrinology, nutrition, and therapy. This paper discusses metabolic therapies aimed at prolonging longevity and/or health. Individual components of these effects are postulated to be related to the energy supply by [...] Read more.

Anti-ageing biology and medicine programmes are a focus of genetics, molecular biology, immunology, endocrinology, nutrition, and therapy. This paper discusses metabolic therapies aimed at prolonging longevity and/or health. Individual components of these effects are postulated to be related to the energy supply by tricarboxylic acid (TCA) cycle intermediates and free radical production processes. This article presents several theories of ageing and clinical descriptions of the top markers of ageing, which define ageing in different categories; additionally, their interactions with age-related changes and diseases related to α-ketoglutarate (AKG) and succinate SC formation and metabolism in pathological states are explained. This review describes convincingly the differences in the mitochondrial characteristics of energy metabolism in animals, with different levels (high and low) of physiological reactivity of functional systems related to the state of different regulatory systems providing oxygen-dependent processes. Much attention is given to the crucial role of AKG and SC in the energy metabolism in cells related to amino acid synthesis, epigenetic regulation, cell stemness, and differentiation, as well as metabolism associated with the development of pathological conditions and, in particular, cancer cells. Another goal was to address the issue of ageing in terms of individual characteristics related to physiological reactivity. This review also demonstrated the role of the Krebs cycle as a key component of cellular energy and ageing, which is closely associated with the development of various age-related pathologies, such as cancer, type 2 diabetes, and cardiovascular or neurodegenerative diseases where the mTOR pathway plays a key role. This article provides postulates of postischaemic phenomena in an ageing organism and demonstrates the dependence of accelerated ageing and age-related pathology on the levels of AKG and SC in studies on different species (roundworm Caenorhabditis elegans, Drosophila, mice, and humans used as models). The findings suggest that this approach may also be useful to show that Krebs cycle metabolites may be involved in age-related abnormalities of the mitochondrial metabolism and may thus induce epigenetic reprogramming that contributes to the senile phenotype and degenerative diseases. The metabolism of these compounds is particularly important when considering ageing mechanisms connected with different levels of initial physiological reactivity and able to initiate individual programmed ageing, depending on the intensity of oxygen consumption, metabolic peculiarities, and behavioural reactions. Full article

(This article belongs to the Special Issue Molecular Aspects of Diseases Origin and Development)

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37 pages, 11104 KiB

Open AccessEditor’s ChoiceReview

Exploring FDA-Approved Frontiers: Insights into Natural and Engineered Peptide Analogues in the GLP-1, GIP, GHRH, CCK, ACTH, and α-MSH Realms

by Othman Al Musaimi

Biomolecules 2024, 14(3), 264; https://doi.org/10.3390/biom14030264 - 22 Feb 2024

Cited by 7 | Viewed by 5716

Abstract

Peptides continue to gain significance in the pharmaceutical arena. Since the unveiling of insulin in 1921, the Food and Drug Administration (FDA) has authorised around 100 peptides for various applications. Peptides, although initially derived from endogenous sources, have evolved beyond their natural origins, [...] Read more.

Peptides continue to gain significance in the pharmaceutical arena. Since the unveiling of insulin in 1921, the Food and Drug Administration (FDA) has authorised around 100 peptides for various applications. Peptides, although initially derived from endogenous sources, have evolved beyond their natural origins, exhibiting favourable therapeutic effectiveness. Medicinal chemistry has played a pivotal role in synthesising valuable natural peptide analogues, providing synthetic alternatives with therapeutic potential. Furthermore, key chemical modifications have enhanced the stability of peptides and strengthened their interactions with therapeutic targets. For instance, selective modifications have extended their half-life and lessened the frequency of their administration while maintaining the desired therapeutic action. In this review, I analyse the FDA approval of natural peptides, as well as engineered peptides for diabetes treatment, growth-hormone-releasing hormone (GHRH), cholecystokinin (CCK), adrenocorticotropic hormone (ACTH), and α-melanocyte stimulating hormone (α-MSH) peptide analogues. Attention will be paid to the structure, mode of action, developmental journey, FDA authorisation, and the adverse effects of these peptides. Full article

(This article belongs to the Special Issue Active Peptides as Functional Biomolecules: In Vitro and In Vivo Studies)

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19 pages, 1770 KiB

Open AccessEditor’s ChoiceArticle

SynerGNet: A Graph Neural Network Model to Predict Anticancer Drug Synergy

by Mengmeng Liu, Gopal Srivastava, J. Ramanujam and Michal Brylinski

Biomolecules 2024, 14(3), 253; https://doi.org/10.3390/biom14030253 - 21 Feb 2024

Cited by 1 | Viewed by 1786

Abstract

Drug combination therapy shows promise in cancer treatment by addressing drug resistance, reducing toxicity, and enhancing therapeutic efficacy. However, the intricate and dynamic nature of biological systems makes identifying potential synergistic drugs a costly and time-consuming endeavor. To facilitate the development of combination [...] Read more.

Drug combination therapy shows promise in cancer treatment by addressing drug resistance, reducing toxicity, and enhancing therapeutic efficacy. However, the intricate and dynamic nature of biological systems makes identifying potential synergistic drugs a costly and time-consuming endeavor. To facilitate the development of combination therapy, techniques employing artificial intelligence have emerged as a transformative solution, providing a sophisticated avenue for advancing existing therapeutic approaches. In this study, we developed SynerGNet, a graph neural network model designed to accurately predict the synergistic effect of drug pairs against cancer cell lines. SynerGNet utilizes cancer-specific featured graphs created by integrating heterogeneous biological features into the human protein–protein interaction network, followed by a reduction process to enhance topological diversity. Leveraging synergy data provided by AZ-DREAM Challenges, the model yields a balanced accuracy of 0.68, significantly outperforming traditional machine learning. Encouragingly, augmenting the training data with carefully constructed synthetic instances improved the balanced accuracy of SynerGNet to 0.73. Finally, the results of an independent validation conducted against DrugCombDB demonstrated that it exhibits a strong performance when applied to unseen data. SynerGNet shows a great potential in detecting drug synergy, positioning itself as a valuable tool that could contribute to the advancement of combination therapy for cancer treatment. Full article

(This article belongs to the Special Issue Artificial Intelligence (AI) in Biomedicine)

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18 pages, 17688 KiB

Open AccessEditor’s ChoiceArticle

Peroxisomal Localization of a Truncated HMG-CoA Reductase under Low Cholesterol Conditions

by Jianqiu Wang, Markus Kunze, Andrea Villoria-González, Isabelle Weinhofer and Johannes Berger

Biomolecules 2024, 14(2), 244; https://doi.org/10.3390/biom14020244 - 19 Feb 2024

Cited by 1 | Viewed by 1566

Abstract

3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase, HMGCR) is one of the rate-limiting enzymes in the mevalonate pathway required for cholesterol biosynthesis. It is an integral membrane protein of the endoplasmic reticulum (ER) but has occasionally been described in peroxisomes. By co-immunofluorescence microscopy using different HMGCR [...] Read more.

3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase, HMGCR) is one of the rate-limiting enzymes in the mevalonate pathway required for cholesterol biosynthesis. It is an integral membrane protein of the endoplasmic reticulum (ER) but has occasionally been described in peroxisomes. By co-immunofluorescence microscopy using different HMGCR antibodies, we present evidence for a dual localization of HMGCR in the ER and peroxisomes in differentiated human monocytic THP-1 cells, primary human monocyte-derived macrophages and human primary skin fibroblasts under conditions of low cholesterol and statin treatment. Using density gradient centrifugation and Western blot analysis, we observed a truncated HMGCR variant of 76 kDa in the peroxisomal fractions, while a full-length HMGCR of 96 kDa was contained in fractions of the ER. In contrast to primary human control fibroblasts, peroxisomal HMGCR was not found in fibroblasts from patients suffering from type-1 rhizomelic chondrodysplasia punctata, who lack functional PEX7 and, thus, cannot import peroxisomal matrix proteins harboring a type-2 peroxisomal targeting signal (PTS2). Moreover, in the N–terminal region of the soluble 76 kDa C-terminal catalytic domain, we identified a PTS2-like motif, which was functional in a reporter context. We propose that under sterol-depleted conditions, part of the soluble HMGCR domain, which is released from the ER by proteolytic processing for further turnover, remains sufficiently long in the cytosol for peroxisomal import via a PTS2/PEX7-dependent mechanism. Altogether, our findings describe a dual localization of HMGCR under combined lipid depletion and statin treatment, adding another puzzle piece to the complex regulation of HMGCR. Full article

(This article belongs to the Special Issue The Role of Peroxisome in Cell Functions and Pathological Consequences of Its Dysfunction)

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31 pages, 2909 KiB

Open AccessEditor’s ChoiceArticle

CLPP-Null Eukaryotes with Excess Heme Biosynthesis Show Reduced L-arginine Levels, Probably via CLPX-Mediated OAT Activation

by Jana Key, Suzana Gispert, Arvind Reddy Kandi, Daniela Heinz, Andrea Hamann, Heinz D. Osiewacz, David Meierhofer and Georg Auburger

Biomolecules 2024, 14(2), 241; https://doi.org/10.3390/biom14020241 - 19 Feb 2024

Cited by 1 | Viewed by 1538

Abstract

The serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome, which presents with growth deficits, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP loss leads to longevity. CLPP substrates [...] Read more.

The serine peptidase CLPP is conserved among bacteria, chloroplasts, and mitochondria. In humans and mice, its loss causes Perrault syndrome, which presents with growth deficits, infertility, deafness, and ataxia. In the filamentous fungus Podospora anserina, CLPP loss leads to longevity. CLPP substrates are selected by CLPX, an AAA+ unfoldase. CLPX is known to target delta-aminolevulinic acid synthase (ALAS) to promote pyridoxal phosphate (PLP) binding. CLPX may also influence cofactor association with other enzymes. Here, the evaluation of P. anserina metabolomics highlighted a reduction in arginine/histidine levels. In Mus musculus cerebellum, reductions in arginine/histidine and citrulline occurred with a concomitant accumulation of the heme precursor protoporphyrin IX. This suggests that the increased biosynthesis of 5-carbon (C5) chain deltaALA consumes not only C4 succinyl-CoA and C1 glycine but also specific C5 delta amino acids. As enzymes responsible for these effects, the elevated abundance of CLPX and ALAS is paralleled by increased OAT (PLP-dependent, ornithine delta-aminotransferase) levels. Possibly as a consequence of altered C1 metabolism, the proteome profiles of P. anserina CLPP-null cells showed strong accumulation of a methyltransferase and two mitoribosomal large subunit factors. The reduced histidine levels may explain the previously observed metal interaction problems. As the main nitrogen-storing metabolite, a deficiency in arginine would affect the urea cycle and polyamine synthesis. Supplementation of arginine and histidine might rescue the growth deficits of CLPP-mutant patients. Full article

(This article belongs to the Section Molecular Biology)

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18 pages, 3327 KiB

Open AccessEditor’s ChoiceArticle

Alendronate-Grafted Nanoemulsions for Bone-Targeted Vincristine Delivery: Preliminary Studies on Cell and Animal Models

by Ian Stoppa, Chiara Dianzani, Nausicaa Clemente, Annalisa Bozza, Valentina Bordano, Sara Garelli, Luigi Cangemi, Umberto Dianzani and Luigi Battaglia

Biomolecules 2024, 14(2), 238; https://doi.org/10.3390/biom14020238 - 18 Feb 2024

Viewed by 1078

Abstract

Bone is a site of distant metastases, which are a common cause of morbidity and mortality with a high socio-economic impact, for many malignant tumours. In order to engineer pharmacological therapies that are suitable for this debilitating disease, this experimental work presents injectable [...] Read more.

Bone is a site of distant metastases, which are a common cause of morbidity and mortality with a high socio-economic impact, for many malignant tumours. In order to engineer pharmacological therapies that are suitable for this debilitating disease, this experimental work presents injectable lipid nanoemulsions, which are endowed with a long history of safe clinical usage in parenteral nutrition, their loading with vincristine and their grafting with alendronate, with a dual purpose: merging the anticancer activity of bisphosphonates and vincristine, and enhancing bone-targeted delivery. In cell studies, alendronate synergised with the anti-migration activity of vincristine, which is important as migration plays a key role in the metastatisation process. In preliminary animal studies, carried out thanks to IVIS technology, alendronate conjugation enhanced the bone targeting of fluorescently labelled nanoemulsions. These encouraging results will drive further studies on suitable animal models of the disease. Full article

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16 pages, 2857 KiB

Open AccessEditor’s ChoiceArticle

Use of Various Sugarcane Byproducts to Produce Lipid Extracts with Bioactive Properties: Physicochemical and Biological Characterization

by Joana Odila Pereira, Diana Oliveira, Margarida Faustino, Susana S. M. P. Vidigal, Ana Margarida Pereira, Carlos M. H. Ferreira, Ana Sofia Oliveira, Joana Durão, Luís M. Rodríguez-Alcalá, Manuela E. Pintado, Ana Raquel Madureira and Ana P. Carvalho

Biomolecules 2024, 14(2), 233; https://doi.org/10.3390/biom14020233 - 17 Feb 2024

Viewed by 1406

Abstract

Sugarcane, a globally cultivated crop constituting nearly 80% of total sugar production, yields residues from harvesting and sugar production known for their renewable bioactive compounds with health-promoting properties. Despite previous studies, the intricate interplay of extracts from diverse sugarcane byproducts and their biological [...] Read more.

Sugarcane, a globally cultivated crop constituting nearly 80% of total sugar production, yields residues from harvesting and sugar production known for their renewable bioactive compounds with health-promoting properties. Despite previous studies, the intricate interplay of extracts from diverse sugarcane byproducts and their biological attributes remains underexplored. This study focused on extracting the lipid fraction from a blend of selected sugarcane byproducts (straw, bagasse, and filter cake) using ethanol. The resulting extract underwent comprehensive characterization, including physicochemical analysis (FT-IR, DSC, particle size distribution, and color) and chemical composition assessment (GC-MS). The biological properties were evaluated through antihypertensive (ACE), anticholesterolemic (HMG-CoA reductase), and antidiabetic (alpha-glucosidase and Dipeptidyl Peptidase-IV) assays, alongside in vitro biocompatibility assessments in Caco-2 and Hep G2 cells. The phytochemicals identified, such as β-sitosterol and 1-octacosanol, likely contribute to the extract’s antidiabetic, anticholesterolemic, and antihypertensive potential, given their association with various beneficial bioactivities. The extract exhibited substantial antidiabetic effects, inhibiting α-glucosidase (5–60%) and DPP-IV activity (25–100%), anticholesterolemic potential with HMG-CoA reductase inhibition (11.4–63.2%), and antihypertensive properties through ACE inhibition (24.0–27.3%). These findings lay the groundwork for incorporating these ingredients into the development of food supplements or nutraceuticals, offering potential for preventing and managing metabolic syndrome-associated conditions. Full article

(This article belongs to the Special Issue Lipids in Health and Diseases)

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18 pages, 3301 KiB

Open AccessEditor’s ChoiceArticle

Steroid Metabolomic Signature in Term and Preterm Infants

by Matthias Heckmann, Anna S. Runkel, Donna E. Sunny, Michaela F. Hartmann, Till Ittermann and Stefan A. Wudy

Biomolecules 2024, 14(2), 235; https://doi.org/10.3390/biom14020235 - 17 Feb 2024

Cited by 2 | Viewed by 1222

Abstract

Adrenal function is essential for survival and well-being of preterm babies. In addition to glucocorticoids, it has been hypothesized that C₁₉-steroids (DHEA-metabolites) from the fetal zone of the adrenal gland may play a role as endogenous neuroprotective steroids. In 39 term-born [...] Read more.

Adrenal function is essential for survival and well-being of preterm babies. In addition to glucocorticoids, it has been hypothesized that C₁₉-steroids (DHEA-metabolites) from the fetal zone of the adrenal gland may play a role as endogenous neuroprotective steroids. In 39 term-born (≥37 weeks gestational age), 42 preterm (30–36 weeks) and 51 early preterm (<30 weeks) infants 38 steroid metabolites were quantified by GC-MS in 24-h urinary samples. In each gestational age group, three distinctive cluster were identified by pattern analysis (k-means clustering). Individual steroidal fingerprints and clinical phenotype were analyzed at the 3rd day of life. Overall, the excretion rates of C₂₁-steroids (glucocorticoid precursors, cortisol, and cortisone metabolites) were low (<99 μg/kg body weight/d) whereas the excretion rates of C₁₉-steroids were up to 10 times higher. There was a shift to higher excretion rates of C₁₉-steroids in both preterm groups compared to term infants but only minor differences in the distribution of C₂₁-steroids. Comparable metabolic patterns were found between gestational age groups: Cluster 1 showed mild elevation of C₂₁- and C₁₉-steroids with the highest incidence of neonatal morbidities in term and severe intraventricular hemorrhage in early preterm infants. In cluster 2 lowest excretion in general was noted but no clinically unique phenotype. Cluster 3 showed highest elevation of C₂₁-steroids and C₁₉-steroids but no clinically unique phenotype. Significant differences in steroid metabolism between clusters are only partly reflected by gestational age and disease severity. In early preterm infants, higher excretion rates of glucocorticoids and their precursors were associated with severe cerebral hemorrhage. High excretion rates of C₁₉-steroids in preterm infants may indicate a biological significance. Full article

(This article belongs to the Special Issue Role of Neuroactive Steroids in Health and Disease)

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18 pages, 6697 KiB

Open AccessEditor’s ChoiceArticle

Antimicrobial Potency of Fmoc-Phe-Phe Dipeptide Hydrogels with Encapsulated Porphyrin Chromophores Is a Promising Alternative in Antimicrobial Resistance

by Chrysanthi Pinelopi Apostolidou, Chrysoula Kokotidou, Varvara Platania, Vasilis Nikolaou, Georgios Landrou, Emmanouil Nikoloudakis, Georgios Charalambidis, Maria Chatzinikolaidou, Athanassios G. Coutsolelos and Anna Mitraki

Biomolecules 2024, 14(2), 226; https://doi.org/10.3390/biom14020226 - 16 Feb 2024

Cited by 1 | Viewed by 1655

Abstract

Antimicrobial resistance (AMR) poses a significant global health risk as a consequence of misuse of antibiotics. Owing to the increasing antimicrobial resistance, it became imperative to develop novel molecules and materials with antimicrobial properties. Porphyrins and metalloporphyrins are compounds which present antimicrobial properties [...] Read more.

Antimicrobial resistance (AMR) poses a significant global health risk as a consequence of misuse of antibiotics. Owing to the increasing antimicrobial resistance, it became imperative to develop novel molecules and materials with antimicrobial properties. Porphyrins and metalloporphyrins are compounds which present antimicrobial properties especially after irradiation. As a consequence, porphyrinoids have recently been utilized as antimicrobial agents in antimicrobial photodynamic inactivation in bacteria and other microorganisms. Herein, we report the encapsulation of porphyrins into peptide hydrogels which serve as delivery vehicles. We selected the self-assembling Fmoc-Phe-Phe dipeptide, a potent gelator, as a scaffold due to its previously reported biocompatibility and three different water-soluble porphyrins as photosensitizers. We evaluated the structural, mechanical and in vitro degradation properties of these hydrogels, their interaction with NIH3T3 mouse skin fibroblasts, and we assessed their antimicrobial efficacy against Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) bacteria. We found out that the hydrogels are cytocompatible and display antimicrobial efficiency against both strains with the zinc porphyrins being more efficient. Therefore, these hydrogels present a promising alternative for combating bacterial infections in the face of growing AMR concerns. Full article

(This article belongs to the Section Biological and Bio- Materials)

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18 pages, 3662 KiB

Open AccessEditor’s ChoiceArticle

Comprehensive Analysis of the Role of Fibrinogen and Thrombin in Clot Formation and Structure for Plasma and Purified Fibrinogen

by Rebecca A. Risman, Heather A. Belcher, Ranjini K. Ramanujam, John W. Weisel, Nathan E. Hudson and Valerie Tutwiler

Biomolecules 2024, 14(2), 230; https://doi.org/10.3390/biom14020230 - 16 Feb 2024

Cited by 2 | Viewed by 2407

Abstract

Altered properties of fibrin clots have been associated with bleeding and thrombotic disorders, including hemophilia or trauma and heart attack or stroke. Clotting factors, such as thrombin and tissue factor, or blood plasma proteins, such as fibrinogen, play critical roles in fibrin network [...] Read more.

Altered properties of fibrin clots have been associated with bleeding and thrombotic disorders, including hemophilia or trauma and heart attack or stroke. Clotting factors, such as thrombin and tissue factor, or blood plasma proteins, such as fibrinogen, play critical roles in fibrin network polymerization. The concentrations and combinations of these proteins affect the structure and stability of clots, which can lead to downstream complications. The present work includes clots made from plasma and purified fibrinogen and shows how varying fibrinogen and activation factor concentrations affect the fibrin properties under both conditions. We used a combination of scanning electron microscopy, confocal microscopy, and turbidimetry to analyze clot/fiber structure and polymerization. We quantified the structural and polymerization features and found similar trends with increasing/decreasing fibrinogen and thrombin concentrations for both purified fibrinogen and plasma clots. Using our compiled results, we were able to generate multiple linear regressions that predict structural and polymerization features using various fibrinogen and clotting agent concentrations. This study provides an analysis of structural and polymerization features of clots made with purified fibrinogen or plasma at various fibrinogen and clotting agent concentrations. Our results could be utilized to aid in interpreting results, designing future experiments, or developing relevant mathematical models. Full article

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30 pages, 9872 KiB

Open AccessEditor’s ChoiceArticle

Bariatric Surgery Induces Alterations in the Immune Profile of Peripheral Blood T Cells

by Pedro Barbosa, Aryane Pinho, André Lázaro, Diogo Paula, José G. Tralhão, Artur Paiva, Maria J. Pereira, Eugenia Carvalho and Paula Laranjeira

Biomolecules 2024, 14(2), 219; https://doi.org/10.3390/biom14020219 - 12 Feb 2024

Cited by 1 | Viewed by 2035

Abstract

Low-grade inflammation is closely linked to obesity and obesity-related comorbidities; therefore, immune cells have become an important topic in obesity research. Here, we performed a deep phenotypic characterization of circulating T cells in people with obesity, using flow cytometry. Forty-one individuals with obesity [...] Read more.

Low-grade inflammation is closely linked to obesity and obesity-related comorbidities; therefore, immune cells have become an important topic in obesity research. Here, we performed a deep phenotypic characterization of circulating T cells in people with obesity, using flow cytometry. Forty-one individuals with obesity (OB) and clinical criteria for bariatric surgery were enrolled in this study. We identified and quantified 44 different circulating T cell subsets and assessed their activation status and the expression of immune-checkpoint molecules, immediately before (T1) and 7–18 months after (T2) the bariatric surgery. Twelve age- and sex-matched healthy individuals (nOB) were also recruited. The OB participants showed higher leukocyte counts and a higher percentage of neutrophils. The percentage of circulating Th1 cells were negatively correlated to HbA1c and insulin levels. OB Th1 cells displayed a higher activation status and lower PD-1 expression. The percentage of Th17 and Th1/17 cells were increased in OB, whereas the CD4⁺ Tregs’ percentage was decreased. Interestingly, a higher proportion of OB CD4⁺ Tregs were polarized toward Th1- and Th1/17-like cells and expressed higher levels of CCR5. Bariatric surgery induced the recovery of CD4⁺ Treg cell levels and the expansion and activation of Tfh and B cells. Our results show alterations in the distribution and phenotype of circulating T cells from OB people, including activation markers and immune-checkpoint proteins, demonstrating that different metabolic profiles are associated to distinct immune profiles, and both are modulated by bariatric surgery. Full article

(This article belongs to the Special Issue Nutrition, Metabolism, and Obesity: Novel Strategies and Molecular Mechanisms—Future Perspectives)

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21 pages, 1053 KiB

Open AccessEditor’s ChoiceReview

The Genetic Basis, Lung Involvement, and Therapeutic Options in Niemann–Pick Disease: A Comprehensive Review

by Claudio Tirelli, Ornella Rondinone, Marta Italia, Sabrina Mira, Luca Alessandro Belmonte, Mauro De Grassi, Gabriele Guido, Sara Maggioni, Michele Mondoni, Monica Rosa Miozzo and Stefano Centanni

Biomolecules 2024, 14(2), 211; https://doi.org/10.3390/biom14020211 - 11 Feb 2024

Cited by 3 | Viewed by 2203

Abstract

Niemann–Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin [...] Read more.

Niemann–Pick Disease (NPD) is a rare autosomal recessive disease belonging to lysosomal storage disorders. Three types of NPD have been described: NPD type A, B, and C. NPD type A and B are caused by mutations in the gene SMPD1 coding for sphingomyelin phosphodiesterase 1, with a consequent lack of acid sphingomyelinase activity. These diseases have been thus classified as acid sphingomyelinase deficiencies (ASMDs). NPD type C is a neurologic disorder due to mutations in the genes NPC1 or NPC2, causing a defect of cholesterol trafficking and esterification. Although all three types of NPD can manifest with pulmonary involvement, lung disease occurs more frequently in NPD type B, typically with interstitial lung disease, recurrent pulmonary infections, and respiratory failure. In this sense, bronchoscopy with broncho-alveolar lavage or biopsy together with high-resolution computed tomography are fundamental diagnostic tools. Although several efforts have been made to find an effective therapy for NPD, to date, only limited therapeutic options are available. Enzyme replacement therapy with Olipudase α is the first and only approved disease-modifying therapy for patients with ASMD. A lung transplant and hematopoietic stem cell transplantation are also described for ASMD in the literature. The only approved disease-modifying therapy in NPD type C is miglustat, a substrate-reduction treatment. The aim of this review was to delineate a state of the art on the genetic basis and lung involvement in NPD, focusing on clinical manifestations, radiologic and histopathologic characteristics of the disease, and available therapeutic options, with a gaze on future therapeutic strategies. Full article

(This article belongs to the Section Molecular Medicine)

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10 pages, 456 KiB

Open AccessEditor’s ChoiceArticle

EEG Frequency Correlates with α₂-Receptor Density in Parkinson’s Disease

by Adam F. Kemp, Martin Kinnerup, Birger Johnsen, Steen Jakobsen, Adjmal Nahimi and Albert Gjedde

Biomolecules 2024, 14(2), 209; https://doi.org/10.3390/biom14020209 - 10 Feb 2024

Viewed by 1201

Abstract

Introduction: Increased theta and delta power and decreased alpha and beta power, measured with quantitative electroencephalography (EEG), have been demonstrated to have utility for predicting the development of dementia in patients with Parkinson’s disease (PD). Noradrenaline modulates cortical activity and optimizes cognitive processes. [...] Read more.

Introduction: Increased theta and delta power and decreased alpha and beta power, measured with quantitative electroencephalography (EEG), have been demonstrated to have utility for predicting the development of dementia in patients with Parkinson’s disease (PD). Noradrenaline modulates cortical activity and optimizes cognitive processes. We claim that the loss of noradrenaline may explain cognitive impairment and the pathological slowing of EEG waves. Here, we test the relationship between the number of noradrenergic α₂ adrenoceptors and changes in the spectral EEG ratio in patients with PD. Methods: We included nineteen patients with PD and thirteen healthy control (HC) subjects in the study. We used positron emission tomography (PET) with [¹¹C]yohimbine to quantify α₂ adrenoceptor density. We used EEG power in the delta (δ, 1.5–3.9 Hz), theta (θ, 4–7.9 Hz), alpha (α, 8–12.9 Hz) and beta (β, 13–30 Hz) bands in regression analyses to test the relationships between α₂ adrenoceptor density and EEG band power. Results: PD patients had higher power in the theta and delta bands compared to the HC volunteers. Patients’ theta band power was inversely correlated with α₂ adrenoceptor density in the frontal cortex. In the HC subjects, age was correlated with, and occipital background rhythm frequency (BRF) was inversely correlated with, α₂ adrenoceptor density in the frontal cortex, while occipital BRF was inversely correlated with α₂ adrenoceptor density in the thalamus. Conclusions: The findings support the claim that the loss or dysfunction of noradrenergic neurotransmission may relate to the parallel processes of cognitive decline and EEG slowing. Full article

(This article belongs to the Special Issue Novel Imaging Biomarkers for Brain PET Imaging)

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16 pages, 9984 KiB

Open AccessEditor’s ChoiceArticle

Neutrophils in HNSCC Can Be Associated with Both a Worse or Favorable Prognosis

by Hendrik Brunkhorst, Sören Schnellhardt, Maike Büttner-Herold, Christoph Daniel, Rainer Fietkau and Luitpold V. Distel

Biomolecules 2024, 14(2), 205; https://doi.org/10.3390/biom14020205 - 9 Feb 2024

Cited by 1 | Viewed by 1229

Abstract

The prognostic significance of tumor-infiltrating neutrophils in head and neck squamous cell carcinoma (HNSCC) is poorly understood. It is unclear how the presence of neutrophils affects prognosis due to their polarization into cytotoxic N1 or immunosuppressive N2. Therefore, we determined the number of [...] Read more.

The prognostic significance of tumor-infiltrating neutrophils in head and neck squamous cell carcinoma (HNSCC) is poorly understood. It is unclear how the presence of neutrophils affects prognosis due to their polarization into cytotoxic N1 or immunosuppressive N2. Therefore, we determined the number of CD66b+ neutrophil granulocytes separately in the stromal and epithelial compartments in cancer tissues from 397 patients with HNSCC. Tumor samples from six historical patient groups were processed into tissue microarrays and stained immunohistochemically. In total, 21.9% were HPV positive (p16+). Neutrophil counts were much lower in the stromal compartment (372 ± 812) than in the epithelial cancer compartment (1040 ± 1477) (p < 0.001), with large differences between groups. In three groups with high neutrophil infiltration, high rates were associated with a favorable prognosis, whereas in two groups, high rates were a negative prognostic factor. In p16- oropharyngeal and hypopharyngeal cancer high infiltration was associated with a favorable prognosis. Cancers with an exclusion of neutrophils in the epithelial compartment were associated with improved prognosis. In oropharyngeal and hypopharyngeal HPV-negative cancer high neutrophil infiltration rates were clearly associated with prolonged survival. Neutrophil granulocytes in HNSCC may contribute to a favorable or unfavorable prognosis. Full article

(This article belongs to the Special Issue Feature Papers in the Natural and Bio-Derived Molecules Section)

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19 pages, 2200 KiB

Open AccessEditor’s ChoiceArticle

Combined Effect of Maternal Separation and Early-Life Immune Activation on Brain and Behaviour of Rat Offspring

by Bharti Biswas, Valsamma Eapen, Margaret J. Morris and Nicole M. Jones

Biomolecules 2024, 14(2), 197; https://doi.org/10.3390/biom14020197 - 7 Feb 2024

Viewed by 1671

Abstract

Adversity during early life, a critical period for brain development, increases vulnerability and can have a lasting impact on the brain and behaviour of a child. However, the long-term effects of cumulative early-life stressors on brain and behaviour are not well known. We [...] Read more.

Adversity during early life, a critical period for brain development, increases vulnerability and can have a lasting impact on the brain and behaviour of a child. However, the long-term effects of cumulative early-life stressors on brain and behaviour are not well known. We studied a 2-hit rat model of early-life adversity using maternal separation (MS) and immune activation (lipopolysaccharide (LPS)). Rat pups underwent MS for 15 (control) or 180 (MS) minutes per day from postnatal day (P)2–14 and were administered saline or LPS (intraperitoneal) on P3. Open-field (OFT) and object-place recognition tests were performed on rat offspring at P33–35 and P42–50, respectively. The pre-frontal cortex (PFC) and hippocampus were removed at the experimental endpoint (P52–55) for mRNA expression. MS induced anxiety-like behaviour in OFT in male and reduced locomotor activity in both male and female offspring. LPS induced a subtle decline in memory in the object-place recognition test in male offspring. MS increased glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor expression in PFC and ionised calcium-binding adapter molecule-1 expression in male hippocampus. MS and LPS resulted in distinct behavioural phenotypes in a sex-specific manner. The combination of MS and LPS had a synergistic effect on the anxiety-like behaviour, locomotor activity, and GFAP mRNA expression outcomes. Full article

(This article belongs to the Special Issue Impact of Inflammation in Neurodevelopment)

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9 pages, 440 KiB

Open AccessEditor’s ChoiceArticle

Effect of 5-Alpha Reductase Inhibitors on Magnetic Resonance Imaging and Prostate Cancer Detection

by Juan Morote, Natàlia Picola, Jesús Muñoz-Rodriguez, Nahuel Paesano, Xavier Ruiz-Plazas, Marta V. Muñoz-Rivero, Ana Celma, Gemma García-de Manuel, Berta Miró, Pol Servian and José M. Abascal

Biomolecules 2024, 14(2), 193; https://doi.org/10.3390/biom14020193 - 5 Feb 2024

Viewed by 1197

Abstract

Concerns exist regarding the effects of 5-alpha reductase inhibitors (5-ARIs) on multipa-rametric magnetic resonance imaging (mpMRI) and clinically significant prostate cancer (csPCa) detection. Our objective is to analyze the effect of 5-ARI on the prostate imaging–reporting and data system (PI-RADS) distribution and csPCa [...] Read more.

Concerns exist regarding the effects of 5-alpha reductase inhibitors (5-ARIs) on multipa-rametric magnetic resonance imaging (mpMRI) and clinically significant prostate cancer (csPCa) detection. Our objective is to analyze the effect of 5-ARI on the prostate imaging–reporting and data system (PI-RADS) distribution and csPCa and insignificant PCa (iPCa) detection. Among 2212 men with serum prostate-specific antigen levels of >3.0 ng/mL and/or suspicious digital rectal examinations who underwent mpMRI and targeted and/or systematic biopsies, 120 individuals exposed to 5-ARI treatment for over a year were identified. CsPCa was defined when the grade group (GG) was >2. The overall csPCa and iPCa detection rates were 44.6% and 18.8%, respectively. Since logistic regression revealed independent predictors of PCa, a randomized matched group of 236 individuals was selected for analysis. The PI-RADS distribution was comparable with 5-ARI exposure (p 0.685). The CsPCa detection rates in 5-ARI-naïve men and 5-ARI-exposed men were 52.6% and 47.4%, respectively (p 0.596). IPCa was detected in 37.6 and 62.5%, respectively (p 0.089). The tumor GG distribution based on 5-ARI exposure was similar (p 0.149) to the rates of csPCa and iPCa across the PI-RADS categories. We conclude that exposure to 5-ARI in suspected PCa men did not change the PI-RADS distribution and the csPCa and iPCa detection rates. Full article

(This article belongs to the Special Issue Prostate Cancer Biomarkers and Therapeutics)

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46 pages, 3197 KiB

Open AccessEditor’s ChoiceReview

Phenotypic Heterogeneity, Bidirectionality, Universal Cues, Plasticity, Mechanics, and the Tumor Microenvironment Drive Cancer Metastasis

by Claudia Tanja Mierke

Biomolecules 2024, 14(2), 184; https://doi.org/10.3390/biom14020184 - 3 Feb 2024

Cited by 1 | Viewed by 2257

Abstract

Tumor diseases become a huge problem when they embark on a path that advances to malignancy, such as the process of metastasis. Cancer metastasis has been thoroughly investigated from a biological perspective in the past, whereas it has still been less explored from [...] Read more.

Tumor diseases become a huge problem when they embark on a path that advances to malignancy, such as the process of metastasis. Cancer metastasis has been thoroughly investigated from a biological perspective in the past, whereas it has still been less explored from a physical perspective. Until now, the intraluminal pathway of cancer metastasis has received the most attention, while the interaction of cancer cells with macrophages has received little attention. Apart from the biochemical characteristics, tumor treatments also rely on the tumor microenvironment, which is recognized to be immunosuppressive and, as has recently been found, mechanically stimulates cancer cells and thus alters their functions. The review article highlights the interaction of cancer cells with other cells in the vascular metastatic route and discusses the impact of this intercellular interplay on the mechanical characteristics and subsequently on the functionality of cancer cells. For instance, macrophages can guide cancer cells on their intravascular route of cancer metastasis, whereby they can help to circumvent the adverse conditions within blood or lymphatic vessels. Macrophages induce microchannel tunneling that can possibly avoid mechanical forces during extra- and intravasation and reduce the forces within the vascular lumen due to vascular flow. The review article highlights the vascular route of cancer metastasis and discusses the key players in this traditional route. Moreover, the effects of flows during the process of metastasis are presented, and the effects of the microenvironment, such as mechanical influences, are characterized. Finally, the increased knowledge of cancer metastasis opens up new perspectives for cancer treatment. Full article

(This article belongs to the Special Issue Cell Mechanics in Cell Biology and Biological Matter Physics)

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14 pages, 2275 KiB

Open AccessEditor’s ChoiceArticle

Impact of Difluoromethylornithine and AMXT 1501 on Gene Expression and Capsule Regulation in Streptococcus pneumoniae

by Moses B. Ayoola, Leslie A. Shack, Otto Phanstiel IV and Bindu Nanduri

Biomolecules 2024, 14(2), 178; https://doi.org/10.3390/biom14020178 - 2 Feb 2024

Viewed by 1404

Abstract

Streptococcus pneumoniae (Spn), a Gram-positive bacterium, poses a significant threat to human health, causing mild respiratory infections to severe invasive conditions. Despite the availability of vaccines, challenges persist due to serotype replacement and antibiotic resistance, emphasizing the need for alternative therapeutic strategies. This [...] Read more.

Streptococcus pneumoniae (Spn), a Gram-positive bacterium, poses a significant threat to human health, causing mild respiratory infections to severe invasive conditions. Despite the availability of vaccines, challenges persist due to serotype replacement and antibiotic resistance, emphasizing the need for alternative therapeutic strategies. This study explores the intriguing role of polyamines, ubiquitous, small organic cations, in modulating virulence factors, especially the capsule, a crucial determinant of Spn’s pathogenicity. Using chemical inhibitors, difluoromethylornithine (DFMO) and AMXT 1501, this research unveils distinct regulatory effects on the gene expression of the Spn D39 serotype in response to altered polyamine homeostasis. DFMO inhibits polyamine biosynthesis, disrupting pathways associated with glucose import and the interconversion of sugars. In contrast, AMXT 1501, targeting polyamine transport, enhances the expression of polyamine and glucose biosynthesis genes, presenting a novel avenue for regulating the capsule independent of glucose availability. Despite ample glucose availability, AMXT 1501 treatment downregulates the glycolytic pathway, fatty acid synthesis, and ATP synthase, crucial for energy production, while upregulating two-component systems responsible for stress management. This suggests a potential shutdown of energy production and capsule biosynthesis, redirecting resources towards stress management. Following DFMO and AMXT 1501 treatments, countermeasures, such as upregulation of stress response genes and ribosomal protein, were observed but appear to be insufficient to overcome the deleterious effects on capsule production. This study highlights the complexity of polyamine-mediated regulation in S. pneumoniae, particularly capsule biosynthesis. Our findings offer valuable insights into potential therapeutic targets for modulating capsules in a polyamine-dependent manner, a promising avenue for intervention against S. pneumoniae infections. Full article

(This article belongs to the Special Issue Polyamine Metabolism and Function)

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23 pages, 1867 KiB

Open AccessEditor’s ChoiceReview

Mechanisms and Functions of the RNA Polymerase II General Transcription Machinery during the Transcription Cycle

by Stephen R. Archuleta, James A. Goodrich and Jennifer F. Kugel

Biomolecules 2024, 14(2), 176; https://doi.org/10.3390/biom14020176 - 1 Feb 2024

Cited by 1 | Viewed by 3321

Abstract

Central to the development and survival of all organisms is the regulation of gene expression, which begins with the process of transcription catalyzed by RNA polymerases. During transcription of protein-coding genes, the general transcription factors (GTFs) work alongside RNA polymerase II (Pol II) [...] Read more.

Central to the development and survival of all organisms is the regulation of gene expression, which begins with the process of transcription catalyzed by RNA polymerases. During transcription of protein-coding genes, the general transcription factors (GTFs) work alongside RNA polymerase II (Pol II) to assemble the preinitiation complex at the transcription start site, open the promoter DNA, initiate synthesis of the nascent messenger RNA, transition to productive elongation, and ultimately terminate transcription. Through these different stages of transcription, Pol II is dynamically phosphorylated at the C-terminal tail of its largest subunit, serving as a control mechanism for Pol II elongation and a signaling/binding platform for co-transcriptional factors. The large number of core protein factors participating in the fundamental steps of transcription add dense layers of regulation that contribute to the complexity of temporal and spatial control of gene expression within any given cell type. The Pol II transcription system is highly conserved across different levels of eukaryotes; however, most of the information here will focus on the human Pol II system. This review walks through various stages of transcription, from preinitiation complex assembly to termination, highlighting the functions and mechanisms of the core machinery that participates in each stage. Full article

(This article belongs to the Section Cellular Biochemistry)

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20 pages, 4905 KiB

Open AccessEditor’s ChoiceArticle

Sex as a Critical Variable in Basic and Pre-Clinical Studies of Fibrodysplasia Ossificans Progressiva

by Lorraine N. Burdick, Amanda H. DelVichio, L. Russell Hanson, Brenden B. Griffith, Keith R. Bouchard, Jeffrey W. Hunter and David J. Goldhamer

Biomolecules 2024, 14(2), 177; https://doi.org/10.3390/biom14020177 - 1 Feb 2024

Viewed by 2161

Abstract

Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino [...] Read more.

Heterotopic ossification (HO) is most dramatically manifested in the rare and severely debilitating disease, fibrodysplasia ossificans progressiva (FOP), in which heterotopic bone progressively accumulates in skeletal muscles and associated soft tissues. The great majority of FOP cases are caused by a single amino acid substitution in the type 1 bone morphogenetic protein (BMP) receptor ACVR1, a mutation that imparts responsiveness to activin A. Although it is well-established that biological sex is a critical variable in a range of physiological and disease processes, the impact of sex on HO in animal models of FOP has not been explored. We show that female FOP mice exhibit both significantly greater and more variable HO responses after muscle injury. Additionally, the incidence of spontaneous HO was significantly greater in female mice. This sex dimorphism is not dependent on gonadally derived sex hormones, and reciprocal cell transplantations indicate that apparent differences in osteogenic activity are intrinsic to the sex of the transplanted cells. By circumventing the absolute requirement for activin A using an agonist of mutant ACVR1, we show that the female-specific response to muscle injury or BMP2 implantation is dependent on activin A. These data identify sex as a critical variable in basic and pre-clinical studies of FOP. Full article

(This article belongs to the Special Issue Fibrodysplasia Ossificans Progressiva (FOP): From Molecular Mechanisms to Therapeutic Strategies)

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14 pages, 1009 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Potential of IL-1 Antagonism in Hidradenitis Suppurativa

by Laura Calabrese, Dalma Malvaso, Giulia Coscarella, Flaminia Antonelli, Alessandra D’Amore, Niccolò Gori, Pietro Rubegni, Ketty Peris and Andrea Chiricozzi

Biomolecules 2024, 14(2), 175; https://doi.org/10.3390/biom14020175 - 1 Feb 2024

Viewed by 2221

Abstract

The immunopathogenesis of HS is partially understood and exhibits features of an autoinflammatory disease; it is associated with the potential involvement of B cells and the contribution of Th1 or Th17 cell subsets. Recently, the pathogenic role of both innate immunity and IL-1 [...] Read more.

The immunopathogenesis of HS is partially understood and exhibits features of an autoinflammatory disease; it is associated with the potential involvement of B cells and the contribution of Th1 or Th17 cell subsets. Recently, the pathogenic role of both innate immunity and IL-1 family cytokines in HS has been deeply investigated. Several agents targeting the IL-1 family pathway at different levels are currently available and under investigation for the treatment of HS. HS is still characterized by unmet clinical needs and represents an expanding field in the current scientific research. The aim of this narrative review is to describe the pathological dysregulation of IL-1 family members in HS and to provide an update on therapeutic strategies targeting IL-1 family cytokine signaling. Further clinical and preclinical data may likely lead to the enrichment of the therapeutic armamentarium of HS with IL-1 family cytokine antagonists. Full article

(This article belongs to the Special Issue Novel Insights into Autoimmune/Autoinflammatory Skin Diseases)

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16 pages, 5646 KiB

Open AccessEditor’s ChoiceArticle

Mitochondrial Dysfunction and Protein Homeostasis in Aging: Insights from a Premature-Aging Mouse Model

by Jaime M. Ross, Lars Olson and Giuseppe Coppotelli

Biomolecules 2024, 14(2), 162; https://doi.org/10.3390/biom14020162 - 30 Jan 2024

Cited by 2 | Viewed by 1760

Abstract

Mitochondrial dysfunction has been implicated in aging and age-related disorders. Disturbed-protein homeostasis and clearance of damaged proteins have also been linked to aging, as well as to neurodegenerative diseases, cancers, and metabolic disorders. However, since mitochondrial oxidative phosphorylation, ubiquitin–proteasome, and autophagy-lysosome systems are [...] Read more.

Mitochondrial dysfunction has been implicated in aging and age-related disorders. Disturbed-protein homeostasis and clearance of damaged proteins have also been linked to aging, as well as to neurodegenerative diseases, cancers, and metabolic disorders. However, since mitochondrial oxidative phosphorylation, ubiquitin–proteasome, and autophagy-lysosome systems are tightly interdependent, it is not understood whether the facets observed in aging are the causes or consequences of one or all of these failed processes. We therefore used prematurely aging mtDNA-mutator mice and normally aging wild-type littermates to elucidate whether mitochondrial dysfunction per se is sufficient to impair cellular protein homeostasis similarly to that which is observed in aging. We found that both mitochondrial dysfunction and normal aging affect the ubiquitin–proteasome system in a tissue-dependent manner, whereas only normal aging markedly impairs the autophagy-lysosome system. Thus, our data show that the proteostasis network control in the prematurely aging mtDNA-mutator mouse differs in certain aspects from that found in normal aging. Taken together, our findings suggest that severe mitochondrial dysfunction drives an aging phenotype associated with the impairment of certain components of the protein homeostasis machinery, while others, such as the autophagy-lysosome system, are not affected or only minimally affected. Taken together, this shows that aging is a multifactorial process resulting from alterations of several integrated biological processes; thus, manipulating one process at the time might not be sufficient to fully recapitulate all changes associated with normal aging. Full article

(This article belongs to the Special Issue Mitochondrial Quality Control in Aging and Neurodegeneration)

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37 pages, 2476 KiB

Open AccessEditor’s ChoiceReview

Understanding the Biological Relationship between Migraine and Depression

by Adrián Viudez-Martínez, Abraham B. Torregrosa, Francisco Navarrete and María Salud García-Gutiérrez

Biomolecules 2024, 14(2), 163; https://doi.org/10.3390/biom14020163 - 30 Jan 2024

Cited by 3 | Viewed by 3057

Abstract

Migraine is a highly prevalent neurological disorder. Among the risk factors identified, psychiatric comorbidities, such as depression, seem to play an important role in its onset and clinical course. Patients with migraine are 2.5 times more likely to develop a depressive disorder; this [...] Read more.

Migraine is a highly prevalent neurological disorder. Among the risk factors identified, psychiatric comorbidities, such as depression, seem to play an important role in its onset and clinical course. Patients with migraine are 2.5 times more likely to develop a depressive disorder; this risk becomes even higher in patients suffering from chronic migraine or migraine with aura. This relationship is bidirectional, since depression also predicts an earlier/worse onset of migraine, increasing the risk of migraine chronicity and, consequently, requiring a higher healthcare expenditure compared to migraine alone. All these data suggest that migraine and depression may share overlapping biological mechanisms. Herein, this review explores this topic in further detail: firstly, by introducing the common epidemiological and risk factors for this comorbidity; secondly, by focusing on providing the cumulative evidence of common biological aspects, with a particular emphasis on the serotoninergic system, neuropeptides such as calcitonin-gene-related peptide (CGRP), pituitary adenylate cyclase-activating polypeptide (PACAP), substance P, neuropeptide Y and orexins, sexual hormones, and the immune system; lastly, by remarking on the future challenges required to elucidate the etiopathological mechanisms of migraine and depression and providing updated information regarding new key targets for the pharmacological treatment of these clinical entities. Full article

(This article belongs to the Section Molecular Biology)

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28 pages, 2183 KiB

Open AccessEditor’s ChoiceArticle

Bioinformatics Prediction for Network-Based Integrative Multi-Omics Expression Data Analysis in Hirschsprung Disease

by Helena Lucena-Padros, Nereida Bravo-Gil, Cristina Tous, Elena Rojano, Pedro Seoane-Zonjic, Raquel María Fernández, Juan A. G. Ranea, Guillermo Antiñolo and Salud Borrego

Biomolecules 2024, 14(2), 164; https://doi.org/10.3390/biom14020164 - 30 Jan 2024

Cited by 1 | Viewed by 1766

Abstract

Hirschsprung’s disease (HSCR) is a rare developmental disorder in which enteric ganglia are missing along a portion of the intestine. HSCR has a complex inheritance, with RET as the major disease-causing gene. However, the pathogenesis of HSCR is still not completely understood. Therefore, [...] Read more.

Hirschsprung’s disease (HSCR) is a rare developmental disorder in which enteric ganglia are missing along a portion of the intestine. HSCR has a complex inheritance, with RET as the major disease-causing gene. However, the pathogenesis of HSCR is still not completely understood. Therefore, we applied a computational approach based on multi-omics network characterization and clustering analysis for HSCR-related gene/miRNA identification and biomarker discovery. Protein–protein interaction (PPI) and miRNA–target interaction (MTI) networks were analyzed by DPClusO and BiClusO, respectively, and finally, the biomarker potential of miRNAs was computationally screened by miRNA-BD. In this study, a total of 55 significant gene–disease modules were identified, allowing us to propose 178 new HSCR candidate genes and two biological pathways. Moreover, we identified 12 key miRNAs with biomarker potential among 137 predicted HSCR-associated miRNAs. Functional analysis of new candidates showed that enrichment terms related to gene ontology (GO) and pathways were associated with HSCR. In conclusion, this approach has allowed us to decipher new clues of the etiopathogenesis of HSCR, although molecular experiments are further needed for clinical validations. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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14 pages, 2836 KiB

Open AccessEditor’s ChoiceArticle

Uptake of 18F-AV45 in the Putamen Provides Additional Insights into Alzheimer’s Disease beyond the Cortex

by Zhengshi Yang, Jefferson W. Kinney, Dietmar Cordes and The Alzheimer’s Disease Neuroimaging Initiative

Biomolecules 2024, 14(2), 157; https://doi.org/10.3390/biom14020157 - 29 Jan 2024

Viewed by 1367

Abstract

Cortical uptake in brain amyloid positron emission tomography (PET) is increasingly used for the biological diagnosis of Alzheimer’s disease (AD); however, the clinical and biological relevance of the striatum beyond the cortex in amyloid PET scans remains unclear. A total of 513 amyloid-positive [...] Read more.

Cortical uptake in brain amyloid positron emission tomography (PET) is increasingly used for the biological diagnosis of Alzheimer’s disease (AD); however, the clinical and biological relevance of the striatum beyond the cortex in amyloid PET scans remains unclear. A total of 513 amyloid-positive participants having 18F-AV45 amyloid PET scans available were included in the analysis. The associations between cognitive scores and striatal uptake were analyzed. The participants were categorized into three groups based on the residual from the linear fitting between 18F-AV45 uptake in the putamen and the cortex in the order of HighP > MidP > LowP group. We then examined the differences between these three groups in terms of clinical diagnosis, APOE genotype, CSF phosphorylated tau (ptau) concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate to evaluate the additional insights provided by the putamen beyond the cortex. The 18F-AV45 uptake in the putamen was more strongly associated with ADAS-cog13 and MoCA scores (p < 0.001) compared to the uptake in the caudate nucleus. Despite comparable cortical uptakes, the HighP group had a two-fold higher risk of being ε4-homozygous or diagnosed with AD dementia compared to the LowP group. These three groups had significantly different CSF ptau concentration, hippocampal volume, entorhinal thickness, and cognitive decline rate. These findings suggest that the assessment of 18F-AV45 uptake in the putamen is of unique value for evaluating disease severity and predicting disease progression. Full article

(This article belongs to the Special Issue The Role of Amyloid in Neurological Disorders)

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22 pages, 1100 KiB

Open AccessEditor’s ChoiceArticle

Proteomic and Metabolomic Analysis of the Quercus ilex–Phytophthora cinnamomi Pathosystem Reveals a Population-Specific Response, Independent of Co-Occurrence of Drought

by Tamara Hernández-Lao, Marta Tienda-Parrilla, Mónica Labella-Ortega, Victor M. Guerrero-Sánchez, María-Dolores Rey, Jesús V. Jorrín-Novo and María Ángeles Castillejo-Sánchez

Biomolecules 2024, 14(2), 160; https://doi.org/10.3390/biom14020160 - 29 Jan 2024

Viewed by 1483

Abstract

Holm oak (Quercus ilex) is considered to be one of the major structural elements of Mediterranean forests and the agrosilvopastoral Spanish “dehesa”, making it an outstanding example of ecological and socioeconomic sustainability in forest ecosystems. The exotic Phytophthora cinnamomi is one [...] Read more.

Holm oak (Quercus ilex) is considered to be one of the major structural elements of Mediterranean forests and the agrosilvopastoral Spanish “dehesa”, making it an outstanding example of ecological and socioeconomic sustainability in forest ecosystems. The exotic Phytophthora cinnamomi is one of the most aggressive pathogens of woody species and, together with drought, is considered to be one of the main drivers of holm oak decline. The effect of and response to P. cinnamomi inoculation were studied in the offspring of mother trees from two Andalusian populations, Cordoba and Huelva. At the two locations, acorns collected from both symptomatic (damaged) and asymptomatic (apparently healthy) trees were sampled. Damage symptoms, mortality, and chlorophyll fluorescence were evaluated in seedlings inoculated under humid and drought conditions. The effect and response depended on the population and were more apparent in Huelva than in Cordoba. An integrated proteomic and metabolomic analysis revealed the involvement of different metabolic pathways in response to the pathogen in both populations, including amino acid metabolism pathways in Huelva, and terpenoid and flavonoid biosynthesis in Cordoba. However, no differential response was observed between seedlings inoculated under humid and drought conditions. A protective mechanism of the photosynthetic apparatus was activated in response to defective photosynthetic activity in inoculated plants, which seemed to be more efficient in the Cordoba population. In addition, enzymes and metabolites of the phenylpropanoid and flavonoid biosynthesis pathways may have conferred higher resistance in the Cordoba population. Some enzymes are proposed as markers of resilience, among which glyoxalase I, glutathione reductase, thioredoxin reductase, and cinnamyl alcohol dehydrogenase are candidates. Full article

(This article belongs to the Special Issue Sowing the Seed to Ensure the Future of Plant Proteomics: Commemorative Issue in Honor of Dr. Dominique Job (1947–2022))

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19 pages, 4840 KiB

Open AccessEditor’s ChoiceArticle

FLVCR1a Controls Cellular Cholesterol Levels through the Regulation of Heme Biosynthesis and Tricarboxylic Acid Cycle Flux in Endothelial Cells

by Marta Manco, Giorgia Ammirata, Sara Petrillo, Francesco De Giorgio, Simona Fontana, Chiara Riganti, Paolo Provero, Sharmila Fagoonee, Fiorella Altruda and Emanuela Tolosano

Biomolecules 2024, 14(2), 149; https://doi.org/10.3390/biom14020149 - 26 Jan 2024

Cited by 1 | Viewed by 1563

Abstract

Feline leukemia virus C receptor 1a (FLVCR1a), initially identified as a retroviral receptor and localized on the plasma membrane, has emerged as a crucial regulator of heme homeostasis. Functioning as a positive regulator of δ-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in [...] Read more.

Feline leukemia virus C receptor 1a (FLVCR1a), initially identified as a retroviral receptor and localized on the plasma membrane, has emerged as a crucial regulator of heme homeostasis. Functioning as a positive regulator of δ-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in the heme biosynthetic pathway, FLVCR1a influences TCA cycle cataplerosis, thus impacting TCA flux and interconnected metabolic pathways. This study reveals an unexplored link between FLVCR1a, heme synthesis, and cholesterol production in endothelial cells. Using cellular models with manipulated FLVCR1a expression and inducible endothelial-specific Flvcr1a-null mice, we demonstrate that FLVCR1a-mediated control of heme synthesis regulates citrate availability for cholesterol synthesis, thereby influencing cellular cholesterol levels. Moreover, alterations in FLVCR1a expression affect membrane cholesterol content and fluidity, supporting a role for FLVCR1a in the intricate regulation of processes crucial for vascular development and endothelial function. Our results underscore FLVCR1a as a positive regulator of heme synthesis, emphasizing its integration with metabolic pathways involved in cellular energy metabolism. Furthermore, this study suggests that the dysregulation of heme metabolism may have implications for modulating lipid metabolism. We discuss these findings in the context of FLVCR1a’s potential heme-independent function as a choline importer, introducing additional complexity to the interplay between heme and lipid metabolism. Full article

(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)

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17 pages, 3311 KiB

Open AccessEditor’s ChoiceArticle

Role of Mitochondrial ROS for Calcium Alternans in Atrial Myocytes

by Yuriana Oropeza-Almazán and Lothar A. Blatter

Biomolecules 2024, 14(2), 144; https://doi.org/10.3390/biom14020144 - 24 Jan 2024

Viewed by 1634

Abstract

Atrial calcium transient (CaT) alternans is defined as beat-to-beat alternations in CaT amplitude and is causally linked to atrial fibrillation (AF). Mitochondria play a significant role in cardiac excitation–contraction coupling and Ca signaling through redox environment regulation. In isolated rabbit atrial myocytes, ROS [...] Read more.

Atrial calcium transient (CaT) alternans is defined as beat-to-beat alternations in CaT amplitude and is causally linked to atrial fibrillation (AF). Mitochondria play a significant role in cardiac excitation–contraction coupling and Ca signaling through redox environment regulation. In isolated rabbit atrial myocytes, ROS production is enhanced during CaT alternans, measured by fluorescence microscopy. Exogenous ROS (tert-butyl hydroperoxide) enhanced CaT alternans, whereas ROS scavengers (dithiothreitol, MnTBAP, quercetin, tempol) alleviated CaT alternans. While the inhibition of cellular NADPH oxidases had no effect on CaT alternans, interference with mitochondrial ROS (ROS_m) production had profound effects: (1) the superoxide dismutase mimetic MitoTempo diminished CaT alternans and shifted the pacing threshold to higher frequencies; (2) the inhibition of cyt c peroxidase by SS-31, and inhibitors of ROS_m production by complexes of the electron transport chain S1QEL1.1 and S3QEL2, decreased the severity of CaT alternans; however (3) the impairment of mitochondrial antioxidant defense by the inhibition of nicotinamide nucleotide transhydrogenase with NBD-Cl and thioredoxin reductase-2 with auranofin enhanced CaT alternans. Our results suggest that intact mitochondrial antioxidant defense provides crucial protection against pro-arrhythmic CaT alternans. Thus, modulating the mitochondrial redox state represents a potential therapeutic approach for alternans-associated arrhythmias, including AF. Full article

(This article belongs to the Collection Feature Papers in Section Molecular Medicine)

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16 pages, 1251 KiB

Open AccessEditor’s ChoiceReview

Kidney Fibrosis and Oxidative Stress: From Molecular Pathways to New Pharmacological Opportunities

by Francesco Patera, Leonardo Gatticchi, Barbara Cellini, Davide Chiasserini and Gianpaolo Reboldi

Biomolecules 2024, 14(1), 137; https://doi.org/10.3390/biom14010137 - 22 Jan 2024

Cited by 7 | Viewed by 2289

Abstract

Kidney fibrosis, diffused into the interstitium, vessels, and glomerulus, is the main pathologic feature associated with loss of renal function and chronic kidney disease (CKD). Fibrosis may be triggered in kidney diseases by different genetic and molecular insults. However, several studies have shown [...] Read more.

Kidney fibrosis, diffused into the interstitium, vessels, and glomerulus, is the main pathologic feature associated with loss of renal function and chronic kidney disease (CKD). Fibrosis may be triggered in kidney diseases by different genetic and molecular insults. However, several studies have shown that fibrosis can be linked to oxidative stress and mitochondrial dysfunction in CKD. In this review, we will focus on three pathways that link oxidative stress and kidney fibrosis, namely: (i) hyperglycemia and mitochondrial energy imbalance, (ii) the mineralocorticoid signaling pathway, and (iii) the hypoxia-inducible factor (HIF) pathway. We selected these pathways because they are targeted by available medications capable of reducing kidney fibrosis, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1alpha-prolyl hydroxylase inhibitors. These drugs have shown a reduction in oxidative stress in the kidney and a reduced collagen deposition across different CKD subtypes. However, there is still a long and winding road to a clear understanding of the anti-fibrotic effects of these compounds in humans, due to the inherent practical and ethical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers measurable in easily accessible matrices like urine. In this narrative review, we will describe these three pathways, their interconnections, and their link to and activity in oxidative stress and kidney fibrosis. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease II)

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9 pages, 2613 KiB

Open AccessEditor’s ChoiceArticle

Antibacterial Metabolites Produced by Limonium lopadusanum, an Endemic Plant of Lampedusa Island

by Ernesto Gargiulo, Emanuela Roscetto, Umberto Galdiero, Giuseppe Surico, Maria Rosaria Catania, Antonio Evidente and Orazio Taglialatela-Scafati

Biomolecules 2024, 14(1), 134; https://doi.org/10.3390/biom14010134 - 22 Jan 2024

Viewed by 1403

Abstract

Lampedusa, the largest island of the Pelagie archipelago, Sicily, Italy, has proven to be a rich source of plants and shrubs used in folk medicine. These plants, often native to the island, have been very poorly investigated for their phytochemical composition and biological [...] Read more.

Lampedusa, the largest island of the Pelagie archipelago, Sicily, Italy, has proven to be a rich source of plants and shrubs used in folk medicine. These plants, often native to the island, have been very poorly investigated for their phytochemical composition and biological potential to be translated into pharmacological applications. To start achieving this purpose, a specimen of Limonium lopadusanum, a plant native to Lampedusa, was investigated for the first time. This manuscript reports the results of a preliminary biological assay, focused on antimicrobial activity, carried out using the plant organic extracts, and the isolation and chemical and biological characterization of the secondary metabolites obtained. Thus 3-hydroxy-4-methoxybenzoic acid methyl ester (syn: methyl isovanillate, (1), methyl syringate (2), pinoresinol (3), erythrinassinate C (4) and tyrosol palmitate (5) were isolated. Their antimicrobial activity was tested on several strains and compound 4 showed promising antibacterial activity against Enterococcus faecalis. Thus, this metabolite has antibiotic potential against the drug-resistant opportunistic pathogen E. faecalis. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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20 pages, 3113 KiB

Open AccessEditor’s ChoiceArticle

Na⁺,K⁺-ATPase with Disrupted Na⁺ Binding Sites I and III Binds Na⁺ with Increased Affinity at Site II and Undergoes Na⁺-Activated Phosphorylation with ATP

by Hang N. Nielsen, Rikke Holm, Ryan Sweazey, Jens Peter Andersen, Pablo Artigas and Bente Vilsen

Biomolecules 2024, 14(1), 135; https://doi.org/10.3390/biom14010135 - 22 Jan 2024

Cited by 1 | Viewed by 1344

Abstract

Na⁺,K⁺-ATPase actively extrudes three cytoplasmic Na⁺ ions in exchange for two extracellular K⁺ ions for each ATP hydrolyzed. The atomic structure with bound Na⁺ identifies three Na⁺ sites, named I, II, and III. It has [...] Read more.

Na⁺,K⁺-ATPase actively extrudes three cytoplasmic Na⁺ ions in exchange for two extracellular K⁺ ions for each ATP hydrolyzed. The atomic structure with bound Na⁺ identifies three Na⁺ sites, named I, II, and III. It has been proposed that site III is the first to be occupied and site II last, when Na⁺ binds from the cytoplasmic side. It is usually assumed that the occupation of all three Na⁺ sites is obligatory for the activation of phosphoryl transfer from ATP. To obtain more insight into the individual roles of the ion-binding sites, we have analyzed a series of seven mutants with substitution of the critical ion-binding residue Ser777, which is a shared ligand between Na⁺ sites I and III. Surprisingly, mutants with large and bulky substituents expected to prevent or profoundly disturb Na⁺ access to sites I and III retain the ability to form a phosphoenzyme from ATP, even with increased apparent Na⁺ affinity. This indicates that Na⁺ binding solely at site II is sufficient to promote phosphorylation. These mutations appear to lock the membrane sector into an E₁-like configuration, allowing Na⁺ but not K⁺ to bind at site II, while the cytoplasmic sector undergoes conformational changes uncoupled from the membrane sector. Full article

(This article belongs to the Special Issue The Role of P-type ATPases in Health and Diseases)

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14 pages, 807 KiB

Open AccessEditor’s ChoiceArticle

Erythropoietin N-glycosylation of Therapeutic Formulations Quantified and Characterized: An Interlab Comparability Study of High-Throughput Methods

by Róisín O’Flaherty, Manuela Amez Martín, Richard A. Gardner, Patrick M. Jennings, Pauline M. Rudd, Daniel I. R. Spencer and David Falck

Biomolecules 2024, 14(1), 125; https://doi.org/10.3390/biom14010125 - 18 Jan 2024

Viewed by 1871

Abstract

Recombinant human erythropoietin (EPO) is a biopharmaceutical frequently used in the treatment of anemia. It is a heavily glycosylated protein with a diverse and complex glycome. EPO N-glycosylation influences important pharmacological parameters, prominently serum half-life. Therefore, EPO N-glycosylation analysis is of [...] Read more.

Recombinant human erythropoietin (EPO) is a biopharmaceutical frequently used in the treatment of anemia. It is a heavily glycosylated protein with a diverse and complex glycome. EPO N-glycosylation influences important pharmacological parameters, prominently serum half-life. Therefore, EPO N-glycosylation analysis is of the utmost importance in terms of controlling critical quality attributes. In this work, we performed an interlaboratory study of glycoanalytical techniques for profiling and in-depth characterization, namely (1) hydrophilic interaction liquid chromatography with fluorescence detection after 2-aminobenzamide labeling (HILIC-FLD(2AB)) and optional weak anion exchange chromatography (WAX) fractionation and exoglycosidase digestion, (2) HILIC-FLD after procainamide labeling (PROC) optionally coupled to electrospray ionization-MS and (3) matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-MS). All techniques showed good precision and were able to differentiate the unique N-glycosylation profiles of the various EPO preparations. HILIC-FLD showed higher precision, while MALDI-TOF-MS covered the most analytes. However, HILIC-FLD differentiated isomeric N-glycans, i.e., N-acetyllactosamine repeats and O-acetylation regioisomers. For routine profiling, HILIC-FLD methods are more accessible and cover isomerism in major structures, while MALDI-MS covers more minor analytes with an attractively high throughput. For in-depth characterization, MALDI-MS and HILIC-FLD(2AB)/WAX give a similar amount of orthogonal information. HILIC-FLD(PROC)-MS is attractive for covering isomerism of major structures with a significantly less extensive workflow compared to HILIC-FLD(2AB)/WAX. Full article

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23 pages, 4557 KiB

Open AccessEditor’s ChoiceReview

Progress to Clarify How NOTCH3 Mutations Lead to CADASIL, a Hereditary Cerebral Small Vessel Disease

by Ikuko Mizuta, Yumiko Nakao-Azuma, Hideki Yoshida, Masamitsu Yamaguchi and Toshiki Mizuno

Biomolecules 2024, 14(1), 127; https://doi.org/10.3390/biom14010127 - 18 Jan 2024

Cited by 1 | Viewed by 2192

Abstract

Notch signaling is conserved in C. elegans, Drosophila, and mammals. Among the four NOTCH genes in humans, NOTCH1, NOTCH2, and NOTCH3 are known to cause monogenic hereditary disorders. Most NOTCH-related disorders are congenital and caused by a gain [...] Read more.

Notch signaling is conserved in C. elegans, Drosophila, and mammals. Among the four NOTCH genes in humans, NOTCH1, NOTCH2, and NOTCH3 are known to cause monogenic hereditary disorders. Most NOTCH-related disorders are congenital and caused by a gain or loss of Notch signaling activity. In contrast, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 is adult-onset and considered to be caused by accumulation of the mutant NOTCH3 extracellular domain (N3ECD) and, possibly, by an impairment in Notch signaling. Pathophysiological processes following mutant N3ECD accumulation have been intensively investigated; however, the process leading to N3ECD accumulation and its association with canonical NOTCH3 signaling remain unknown. We reviewed the progress in clarifying the pathophysiological process involving mutant NOTCH3. Full article

(This article belongs to the Special Issue Regulation of Notch Signaling Pathway and Its Relation to Diseases)

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13 pages, 2604 KiB

Open AccessEditor’s ChoiceArticle

Ladostigil Reduces the Adenoside Triphosphate/Lipopolysaccharide-Induced Secretion of Pro-Inflammatory Cytokines from Microglia and Modulate-Immune Regulators, TNFAIP3, and EGR1

by Fanny Reichert, Keren Zohar, Elyad Lezmi, Tsiona Eliyahu, Shlomo Rotshenker, Michal Linial and Marta Weinstock

Biomolecules 2024, 14(1), 112; https://doi.org/10.3390/biom14010112 - 16 Jan 2024

Viewed by 1514

Abstract

Treatment of aging rats for 6 months with ladostigil (1 mg/kg/day) prevented a decline in recognition and spatial memory and suppressed the overexpression of gene-encoding pro-inflammatory cytokines, TNFα, IL1β, and IL6 in the brain and microglial cultures. Primary cultures of mouse microglia stimulated [...] Read more.

Treatment of aging rats for 6 months with ladostigil (1 mg/kg/day) prevented a decline in recognition and spatial memory and suppressed the overexpression of gene-encoding pro-inflammatory cytokines, TNFα, IL1β, and IL6 in the brain and microglial cultures. Primary cultures of mouse microglia stimulated by lipopolysaccharides (LPS, 0.75 µg/mL) and benzoyl ATPs (BzATP) were used to determine the concentration of ladostigil that reduces the secretion of these cytokine proteins. Ladostigil (1 × 10⁻¹¹ M), a concentration compatible with the blood of aging rats in, prevented memory decline and reduced secretion of IL1β and IL6 by ≈50%. RNA sequencing analysis showed that BzATP/LPS upregulated 25 genes, including early-growth response protein 1, (Egr1) which increased in the brain of subjects with neurodegenerative diseases. Ladostigil significantly decreased Egr1 gene expression and levels of the protein in the nucleus and increased TNF alpha-induced protein 3 (TNFaIP3), which suppresses cytokine release, in the microglial cytoplasm. Restoration of the aberrant signaling of these proteins in ATP/LPS-activated microglia in vivo might explain the prevention by ladostigil of the morphological and inflammatory changes in the brain of aging rats. Full article

(This article belongs to the Special Issue Biomolecular Approaches and Drugs for Neurodegeneration)

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15 pages, 2991 KiB

Open AccessEditor’s ChoiceArticle

The 2.6 Å Structure of a Tulane Virus Variant with Minor Mutations Leading to Receptor Change

by Chen Sun, Pengwei Huang, Xueyong Xu, Frank S. Vago, Kunpeng Li, Thomas Klose, Xi Jason Jiang and Wen Jiang

Biomolecules 2024, 14(1), 119; https://doi.org/10.3390/biom14010119 - 16 Jan 2024

Viewed by 1573

Abstract

Human noroviruses (HuNoVs) are a major cause of acute gastroenteritis, contributing significantly to annual foodborne illness cases. However, studying these viruses has been challenging due to limitations in tissue culture techniques for over four decades. Tulane virus (TV) has emerged as a crucial [...] Read more.

Human noroviruses (HuNoVs) are a major cause of acute gastroenteritis, contributing significantly to annual foodborne illness cases. However, studying these viruses has been challenging due to limitations in tissue culture techniques for over four decades. Tulane virus (TV) has emerged as a crucial surrogate for HuNoVs due to its close resemblance in amino acid composition and the availability of a robust cell culture system. Initially isolated from rhesus macaques in 2008, TV represents a novel Calicivirus belonging to the Recovirus genus. Its significance lies in sharing the same host cell receptor, histo-blood group antigen (HBGA), as HuNoVs. In this study, we introduce, through cryo-electron microscopy (cryo-EM), the structure of a specific TV variant (the 9-6-17 TV) that has notably lost its ability to bind to its receptor, B-type HBGA—a finding confirmed using an enzyme-linked immunosorbent assay (ELISA). These results offer a profound insight into the genetic modifications occurring in TV that are necessary for adaptation to cell culture environments. This research significantly contributes to advancing our understanding of the genetic changes that are pivotal to successful adaptation, shedding light on fundamental aspects of Calicivirus evolution. Full article

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11 pages, 2078 KiB

Open AccessEditor’s ChoiceArticle

The Identification and Heterologous Expression of the Biosynthetic Gene Cluster Encoding the Antibiotic and Anticancer Agent Marinomycin

by Emily Abraham, Hannah A. Lawther, Yunpeng Wang, Joseph S. Zarins-Tutt, Gerry Sann Rivera, Chengcang Wu, Jack A. Connolly, Gordon Florence, Matthias Agbo, Hong Gao and Rebecca J. M. Goss

Biomolecules 2024, 14(1), 117; https://doi.org/10.3390/biom14010117 - 16 Jan 2024

Viewed by 1517

Abstract

With the rise in antimicrobial resistance, there is an urgent need for new classes of antibiotic with which to treat infectious disease. Marinomycin, a polyene antibiotic from a marine microbe, has been shown capable of killing methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus [...] Read more.

With the rise in antimicrobial resistance, there is an urgent need for new classes of antibiotic with which to treat infectious disease. Marinomycin, a polyene antibiotic from a marine microbe, has been shown capable of killing methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF), as well as having promising activity against melanoma. An attractive solution to the photoprotection of this antibiotic has been demonstrated. Here, we report the identification and analysis of the marinomycin biosynthetic gene cluster (BGC), and the biosynthetic assembly of the macrolide. The marinomycin BGC presents a challenge in heterologous expression due to its large size and high GC content, rendering the cluster prone to rearrangement. We demonstrate the transformation of Streptomyces lividans using a construct containing the cluster, and the heterologous expression of the encoded biosynthetic machinery and production of marinomycin B. Full article

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26 pages, 3188 KiB

Open AccessEditor’s ChoiceReview

A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment

by Jonghwa Lee, Jessica L. Beers, Raeanne M. Geffert and Klarissa D. Jackson

Biomolecules 2024, 14(1), 99; https://doi.org/10.3390/biom14010099 - 12 Jan 2024

Cited by 7 | Viewed by 3791

Abstract

Drug metabolism is a major determinant of drug concentrations in the body. Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs can lead to alteration in the exposure of the victim drug, raising safety or effectiveness concerns. Assessment of the DDI potential [...] Read more.

Drug metabolism is a major determinant of drug concentrations in the body. Drug-drug interactions (DDIs) caused by the co-administration of multiple drugs can lead to alteration in the exposure of the victim drug, raising safety or effectiveness concerns. Assessment of the DDI potential starts with in vitro experiments to determine kinetic parameters and identify risks associated with the use of comedication that can inform future clinical studies. The diverse range of experimental models and techniques has significantly contributed to the examination of potential DDIs. Cytochrome P450 (CYP) enzymes are responsible for the biotransformation of many drugs on the market, making them frequently implicated in drug metabolism and DDIs. Consequently, there has been a growing focus on the assessment of DDI risk for CYPs. This review article provides mechanistic insights underlying CYP inhibition/induction and an overview of the in vitro assessment of CYP-mediated DDIs. Full article

(This article belongs to the Special Issue Novel Insights into Cytochrome P450 Enzymes in Drug Metabolism)

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21 pages, 1253 KiB

Open AccessEditor’s ChoiceReview

The Need for Novel Asexual Blood-Stage Malaria Vaccine Candidates for Plasmodium falciparum

by Eizo Takashima, Hitoshi Otsuki, Masayuki Morita, Daisuke Ito, Hikaru Nagaoka, Takaaki Yuguchi, Ifra Hassan and Takafumi Tsuboi

Biomolecules 2024, 14(1), 100; https://doi.org/10.3390/biom14010100 - 12 Jan 2024

Cited by 5 | Viewed by 2180

Abstract

Extensive control efforts have significantly reduced malaria cases and deaths over the past two decades, but in recent years, coupled with the COVID-19 pandemic, success has stalled. The WHO has urged the implementation of a number of interventions, including vaccines. The modestly effective [...] Read more.

Extensive control efforts have significantly reduced malaria cases and deaths over the past two decades, but in recent years, coupled with the COVID-19 pandemic, success has stalled. The WHO has urged the implementation of a number of interventions, including vaccines. The modestly effective RTS,S/AS01 pre-erythrocytic vaccine has been recommended by the WHO for use in sub-Saharan Africa against Plasmodium falciparum in children residing in moderate to high malaria transmission regions. A second pre-erythrocytic vaccine, R21/Matrix-M, was also recommended by the WHO on 3 October 2023. However, the paucity and limitations of pre-erythrocytic vaccines highlight the need for asexual blood-stage malaria vaccines that prevent disease caused by blood-stage parasites. Few asexual blood-stage vaccine candidates have reached phase 2 clinical development, and the challenges in terms of their efficacy include antigen polymorphisms and low immunogenicity in humans. This review summarizes the history and progress of asexual blood-stage malaria vaccine development, highlighting the need for novel candidate vaccine antigens/molecules. Full article

(This article belongs to the Special Issue Innovative Immunology: A Themed Issue Dedicated to Professor Moriya Tsuji)

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21 pages, 5968 KiB

Open AccessEditor’s ChoiceArticle

Development of a Novel Covalently Bonded Conjugate of Caprylic Acid Tripeptide (Isoleucine–Leucine–Aspartic Acid) for Wound-Compatible and Injectable Hydrogel to Accelerate Healing

by Sachin B. Baravkar, Yan Lu, Abdul-Razak Masoud, Qi Zhao, Jibao He and Song Hong

Biomolecules 2024, 14(1), 94; https://doi.org/10.3390/biom14010094 - 11 Jan 2024

Cited by 1 | Viewed by 1565

Abstract

Third-degree burn injuries pose a significant health threat. Safer, easier-to-use, and more effective techniques are urgently needed for their treatment. We hypothesized that covalently bonded conjugates of fatty acids and tripeptides can form wound-compatible hydrogels that can accelerate healing. We first designed conjugated [...] Read more.

Third-degree burn injuries pose a significant health threat. Safer, easier-to-use, and more effective techniques are urgently needed for their treatment. We hypothesized that covalently bonded conjugates of fatty acids and tripeptides can form wound-compatible hydrogels that can accelerate healing. We first designed conjugated structures as fatty acid–aminoacid1–amonoacid2–aspartate amphiphiles (Cn acid–AA1–AA2–D), which were potentially capable of self-assembling into hydrogels according to the structure and properties of each moiety. We then generated 14 novel conjugates based on this design by using two Fmoc/tBu solid-phase peptide synthesis techniques; we verified their structures and purities through liquid chromatography with tandem mass spectrometry and nuclear magnetic resonance spectroscopy. Of them, 13 conjugates formed hydrogels at low concentrations (≥0.25% w/v), but C8 acid-ILD-NH₂ showed the best hydrogelation and was investigated further. Scanning electron microscopy revealed that C8 acid-ILD-NH₂ formed fibrous network structures and rapidly formed hydrogels that were stable in phosphate-buffered saline (pH 2–8, 37 °C), a typical pathophysiological condition. Injection and rheological studies revealed that the hydrogels manifested important wound treatment properties, including injectability, shear thinning, rapid re-gelation, and wound-compatible mechanics (e.g., moduli G″ and G′, ~0.5–15 kPa). The C8 acid-ILD-NH₂(2) hydrogel markedly accelerated the healing of third-degree burn wounds on C57BL/6J mice. Taken together, our findings demonstrated the potential of the Cn fatty acid–AA1–AA2–D molecular template to form hydrogels capable of promoting the wound healing of third-degree burns. Full article

(This article belongs to the Special Issue Biomolecules and Biomaterials for Tissue Engineering)

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15 pages, 1706 KiB

Open AccessEditor’s ChoiceArticle

Multipurpose Iron-Chelating Ligands Inspired by Bioavailable Molecules

by Elena Cini, Guido Crisponi, Alessandra Fantasia, Rosita Cappai, Sofia Siciliano, Giuseppe Di Florio, Valeria M. Nurchi and Maddalena Corsini

Biomolecules 2024, 14(1), 92; https://doi.org/10.3390/biom14010092 - 11 Jan 2024

Cited by 1 | Viewed by 1261

Abstract

Because of their capacity to bind metals, metal chelators are primarily employed for therapeutic purposes, but they can also find applications as colorimetric reagents and cleaning solutions as well as in soil remediation, electroplating, waste treatment, and so on. For instance, iron-chelation therapy, [...] Read more.

Because of their capacity to bind metals, metal chelators are primarily employed for therapeutic purposes, but they can also find applications as colorimetric reagents and cleaning solutions as well as in soil remediation, electroplating, waste treatment, and so on. For instance, iron-chelation therapy, which is used to treat iron-overload disorders, involves removing excess iron from the blood through the use of particular molecules, like deferoxamine, that have the ability to chelate the metal. The creation of bioinspired and biodegradable chelating agents is a crucial objective that draws inspiration from natural products. In this context, starting from bioavailable molecules such as maltol and pyrogallol, new molecules have been synthetized and characterized by potentiometry, infrared spectroscopy and cyclic voltammetry. Finally, the ability of these to bind iron has been investigated, and the stability constants of ferric complexes are measured using spectrophotometry. These compounds offer intriguing scaffolds for an innovative class of versatile, multipurpose chelating agents. Full article

(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2022-2023)

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14 pages, 4228 KiB

Open AccessEditor’s ChoiceArticle

Eosinophils Contribute to Oral Tolerance via Induction of RORγt-Positive Antigen-Presenting Cells and RORγt-Positive Regulatory T Cells

by Shunjiro Kurihara, Kotaro Suzuki, Masaya Yokota, Takashi Ito, Yuki Hayashi, Ryo Kikuchi, Takahiro Kageyama, Kazuyuki Meguro, Shigeru Tanaka, Arifumi Iwata, Yoshiyuki Goto, Akira Suto and Hiroshi Nakajima

Biomolecules 2024, 14(1), 89; https://doi.org/10.3390/biom14010089 - 10 Jan 2024

Cited by 1 | Viewed by 1653

Abstract

Oral tolerance has been defined as the specific suppression of immune responses to an antigen by prior oral administration of the antigen. It has been thought to serve to suppress food allergy. Previous studies have shown that dendritic cells (DCs) and regulatory T [...] Read more.

Oral tolerance has been defined as the specific suppression of immune responses to an antigen by prior oral administration of the antigen. It has been thought to serve to suppress food allergy. Previous studies have shown that dendritic cells (DCs) and regulatory T cells (Tregs) are involved in the induction of oral tolerance. However, the detailed mechanisms of Treg induction in oral tolerance remain largely unknown. Eosinophils have been recognized as effector cells in allergic diseases, but in recent years, the diverse functions of tissue-resident eosinophils have been reported. Eosinophils in the intestine have been reported to induce Tregs by releasing TGF-β, but the role of eosinophils in oral tolerance is still controversial. In this study, we analyzed the roles of eosinophils in oral tolerance using eosinophil-deficient ΔdblGATA mice (mice lacking a high-affinity GATA-binding site in the GATA1 promoter). ΔdblGATA mice showed impaired antigen-induced oral tolerance compared to wild-type mice. The induction of RORγt⁺ Tregs in mesenteric lymph nodes (MLNs) by oral tolerance induction was impaired in ΔdblGATA mice compared to wild-type mice. An increase in RORγt⁺ antigen-presenting cells (APCs), which are involved in RORγt⁺ Treg differentiation, in the intestine and MLNs was not seen in ΔdblGATA mice. Notably, the expansion of group 3 innate lymphoid cells (ILC3s), a subset of RORγt⁺ APCs, by oral tolerance induction was seen in wild-type mice but not ΔdblGATA mice. These results suggest that eosinophils are crucial in the induction of oral tolerance, possibly via the induction of RORγt⁺ APCs and RORγt⁺ Tregs. Full article

(This article belongs to the Special Issue Eosinophils in Allergy and Related Diseases—Selected Papers from “The Workshop on Eosinophils in Allergy and Related Diseases 2022 and 2023”)

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