Biomolecules

22 pages, 7650 KiB

Open AccessArticle

Identification of Multifunctional Putative Bioactive Peptides in the Insect Model Red Palm Weevil (Rhynchophorus ferrugineus)

by Carmen Scieuzo, Roberta Rinaldi, Fabiana Giglio, Rosanna Salvia, Mohammed Ali AlSaleh, Jernej Jakše, Arnab Pain, Binu Antony and Patrizia Falabella

Biomolecules 2024, 14(10), 1332; https://doi.org/10.3390/biom14101332 (registering DOI) - 19 Oct 2024

Abstract

Innate immunity, the body’s initial defense against bacteria, fungi, and viruses, heavily depends on antimicrobial peptides (AMPs), which are small molecules produced by all living organisms. Insects, with their vast biodiversity, are one of the most abundant and innovative sources of AMPs. In [...] Read more.

Innate immunity, the body’s initial defense against bacteria, fungi, and viruses, heavily depends on antimicrobial peptides (AMPs), which are small molecules produced by all living organisms. Insects, with their vast biodiversity, are one of the most abundant and innovative sources of AMPs. In this study, AMPs from the red palm weevil (RPW) Rhynchophorus ferrugineus (Coleoptera: Curculionidae), a known invasive pest of palm species, were examined. The AMPs were identified in the transcriptomes from different body parts of male and female adults, under different experimental conditions, including specimens collected from the field and those reared in the laboratory. The RPW transcriptomes were examined to predict antimicrobial activity, and all sequences putatively encoding AMPs were analyzed using several machine learning algorithms available in the CAMP_R3 database. Additionally, anticancer, antiviral, and antifungal activity of the peptides were predicted using iACP, AVPpred, and Antifp server tools, respectively. Physicochemical parameters were assessed using the Antimicrobial Peptide Database Calculator and Predictor. From these analyses, 198 putatively active peptides were identified, which can be tested in future studies to validate the in silico predictions. Genome-wide analysis revealed that several AMPs have predominantly emerged through gene duplication. Noticeably, we detect a newly originated defensin allele from an ancestral defensin via the deletion of two amino acids following gene duplication in RPW, which may confer an enhanced resilience to microbial infection. Our study shed light on AMP gene families and shows that high duplication and deletion rates are essential to achieve a diversity of antimicrobial mechanisms; hence, we propose the RPW AMPs as a model for exploring gene duplication and functional variations against microbial infection. Full article

(This article belongs to the Special Issue State of the Art and Perspectives in Antimicrobial Peptides)

► Show Figures

Figure 1

17 pages, 4282 KiB

Open AccessArticle

A Novel Peptide from VP1 of EV-D68 Exhibits Broad-Spectrum Antiviral Activity Against Human Enteroviruses

by Xiaojing Lin, Qiang Sun, Yang Cao, Zi Li, Cuiling Xu, Jun Liu, Jingdong Song, Kun Qin, Yong Zhang and Jianfang Zhou

Biomolecules 2024, 14(10), 1331; https://doi.org/10.3390/biom14101331 (registering DOI) - 19 Oct 2024

Abstract

Enteroviruses have been a historical concern since the identification of polioviruses in humans. Wild polioviruses have almost been eliminated, while multiple species of non-polio enteroviruses and their variants co-circulate annually. To date, at least 116 types have been found in humans and are [...] Read more.

Enteroviruses have been a historical concern since the identification of polioviruses in humans. Wild polioviruses have almost been eliminated, while multiple species of non-polio enteroviruses and their variants co-circulate annually. To date, at least 116 types have been found in humans and are grouped into the species Enterovirus A–D and Rhinovirus A–C. However, there are few available antiviral drugs, especially with a universal pharmaceutical effect. Here, we demonstrate that peptide P25 from EV-D68 has broad antiviral activity against Ev A–D enteroviruses in vitro. P25, derived from the HI loop and β-I sheet of VP1, operates through a conserved hydrophilic motif -R---K-K--K- and the hydrophobic F near the N-terminus. It could prevent viral infection of EV-A71 by competing for the heparan sulfate (HS) receptor, and binding and stabilizing virions by suppressing the release of the viral genome. P25 also inhibited the generation of infectious viral particles by reducing viral protein synthesis. The molecular docking revealed that P25 might bind to the pocket opening area, a potential target for broad-spectrum antivirals. Our findings implicate the multiple antiviral effects of peptide P25, including blocking viral binding to the HS receptor, impeding viral genome release, and reducing progeny particles, which could be a novel universal anti-enterovirus drug candidate. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

► Show Figures

Figure 1

26 pages, 1530 KiB

Open AccessReview

A Survey on Computational Methods in Drug Discovery for Neurodegenerative Diseases

by Caterina Vicidomini, Francesco Fontanella, Tiziana D’Alessandro and Giovanni N. Roviello

Biomolecules 2024, 14(10), 1330; https://doi.org/10.3390/biom14101330 (registering DOI) - 19 Oct 2024

Viewed by 14

Abstract

Currently, the age structure of the world population is changing due to declining birth rates and increasing life expectancy. As a result, physicians worldwide have to treat an increasing number of age-related diseases, of which neurological disorders represent a significant part. In this [...] Read more.

Currently, the age structure of the world population is changing due to declining birth rates and increasing life expectancy. As a result, physicians worldwide have to treat an increasing number of age-related diseases, of which neurological disorders represent a significant part. In this context, there is an urgent need to discover new therapeutic approaches to counteract the effects of neurodegeneration on human health, and computational science can be of pivotal importance for more effective neurodrug discovery. The knowledge of the molecular structure of the receptors and other biomolecules involved in neurological pathogenesis facilitates the design of new molecules as potential drugs to be used in the fight against diseases of high social relevance such as dementia, Alzheimer’s disease (AD) and Parkinson’s disease (PD), to cite only a few. However, the absence of comprehensive guidelines regarding the strengths and weaknesses of alternative approaches creates a fragmented and disconnected field, resulting in missed opportunities to enhance performance and achieve successful applications. This review aims to summarize some of the most innovative strategies based on computational methods used for neurodrug development. In particular, recent applications and the state-of-the-art of molecular docking and artificial intelligence for ligand- and target-based approaches in novel drug design were reviewed, highlighting the crucial role of in silico methods in the context of neurodrug discovery for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery: 2nd Edition)

► Show Figures

Figure 1

17 pages, 971 KiB

Open AccessReview

Aspirin Hypersensitivity in Patients with Coronary Artery Disease: An Updated Review and Practical Recommendations

by Luigi Cappannoli, Stefania Colantuono, Francesco Maria Animati, Francesco Fracassi, Mattia Galli, Cristina Aurigemma, Enrico Romagnoli, Rocco Antonio Montone, Mattia Lunardi, Lazzaro Paraggio, Carolina Ierardi, Ilaria Baglivo, Cristiano Caruso, Carlo Trani and Francesco Burzotta

Biomolecules 2024, 14(10), 1329; https://doi.org/10.3390/biom14101329 (registering DOI) - 19 Oct 2024

Viewed by 79

Abstract

Acetylsalicylic acid (ASA) represents a cornerstone of antiplatelet therapy for the treatment of atherosclerotic coronary artery disease (CAD). ASA is in fact indicated in case of an acute coronary syndrome or after a percutaneous coronary intervention with stent implantation. Aspirin hypersensitivity is frequently [...] Read more.

Acetylsalicylic acid (ASA) represents a cornerstone of antiplatelet therapy for the treatment of atherosclerotic coronary artery disease (CAD). ASA is in fact indicated in case of an acute coronary syndrome or after a percutaneous coronary intervention with stent implantation. Aspirin hypersensitivity is frequently reported by patients, and this challenging situation requires a careful evaluation of the true nature of the presumed sensitivity and of its mechanisms, as well as to differentiate it from a more frequent (and more easily manageable) aspirin intolerance. Two main strategies are available to allow ASA administration for patients with CAD and suspected ASA hypersensitivity: a low-dose ASA challenge, aimed at assessing the tolerability of ASA at the antiplatelet dose of 100 mg, and desensitization, a therapeutic procedure which aims to induce tolerance to ASA. For those patients who cannot undergo ASA challenge and desensitization due to previous serious adverse reactions, or for those in whom desensitization was unsuccessful, a number of further alternative strategies are available, even if these have not been validated and approved by guidelines. The aim of this state-of-the-art review is therefore to summarize the established evidence regarding pathophysiology, clinical presentation, diagnosis, and management of aspirin hypersensitivity and to provide a practical guide for cardiologists (and clinicians) who have to face the not uncommon situation of a patient with concomitant coronary artery disease and aspirin hypersensitivity. Full article

(This article belongs to the Special Issue New Discoveries in Biological Functions of Platelet)

► Show Figures

Figure 1

17 pages, 722 KiB

Open AccessArticle

The Biological Effect of Enriching the Plasma Content in Platelet-Rich Plasma: An In Vitro Study

by Eduardo Anitua, Mar Zalduendo, Roberto Prado, María Troya, Roberto Tierno, María de la Fuente and Mohammad H. Alkhraisat

Biomolecules 2024, 14(10), 1328; https://doi.org/10.3390/biom14101328 (registering DOI) - 18 Oct 2024

Viewed by 241

Abstract

BACKGROUND: Platelet-rich plasma (PRP) formulations have become valuable therapeutic tools in regenerative medicine. In addition, these blood derivates have been successfully included in cell therapy as fetal bovine serum substitutes, due to the real need to avoid the risk of host immunologic reactions [...] Read more.

BACKGROUND: Platelet-rich plasma (PRP) formulations have become valuable therapeutic tools in regenerative medicine. In addition, these blood derivates have been successfully included in cell therapy as fetal bovine serum substitutes, due to the real need to avoid the risk of host immunologic reactions and the animal disease transmission associated with reagents from animal origin. However, the protocols for obtaining them should be optimized to improve their biological potential. METHODS: PRP-derived preparations with different concentrations of the platelet and plasma components were obtained from the blood of five donors by freeze-drying. Measurements of the pH, protein, and growth factor concentration were performed. Moreover, their biological effects on cell proliferation and migration and their angiogenic potential were assessed. RESULTS: An increased plasma component concentration resulted in an augmented quantity of the total protein content, a significative variation in the hepatocyte growth factor concentration, and an experimental but clinically irrelevant alteration of the pH value. No significant changes were induced in their potential to enhance proliferative and migratory responses in epithelial cells, with the latter being reduced for dermal fibroblasts. The endothelial cell capacity for tube formation was significatively reduced. CONCLUSIONS: An increased blood plasma content did not improve the biological potential of the formulations. However, they have emerged as a promising approach for regenerative therapies where neovascularization must be avoided. Full article

15 pages, 1488 KiB

Open AccessArticle

Pulling Forces Differentially Affect Refolding Pathways due to Entangled Misfolded States in SARS-CoV-1 and SARS-CoV-2 Receptor Binding Domain

by Pham Dang Lan, Edward P. O’Brien and Mai Suan Li

Biomolecules 2024, 14(10), 1327; https://doi.org/10.3390/biom14101327 (registering DOI) - 18 Oct 2024

Viewed by 177

Abstract

Single-molecule force spectroscopy (SMFS) experiments can monitor protein refolding by applying a small force of a few piconewtons (pN) and slowing down the folding process. Bell theory predicts that in the narrow force regime where refolding can occur, the folding time should increase [...] Read more.

Single-molecule force spectroscopy (SMFS) experiments can monitor protein refolding by applying a small force of a few piconewtons (pN) and slowing down the folding process. Bell theory predicts that in the narrow force regime where refolding can occur, the folding time should increase exponentially with increased external force. In this work, using coarse-grained molecular dynamics simulations, we compared the refolding pathways of SARS-CoV-1 RBD and SARS-CoV-2 RBD (RBD refers to the receptor binding domain) starting from unfolded conformations with and without a force applied to the protein termini. For SARS-CoV-2 RBD, the number of trajectories that fold is significantly reduced with the application of a 5 pN force, indicating that, qualitatively consistent with Bell theory, refolding is slowed down when a pulling force is applied to the termini. In contrast, the refolding times of SARS-CoV-1 RBD do not change meaningfully when a force of 5 pN is applied. How this lack of a Bell response could arise at the molecular level is unknown. Analysis of the entanglement changes of the folded conformations revealed that in the case of SARS-CoV-1 RBD, an external force minimizes misfolding into kinetically trapped states, thereby promoting efficient folding and offsetting any potential slowdown due to the external force. These misfolded states contain non-native entanglements that do not exist in the native state of either SARS-CoV-1-RBD or SARS-CoV-2-RBD. These results indicate that non-Bell behavior can arise from this class of misfolding and, hence, may be a means of experimentally detecting these elusive, theoretically predicted states. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

► Show Figures

Graphical abstract

23 pages, 2482 KiB

Open AccessArticle

From Organotypic Mouse Brain Slices to Human Alzheimer’s Plasma Biomarkers: A Focus on Nerve Fiber Outgrowth

by Sakir Necat Yilmaz, Katharina Steiner, Josef Marksteiner, Klaus Faserl, Mathias Villunger, Bettina Sarg and Christian Humpel

Biomolecules 2024, 14(10), 1326; https://doi.org/10.3390/biom14101326 (registering DOI) - 18 Oct 2024

Viewed by 167

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory loss and progressive deterioration of cognitive functions. Being able to identify reliable biomarkers in easily available body fluids such as blood plasma is vital for the disease. To achieve this, we used a [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by memory loss and progressive deterioration of cognitive functions. Being able to identify reliable biomarkers in easily available body fluids such as blood plasma is vital for the disease. To achieve this, we used a technique that applied human plasma to organotypic brain slice culture via microcontact printing. After a 2-week culture period, we performed immunolabeling for neurofilament and myelin oligodendrocyte glycoprotein (MOG) to visualize newly formed nerve fibers and oligodendrocytes. There was no significant change in the number of new nerve fibers in the AD plasma group compared to the healthy control group, while the length of the produced fibers significantly decreased. A significant increase in the number of MOG+ dots around these new fibers was detected in the patient group. According to our hypothesis, there are factors in the plasma of AD patients that affect the growth of new nerve fibers, which also affect the oligodendrocytes. Based on these findings, we selected the most promising plasma samples and conducted mass spectrometry using a differential approach and we identified three putative biomarkers: aldehyde-dehydrogenase 1A1, alpha-synuclein and protein S100-A4. Our method represents a novel and innovative approach for translating research findings from mouse models to human applications. Full article

(This article belongs to the Section Molecular Biomarkers)

► Show Figures

Graphical abstract

10 pages, 1292 KiB

Open AccessArticle

Endometrial Dysbiosis: A Possible Association with Estrobolome Alteration

by Giorgia Scarfò, Simona Daniele, Elisa Chelucci, Francesca Papini, Francesco Epifani, Maria Ruggiero, Vito Cela, Ferdinando Franzoni and Paolo Giovanni Artini

Biomolecules 2024, 14(10), 1325; https://doi.org/10.3390/biom14101325 (registering DOI) - 18 Oct 2024

Viewed by 150

Abstract

Background/Objectives: Microbiota modification at the endometrial level can favor gynecological diseases and impair women’s fertility. The overgrowth of pathogen microorganisms is related to the contemporary alteration of estrogen-metabolizing bacteria, including β-glucuronidase, thereby enhancing estrogen-related inflammatory states and decreasing anti-inflammatory cells. The possible connection [...] Read more.

Background/Objectives: Microbiota modification at the endometrial level can favor gynecological diseases and impair women’s fertility. The overgrowth of pathogen microorganisms is related to the contemporary alteration of estrogen-metabolizing bacteria, including β-glucuronidase, thereby enhancing estrogen-related inflammatory states and decreasing anti-inflammatory cells. The possible connection between estrobolome impairment and gynecological diseases has been suggested in animal models. Nevertheless, in humans, coherent evidence on the estrobolome alteration and functionality of the female reproductive tract is still lacking. The objective of this study was to explore alterations in estrogen-related signaling and the putative link with endometrial dysbiosis. Methods: Women with infertility and repeated implantation failure (RIF, N = 40) were enrolled in order to explore the putative link between estrogen metabolism and endometrial dysbiosis. Endometrial biopsies were used to measure inflammatory and growth factor molecules. β-glucuronidase enzyme activity and estrogen receptor (ER) expression were also assessed. Results: Herein, increased levels of inflammatory molecules (i.e., IL-1β and HIF-1α) and decreased levels of the growth factor IGF-1 were found in the endometrial biopsies of patients presenting dysbiosis compared to eubiotic ones. β-glucuronidase activity and the expression of ERβ were significantly enhanced in patients in the dysbiosis group. Interestingly, Lactobacilli abundance was inversely related to β-glucuronidase activity and to ERβ expression, thus suggesting that an alteration of the estrogen-activating enzyme may affect the expression of ERs as well. Conclusions. Overall, these preliminary data suggested a link between endometrial dysbiosis and estrobolome impairment as possible synergistic contributing factors to women infertility and RIF. Full article

(This article belongs to the Special Issue Molecular Aspects of Female Infertility)

► Show Figures

Figure 1

15 pages, 577 KiB

Open AccessReview

Targeting Protein Aggregation in ALS

by Michele Perni and Benedetta Mannini

Biomolecules 2024, 14(10), 1324; https://doi.org/10.3390/biom14101324 - 18 Oct 2024

Viewed by 269

Abstract

Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining the balance of the proteome is a finely regulated process managed by a complex network of cellular machinery responsible for protein synthesis, folding, and degradation. However, stress and ageing can disrupt this balance, leading [...] Read more.

Proteinopathies involve the abnormal accumulation of specific proteins. Maintaining the balance of the proteome is a finely regulated process managed by a complex network of cellular machinery responsible for protein synthesis, folding, and degradation. However, stress and ageing can disrupt this balance, leading to widespread protein aggregation. Currently, several therapies targeting protein aggregation are in clinical trials for ALS. These approaches mainly focus on two strategies: addressing proteins that are prone to aggregation due to mutations and targeting the cellular mechanisms that maintain protein homeostasis to prevent aggregation. This review will cover these emerging drugs. Advances in ALS research not only offer hope for better outcomes for ALS patients but also provide valuable insights and methodologies that can benefit the broader field of neurodegenerative disease drug discovery. Full article

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

► Show Figures

Graphical abstract

12 pages, 687 KiB

Open AccessReview

The Emerging Role of Immunoglobulins and Complement in the Stimulation of Neuronal Activity and Repair: Not as Simple as We Thought

by Tatyana Veremeyko, Natasha S. Barteneva, Ivan Vorobyev and Eugene D. Ponomarev

Biomolecules 2024, 14(10), 1323; https://doi.org/10.3390/biom14101323 - 18 Oct 2024

Viewed by 241

Abstract

Neurologic disorders such as traumatic brain injury, multiple sclerosis, Alzheimer’s disease, and drug-resistant epilepsy have a high socioeconomic impact around the world. Current therapies for these disorders are often not effective. This creates a demand for the development of new therapeutic approaches to [...] Read more.

Neurologic disorders such as traumatic brain injury, multiple sclerosis, Alzheimer’s disease, and drug-resistant epilepsy have a high socioeconomic impact around the world. Current therapies for these disorders are often not effective. This creates a demand for the development of new therapeutic approaches to treat these disorders. Recent data suggest that autoreactive naturally occurring immunoglobulins produced by subsets of B cells, called B1 B cells, combined with complement, are actively involved in the processes of restoration of neuronal functions during pathological conditions and remyelination. The focus of this review is to discuss the possibility of creating specific therapeutic antibodies that can activate and fix complement to enhance neuronal survival and promote central nervous system repair after injuries associated with many types of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Recent Advances in Neurological Diseases)

► Show Figures

Figure 1

20 pages, 1446 KiB

Open AccessArticle

The Role of Keeving in Modulating Fermentation and the Flavour Profiles of Apple Brandy

by Magdalena Januszek, Paweł Satora, Aneta Pater and Łukasz Wajda

Biomolecules 2024, 14(10), 1322; https://doi.org/10.3390/biom14101322 - 18 Oct 2024

Viewed by 316

Abstract

Keeving is the removal of nutrients from apple musts due to their binding to pectin, resulting in a slower fermentation and spontaneous arrest. The aim of this study was to determine the effect of keeving on the chemical composition of fermented apple must [...] Read more.

Keeving is the removal of nutrients from apple musts due to their binding to pectin, resulting in a slower fermentation and spontaneous arrest. The aim of this study was to determine the effect of keeving on the chemical composition of fermented apple must and on the volatile profile and sensory analysis of apple brandies. We compared the application of keeving during spontaneous fermentation with fermentation carried out by Saccharomyces cerevisiae (SafSpirit HG-1). We evaluated the impact of adding different doses of calcium chloride on various parameters of fermented musts and distillates. Calcium chloride had a greater effect on the ethanol concentration, total extract, and fermentation efficiency than on the type of fermentation used. However, a different phenomenon was observed with respect to the volatiles. The concentration of most of the higher alcohols, acetaldehyde, dodecanal, and geranylaceton, decreased after spontaneous fermentation and increased during the fermentation carried out with Saccharomyces cerevisiae SafSpirit HG-1. In general, the application of keeving contributed to a decrease in the concentration of ethyl and methyl esters, but caused an increase in the concentration of all acetate esters and terpenoids. When the amount of nutrients in the environment is limited and starvation occurs, microorganisms use the available nutrients for basic metabolic processes that allow them to survive and limit the formation of side metabolites such as volatiles. However, most of the samples fermented after the faecal depletion achieved high scores for the floral, fruity, and “overall note” parameters in the sensory analysis. This means that this method, carried out with a properly selected yeast strain, could be feasible for the distilling industry. Full article

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

► Show Figures

Figure 1

21 pages, 7042 KiB

Open AccessArticle

Glucocorticoid-Induced Leucine Zipper Protein and Yeast-Extracted Compound Alleviate Colitis and Reduce Fungal Dysbiosis

by Marco Gentili, Samuele Sabbatini, Emilia Nunzi, Eleonora Lusenti, Luigi Cari, Antonella Mencacci, Nathalie Ballet, Graziella Migliorati, Carlo Riccardi, Simona Ronchetti and Claudia Monari

Biomolecules 2024, 14(10), 1321; https://doi.org/10.3390/biom14101321 - 17 Oct 2024

Viewed by 301

Abstract

Inflammatory bowel diseases (IBD) have a complex, poorly understood pathogenesis and lack long-lasting effective treatments. Recent research suggests that intestinal fungal dysbiosis may play a role in IBD development. This study investigates the effects of the glucocorticoid-induced leucine zipper protein (GILZp)”, known for [...] Read more.

Inflammatory bowel diseases (IBD) have a complex, poorly understood pathogenesis and lack long-lasting effective treatments. Recent research suggests that intestinal fungal dysbiosis may play a role in IBD development. This study investigates the effects of the glucocorticoid-induced leucine zipper protein (GILZp)”, known for its protective role in gut mucosa, and a yeast extract (Py) with prebiotic properties, either alone or combined, in DSS-induced colitis. Both treatments alleviated symptoms via overlapping or distinct mechanisms. In particular, they reduced the transcription levels of pro-inflammatory cytokines IL-1β and TNF-α, as well as the expression of the tight junction protein Claudin-2. Additionally, GILZp increased MUC2 transcription, while Py reduced IL-12p40 and IL-6 levels. Notably, both treatments were effective in restoring the intestinal burden of clinically important Candida and related species. Intestinal mycobiome analysis revealed that they were able to reduce colitis-associated fungal dysbiosis, and this effect was mainly the result of a decreased abundance of the Meyerozima genus, which was dominant in colitic mice. Overall, our results suggest that combined treatment regimens with GILZp and Py could represent a new strategy for the treatment of IBD by targeting multiple mechanisms, including the fungal dysbiosis. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

36 pages, 3132 KiB

Open AccessReview

The Ambivalence of Post COVID-19 Vaccination Responses in Humans

by Radha Gopalaswamy, Vivekanandhan Aravindhan and Selvakumar Subbian

Biomolecules 2024, 14(10), 1320; https://doi.org/10.3390/biom14101320 - 17 Oct 2024

Viewed by 521

Abstract

The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has prompted a massive global vaccination campaign, leading to the rapid development and deployment of several vaccines. Various COVID-19 vaccines are under different phases of clinical trials and include [...] Read more.

The Coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has prompted a massive global vaccination campaign, leading to the rapid development and deployment of several vaccines. Various COVID-19 vaccines are under different phases of clinical trials and include the whole virus or its parts like DNA, mRNA, or protein subunits administered directly or through vectors. Beginning in 2020, a few mRNA (Pfizer-BioNTech BNT162b2 and Moderna mRNA-1273) and adenovirus-based (AstraZeneca ChAdOx1-S and the Janssen Ad26.COV2.S) vaccines were recommended by WHO for emergency use before the completion of the phase 3 and 4 trials. These vaccines were mostly administered in two or three doses at a defined frequency between the two doses. While these vaccines, mainly based on viral nucleic acids or protein conferred protection against the progression of SARS-CoV-2 infection into severe COVID-19, and prevented death due to the disease, their use has also been accompanied by a plethora of side effects. Common side effects include localized reactions such as pain at the injection site, as well as systemic reactions like fever, fatigue, and headache. These symptoms are generally mild to moderate and resolve within a few days. However, rare but more serious side effects have been reported, including allergic reactions such as anaphylaxis and, in some cases, myocarditis or pericarditis, particularly in younger males. Ongoing surveillance and research efforts continue to refine the understanding of these adverse effects, providing critical insights into the risk-benefit profile of COVID-19 vaccines. Nonetheless, the overall safety profile supports the continued use of these vaccines in combating the pandemic, with regulatory agencies and health organizations emphasizing the importance of vaccination in preventing COVID-19’s severe outcomes. In this review, we describe different types of COVID-19 vaccines and summarize various adverse effects due to autoimmune and inflammatory response(s) manifesting predominantly as cardiac, hematological, neurological, and psychological dysfunctions. The incidence, clinical presentation, risk factors, diagnosis, and management of different adverse effects and possible mechanisms contributing to these effects are discussed. The review highlights the potential ambivalence of human response post-COVID-19 vaccination and necessitates the need to mitigate the adverse side effects. Full article

(This article belongs to the Special Issue Viral Respiratory Infection including COVID-19: From Molecular Mechanisms to Therapies Strategies)

► Show Figures

Figure 1

12 pages, 1430 KiB

Open AccessReview

N6-Methyladenosine Methyltransferase Component KIAA1429 Is a Potential Target of Cancer Therapy

by Junjun Huang, Jihua Guo and Rong Jia

Biomolecules 2024, 14(10), 1319; https://doi.org/10.3390/biom14101319 - 17 Oct 2024

Viewed by 237

Abstract

N6-methyladenosine (m⁶A), the most abundant RNA modification in eukaryotes, has a crucial impact on tumorigenesis. KIAA1429 is the key component of the m⁶A methyltransferase complex, in which KIAA1429 functions as a scaffold to bridge the catalytic core proteins. KIAA1429 [...] Read more.

N6-methyladenosine (m⁶A), the most abundant RNA modification in eukaryotes, has a crucial impact on tumorigenesis. KIAA1429 is the key component of the m⁶A methyltransferase complex, in which KIAA1429 functions as a scaffold to bridge the catalytic core proteins. KIAA1429 is often overexpressed in malignances, associated with patient prognosis, and required for tumorigenesis. KIAA1429 regulates the expression of a number of tumor-associated genes in an m⁶A -dependent manner, and thus, contributes to cell proliferation, migration, drug resistance, tumor formation and metastasis. This review focuses on recent progress in the understanding of roles and mechanisms of KIAA1429 in cancers, and offers ideas for potential anti-cancer therapeutic methods by targeting KIAA1429. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

19 pages, 1565 KiB

Open AccessReview

The Role of Mitochondrial Permeability Transition in Bone Metabolism, Bone Healing, and Bone Diseases

by Xiting Zhu, Ziqi Qin, Min Zhou, Chen Li, Junjun Jing, Wushuang Ye and Xueqi Gan

Biomolecules 2024, 14(10), 1318; https://doi.org/10.3390/biom14101318 - 17 Oct 2024

Viewed by 248

Abstract

Bone is a dynamic organ with an active metabolism and high sensitivity to mitochondrial dysfunction. The mitochondrial permeability transition pore (mPTP) is a low-selectivity channel situated in the inner mitochondrial membrane (IMM), permitting the exchange of molecules of up to 1.5 kDa in [...] Read more.

Bone is a dynamic organ with an active metabolism and high sensitivity to mitochondrial dysfunction. The mitochondrial permeability transition pore (mPTP) is a low-selectivity channel situated in the inner mitochondrial membrane (IMM), permitting the exchange of molecules of up to 1.5 kDa in and out of the IMM. Recent studies have highlighted the critical role of the mPTP in bone tissue, but there is currently a lack of reviews concerning this topic. This review discusses the structure and function of the mPTP and its impact on bone-related cells and bone-related pathological states. The mPTP activity is reduced during the osteogenic differentiation of mesenchymal stem cells (MSCs), while its desensitisation may underlie the mechanism of enhanced resistance to apoptosis in neoplastic osteoblastic cells. mPTP over-opening triggers mitochondrial swelling, regulated cell death, and inflammatory response. In particular, mPTP over-opening is involved in dexamethasone-induced osteoblast dysfunction and bisphosphonate-induced osteoclast apoptosis. In vivo, the mPTP plays a significant role in maintaining bone homeostasis, with many bone disorders linked to its excessive opening. Genetic deletion or pharmacological inhibition of the over-opening of mPTP has shown potential in enhancing bone injury recovery and alleviating bone diseases. Here, we review the findings on the relationship of the mPTP and bone at both the cellular and disease levels, highlighting novel avenues for pharmacological approaches targeting mitochondrial function to promote bone healing and manage bone-related disorders. Full article

(This article belongs to the Section Cellular Biochemistry)

► Show Figures

Figure 1

16 pages, 2015 KiB

Open AccessReview

The Roles of Mitochondria in Human Being’s Life and Aging

by Hiroko P. Indo, Moragot Chatatikun, Ikuo Nakanishi, Ken-ichiro Matsumoto, Motoki Imai, Fumitaka Kawakami, Makoto Kubo, Hiroshi Abe, Hiroshi Ichikawa, Yoshikazu Yonei, Hisashi J. Beppu, Yukiko Minamiyama, Takuro Kanekura, Takafumi Ichikawa, Atthaphong Phongphithakchai, Lunla Udomwech, Suriyan Sukati, Nurdina Charong, Voravuth Somsak, Jitbanjong Tangpong, Sachiyo Nomura and Hideyuki J. Majima Show full author list Hide full author list

Biomolecules 2024, 14(10), 1317; https://doi.org/10.3390/biom14101317 - 17 Oct 2024

Viewed by 510

Abstract

The universe began 13.8 billion years ago, and Earth was born 4.6 billion years ago. Early traces of life were found as soon as 4.1 billion years ago; then, ~200,000 years ago, the human being was born. The evolution of life on earth [...] Read more.

The universe began 13.8 billion years ago, and Earth was born 4.6 billion years ago. Early traces of life were found as soon as 4.1 billion years ago; then, ~200,000 years ago, the human being was born. The evolution of life on earth was to become individual rather than cellular life. The birth of mitochondria made this possible to be the individual life. Since then, individuals have had a limited time of life. It was 1.4 billion years ago that a bacterial cell began living inside an archaeal host cell, a form of endosymbiosis that is the development of eukaryotic cells, which contain a nucleus and other membrane-bound compartments. The bacterium started to provide its host cell with additional energy, and the interaction eventually resulted in a eukaryotic cell, with both archaeal (the host cell) and bacterial (mitochondrial) origins still having genomes. The cells survived high concentrations of oxygen producing more energy inside the cell. Further, the roles of mitochondria in human being’s life and aging will be discussed. Full article

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

► Show Figures

Graphical abstract

13 pages, 1968 KiB

Open AccessArticle

Gintonin Stimulates Glucose Uptake in Myocytes: Involvement of Calcium and Extracellular Signal-Regulated Kinase Signaling

by Rami Lee, Kyung-Jong Won, Ji-Hun Kim, Byung-Hwan Lee, Sung-Hee Hwang and Seung-Yeol Nah

Biomolecules 2024, 14(10), 1316; https://doi.org/10.3390/biom14101316 - 17 Oct 2024

Viewed by 287

Abstract

Ginseng has anti-hyperglycemic effects. Gintonin, a glycolipoprotein derived from ginseng, also stimulates insulin release from pancreatic beta cells. However, the role of gintonin in glucose metabolism within skeletal muscle is unknown. Here, we showed the effect of gintonin on glucose uptake, glycogen content, [...] Read more.

Ginseng has anti-hyperglycemic effects. Gintonin, a glycolipoprotein derived from ginseng, also stimulates insulin release from pancreatic beta cells. However, the role of gintonin in glucose metabolism within skeletal muscle is unknown. Here, we showed the effect of gintonin on glucose uptake, glycogen content, glucose transporter (GLUT) 4 expression, and adenosine triphosphate (ATP) content in C2C12 myotubes. Gintonin (3–30 μg/mL) dose-dependently stimulated glucose uptake in myotubes. The expression of GLUT4 on the cell membrane was increased by gintonin treatment. Treatment with 1–3 μg/mL of gintonin increased glycogen content in myotubes, but the content was decreased at 30 μg/mL of gintonin. The ATP content in myotubes increased following treatment with 10–100 μg/mL gintonin. Gintonin transiently elevated intracellular calcium concentrations and increased the phosphorylation of extracellular signal-regulated kinase (ERK). Gintonin-induced transient calcium increases were inhibited by treatment with the lysophosphatidic acid receptor inhibitor Ki16425, the phospholipase C inhibitor U73122, and the inositol 1,4,5-trisphosphate receptor antagonist 2-aminoethoxydiphenyl borate. Gintonin-stimulated glucose uptake was decreased by treatment with U73122, the intracellular calcium chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl) ester, and the ERK inhibitor PD98059. These results show that gintonin plays a role in glucose metabolism by increasing glucose uptake through transient calcium increases and ERK signaling pathways. Thus, gintonin may be beneficial for glucose metabolism control. Full article

(This article belongs to the Special Issue Therapeutic Potential of Natural Products in Metabolic Diseases)

► Show Figures

Figure 1

14 pages, 2418 KiB

Open AccessReview

Fungal L-Methionine Biosynthesis Pathway Enzymes and Their Applications in Various Scientific and Commercial Fields

by Kamila Rząd, Aleksandra Kuplińska and Iwona Gabriel

Biomolecules 2024, 14(10), 1315; https://doi.org/10.3390/biom14101315 - 17 Oct 2024

Viewed by 311

Abstract

L-methionine (L-Met) is one of the nine proteinogenic amino acids essential for humans since, in human cells, there are no complete pathways for its biosynthesis from simple precursors. L-Met plays a crucial role in cellular function as it is required for proper protein [...] Read more.

L-methionine (L-Met) is one of the nine proteinogenic amino acids essential for humans since, in human cells, there are no complete pathways for its biosynthesis from simple precursors. L-Met plays a crucial role in cellular function as it is required for proper protein synthesis, acting as an initiator. Additionally, this amino acid participates in various metabolic processes and serves as a precursor for the synthesis of S-adenosylmethionine (AdoMet), which is involved in the methylation of DNA molecules and phospholipids, as well as in maintaining genome stability. Due to its importance, fungal L-methionine biosynthesis pathway enzymes are being intensively studied. This review presents the current state of the art in terms of their cellular function, usefulness as molecular markers, antifungal targets, or industrial approaches. Full article

(This article belongs to the Section Enzymology)

► Show Figures

Figure 1

12 pages, 2239 KiB

Open AccessArticle

Some Glycoproteins Expressed on the Surface of Immune Cells and Cytokine Plasma Levels Can Be Used as Potential Biomarkers in Patients with Colorectal Cancer

by Tsvetelina Batsalova, Denitsa Uzunova, Gergana Chavdarova, Tatyana Apostolova and Balik Dzhambazov

Biomolecules 2024, 14(10), 1314; https://doi.org/10.3390/biom14101314 - 16 Oct 2024

Viewed by 412

Abstract

Colorectal cancer (CRC) is a leading cause of mortality worldwide. Its incidence holds a major position among the most common life-threatening diseases. Hence, the early identification and precise characterization of disease activity based on proper biomarkers are of utmost importance for therapeutic strategy [...] Read more.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. Its incidence holds a major position among the most common life-threatening diseases. Hence, the early identification and precise characterization of disease activity based on proper biomarkers are of utmost importance for therapeutic strategy and patient survival. The identification of new biomarkers for colorectal cancer or disease-specific levels/combinations of biomarkers will significantly contribute to precise diagnosis and improved personalized treatment of patients. Therefore, the present study aims to identify colorectal cancer-specific immunological biomarkers. The plasma levels of several cytokines (interleukin-1β /IL-1β/, IL-2, IL-4, IL-10, IL-12, IL-15, TGFβ and IFNγ) of 20 patients with colorectal cancer and 21 healthy individuals were determined by ELISA. The expression of several types of glycoproteins on the surface of peripheral blood leukocytes isolated from CRC patients and healthy volunteers was evaluated by flow cytometry. Correlations between cytokine levels and cell surface glycoprotein expression were analyzed. The obtained results demonstrated significantly elevated levels of CD80, CD86, CD279 and CD274 expressing leukocyte populations in the cancer patient group, while the numbers of NK cells and CD8- and CD25-positive cells were decreased. Based on these data and the correlations with cytokine levels, it can be concluded that CD25, CD80, CD86, CD274 and CD279 glycoproteins combined with specific plasma levels of IL-1β, IL-2, IL-15 and TGFβ could represent potential biomarkers for colorectal cancer. Full article

(This article belongs to the Special Issue Immune-Related Biomarkers: 2nd Edition)

► Show Figures

Figure 1

16 pages, 685 KiB

Open AccessArticle

Altered Gut Microbiota Patterns in Young Children with Recent Maltreatment Exposure

by Gergana Karaboycheva, Melanie L. Conrad, Peggy Dörr, Katja Dittrich, Elena Murray, Karolina Skonieczna-Żydecka, Mariusz Kaczmarczyk, Igor Łoniewski, Heiko Klawitter, Claudia Buss, Sonja Entringer, Elisabeth Binder, Sibylle M. Winter and Christine Heim

Biomolecules 2024, 14(10), 1313; https://doi.org/10.3390/biom14101313 - 16 Oct 2024

Viewed by 389

Abstract

Background: The brain and the intestinal microbiota are highly interconnected and especially vulnerable to disruptions in early life. Emerging evidence indicates that psychosocial adversity detrimentally impacts the intestinal microbiota, affecting both physical and mental health. This study aims to investigate the gut microbiome [...] Read more.

Background: The brain and the intestinal microbiota are highly interconnected and especially vulnerable to disruptions in early life. Emerging evidence indicates that psychosocial adversity detrimentally impacts the intestinal microbiota, affecting both physical and mental health. This study aims to investigate the gut microbiome in young children in the immediate aftermath of maltreatment exposure. Methods: Maltreatment exposure was assessed in 88 children (ages 3–7) using the Maternal Interview for the Classification of Maltreatment [MICM]. Children were allocated to three groups according to the number of experienced maltreatment categories: no maltreatment, low maltreatment, and high maltreatment exposures. Stool samples were collected and analyzed by 16S rRNA sequencing. Results: Children subjected to high maltreatment exposure exhibited lower alpha diversity in comparison to those with both no and low maltreatment exposure (Simpson Index, Tukey post hoc, p = 0.059 and p = 0.007, respectively). No significant distinctions in beta diversity were identified. High maltreatment exposure was associated with the enrichment of several genera from the class Clostridia (Clostridium, Intestinibacter, Howardella and Butyrivibrio) and the depletion of the genus Phocaeicola (class Bacteriodia). Conclusions: Severe maltreatment exposure is associated with alterations in the gut microbiota of young children. Longitudinal trajectories of intestinal microbiota composition in the context of maltreatment may reveal important insights related to psychiatric and somatic health outcomes. Full article

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

► Show Figures

Figure 1

16 pages, 2591 KiB

Open AccessArticle

Short Link N Modulates Inflammasome Activity in Intervertebral Discs Through Interaction with CD14

by Muskan Alad, Michael P. Grant, Laura M. Epure, Sunny Y. Shih, Geraldine Merle, Hee-Jeong Im, John Antoniou and Fackson Mwale

Biomolecules 2024, 14(10), 1312; https://doi.org/10.3390/biom14101312 - 16 Oct 2024

Viewed by 424

Abstract

Intervertebral disc degeneration and pain are associated with the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome activation and the processing of interleukin-1 beta (IL-1β). Activation of thehm inflammasome is triggered by Toll-like receptor stimulation and requires the cofactor receptor cluster [...] Read more.

Intervertebral disc degeneration and pain are associated with the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing 3 (NLRP3) inflammasome activation and the processing of interleukin-1 beta (IL-1β). Activation of thehm inflammasome is triggered by Toll-like receptor stimulation and requires the cofactor receptor cluster of differentiation 14 (CD14). Short Link N (sLN), a peptide derived from link protein, has been shown to modulate inflammation and pain in discs in vitro and in vivo; however, the underlying mechanisms remain elusive. This study aims to assess whether sLN modulates IL-1β and inflammasome activity through interaction with CD14. Disc cells treated with lipopolysaccharides (LPS) with or without sLN were used to assess changes in Caspase-1, IL-1β, and phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Peptide docking of sLN to CD14 and immunoprecipitation were performed to determine their interaction. The results indicated that sLN inhibited LPS-induced NFκB and Caspase-1 activation, reducing IL-1β maturation and secretion in disc cells. A significant decrease in inflammasome markers was observed with sLN treatment. Immunoprecipitation studies revealed a direct interaction between sLN and the LPS-binding pocket of CD14. Our results suggest that sLN could be a potential therapeutic agent for discogenic pain by mitigating IL-1β and inflammasome activity within discs. Full article

(This article belongs to the Section Molecular Biology)

► Show Figures

Figure 1

17 pages, 3440 KiB

Open AccessArticle

Caution for Multidrug Therapy: Significant Baroreflex Afferent Neuroexcitation Coordinated by Multi-Channels/Pumps Under the Threshold Concentration of Yoda1 and Dobutamine Combination

by Yin-zhi Xu, Zhao-yuan Xu, Hui-xiao Fu, Mao Yue, Jia-qun Li, Chang-peng Cui, Di Wu and Bai-yan Li

Biomolecules 2024, 14(10), 1311; https://doi.org/10.3390/biom14101311 - 16 Oct 2024

Viewed by 295

Abstract

Multi-drug therapies are common in cardiovascular disease intervention; however, io channel/pump coordination has not been tested electrophysiologically. Apparently, inward currents were not elicited by Yoda1/10 nM or Dobutamine/100 nM alone in Ah-type baroreceptor neurons, but were by their combination. To verify this, electroneurography [...] Read more.

Multi-drug therapies are common in cardiovascular disease intervention; however, io channel/pump coordination has not been tested electrophysiologically. Apparently, inward currents were not elicited by Yoda1/10 nM or Dobutamine/100 nM alone in Ah-type baroreceptor neurons, but were by their combination. To verify this, electroneurography and the whole-cell patch-clamp technique were performed. The results showed that Ah- and C-volley were dramatically increased by the combination at 0.5 V and 5 V, in contrast to A-volley, as consistent with repetitive discharge elicited by step and ramp with markedly reduced current injection/stimulus intensity. Notably, a frequency-dependent action potential (AP) duration was increased with Iberiotoxin-sensitive K⁺ component. Furthermore, an increased peak in AP measured in phase plots suggested enhanced Na⁺ influx, cytoplasmic Ca²⁺ accumulation through reverse mode of Na⁺/Ca²⁺ exchanger, and, consequently, functional KCa1.1 up-regulation. Strikingly, the Yoda1- or Dbtm-mediated small/transient Na⁺/K⁺-pump currents were robustly increased by their combination, implying a quick ion equilibration that may also be synchronized by hyperpolarization-induced voltage-sag, enabling faster repetitive firing. These novel findings demonstrate multi-channel/pump collaboration together to integrate neurotransmission at the cellular level for baroreflex, providing an afferent explanation in sexual dimorphic blood pressure regulation, and raising the caution regarding the individual drug concentration in multi-drug therapies to optimize efficacy and minimize toxicity. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

29 pages, 18284 KiB

Open AccessArticle

Enhancing Cellular Homeostasis: Targeted Botanical Compounds Boost Cellular Health Functions in Normal and Premature Aging Fibroblasts

by Ramona Hartinger, Khushboo Singh, Jesse Leverett and Karima Djabali

Biomolecules 2024, 14(10), 1310; https://doi.org/10.3390/biom14101310 - 16 Oct 2024

Viewed by 483

Abstract

The human skin, the body’s largest organ, undergoes continuous renewal but is significantly impacted by aging, which impairs its function and leads to visible changes. This study aimed to identify botanical compounds that mimic the anti-aging effects of baricitinib, a known JAK1/2 inhibitor. [...] Read more.

The human skin, the body’s largest organ, undergoes continuous renewal but is significantly impacted by aging, which impairs its function and leads to visible changes. This study aimed to identify botanical compounds that mimic the anti-aging effects of baricitinib, a known JAK1/2 inhibitor. Through in silico screening of a botanical compound library, 14 potential candidates were identified, and 7 were further analyzed for their effects on cellular aging. The compounds were tested on both normal aged fibroblasts and premature aging fibroblasts derived from patients with Hutchinson–Gilford Progeria Syndrome (HGPS). Results showed that these botanical compounds effectively inhibited the JAK/STAT pathway, reduced the levels of phosphorylated STAT1 and STAT3, and ameliorated phenotypic changes associated with cellular aging. Treatments improved cell proliferation, reduced senescence markers, and enhanced autophagy without inducing cytotoxicity. Compounds, such as Resveratrol, Bisdemethoxycurcumin, Pinosylvin, Methyl P-Hydroxycinnamate, cis-Pterostilbene, and (+)-Gallocatechin, demonstrated significant improvements in both control and HGPS fibroblasts. These findings suggest that these botanical compounds have the potential to mitigate age-related cellular alterations, offering promising strategies for anti-aging therapies, particularly for skin health. Further in vivo studies are warranted to validate these results and explore their therapeutic applications. Full article

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

► Show Figures

Figure 1

14 pages, 1513 KiB

Open AccessArticle

Genotype-Dependent Variations in Oxidative Stress Markers and Bioactive Proteins in Hereford Bulls: Associations with DGAT1, LEP, and SCD1 Genes

by Piotr Kostusiak, Emilia Bagnicka, Beata Żelazowska, Magdalena Zalewska, Tomasz Sakowski, Jan Slósarz, Marcin Gołębiewski and Kamila Puppel

Biomolecules 2024, 14(10), 1309; https://doi.org/10.3390/biom14101309 - 16 Oct 2024

Viewed by 366

Abstract

The objective of this study is to assess the influence of genetic polymorphisms in DGAT1, LEP, and SCD1 on the oxidative stress biomarkers and bioactive protein levels in Hereford bulls. A total of sixty-eight bulls were analyzed at 22 months of [...] Read more.

The objective of this study is to assess the influence of genetic polymorphisms in DGAT1, LEP, and SCD1 on the oxidative stress biomarkers and bioactive protein levels in Hereford bulls. A total of sixty-eight bulls were analyzed at 22 months of age to assess growth metrics and carcass quality, with a focus on polymorphisms in these genes. The key markers of oxidative stress, including malondialdehyde (MDA), and the activities of antioxidant enzymes such as glutathione reductase (GluRed), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were measured, alongside bioactive compounds like taurine, carnosine, and anserine. The results show that the TT genotype of DGAT1 is linked to significantly higher MDA levels, reflecting increased lipid peroxidation, but is also associated with higher GluRed and GPx activities and elevated levels of taurine, carnosine, and anserine, suggesting an adaptive response to oxidative stress. The LEP gene analysis revealed that the CC genotype had the highest MDA levels but also exhibited increased GPx and SOD activities, with the CT genotype showing the highest SOD activity and the TT genotype the highest total antioxidant status (TAS). The SCD1 AA genotype displayed the highest activities of GluRed, GPx, and SOD, indicating a more effective antioxidant defence, while the VA genotype had the highest MDA levels and the VV genotype showed lower MDA levels, suggesting protective effects against oxidative damage. These findings highlight genotype specific variations in the oxidative stress markers and bioactive compound levels, providing insights into the genetic regulation of oxidative stress and antioxidant defences, which could inform breeding strategies for improving oxidative stress resistance in livestock and managing related conditions. Full article

► Show Figures

Figure 1

15 pages, 1641 KiB

Open AccessArticle

Expression of Myeloperoxidase in Patient-Derived Endothelial Colony-Forming Cells—Associations with Coronary Artery Disease and Mitochondrial Function

by Weiqian Eugene Lee, Elijah Genetzakis, Giannie Barsha, Joshua Vescovi, Carmen Mifsud, Stephen T. Vernon, Tung Viet Nguyen, Michael P. Gray, Stuart M. Grieve and Gemma A. Figtree

Biomolecules 2024, 14(10), 1308; https://doi.org/10.3390/biom14101308 - 16 Oct 2024

Viewed by 387

Abstract

Background and Aims: Myeloperoxidase (MPO) plays a critical role in the innate immune response and has been suggested to be a surrogate marker of oxidative stress and inflammation, with elevated levels implicated in cardiovascular diseases, such as atherosclerosis and heart failure, as well [...] Read more.

Background and Aims: Myeloperoxidase (MPO) plays a critical role in the innate immune response and has been suggested to be a surrogate marker of oxidative stress and inflammation, with elevated levels implicated in cardiovascular diseases, such as atherosclerosis and heart failure, as well as in conditions like rheumatoid arthritis and cancer. While MPO is well-known in leukocytes, its expression and function in human endothelial cells remain unclear. This study investigates MPO expression in patient-derived endothelial colony-forming cells (ECFCs) and its potential association with CAD and mitochondrial function. Methods: ECFCs were cultured from the peripheral blood of 93 BioHEART-CT patients. MPO expression and associated functions were examined using qRT-PCR, immunochemistry, flow cytometry, and MPO activity assays. CAD presence was defined using CT coronary angiography (CACS > 0). Results: We report MPO presence in patient-derived ECFCs for the first time. MPO protein expression occurred in 70.7% of samples (n = 41) which had nuclear co-localisation, an atypical observation given its conventional localisation in the granules of neutrophils and monocytes. This suggests potential alternative roles for MPO in nuclear processes. MPO mRNA expression was detected in 66.23% of samples (n = 77). CAD patients had a lower proportion of MPO-positive ECFCs compared to non-CAD controls (57.45% vs. 80%, p = 0.04), a difference that persisted in the statin-naïve sub-cohort (53.85% vs. 84.62%, p = 0.02). Non-CAD patients with MPO expression showed upregulated mitochondrial-antioxidant genes (AIFM2, TXNRD1, CAT, PRDX3, PRDX6). In contrast, CAD patients with MPO gene expression had heightened mROS production and mitochondrial mass and decreased mitochondrial function compared to that of CAD patients without MPO gene expression. Conclusions: MPO is present in the nucleus of ECFCs. In non-CAD ECFCs, MPO expression is linked to upregulated mitochondrial-antioxidant genes, whereas in CAD ECFCs, it is associated with greater mitochondrial dysfunction. Full article

► Show Figures

Figure 1

31 pages, 1150 KiB

Open AccessReview

How Do ROS Induce NETosis? Oxidative DNA Damage, DNA Repair, and Chromatin Decondensation

by Dhia Azzouz and Nades Palaniyar

Biomolecules 2024, 14(10), 1307; https://doi.org/10.3390/biom14101307 - 16 Oct 2024

Viewed by 368

Abstract

Neutrophil extracellular traps (NETs) are intricate, DNA-based, web-like structures adorned with cytotoxic proteins. They play a crucial role in antimicrobial defense but are also implicated in autoimmune diseases and tissue injury. The process of NET formation, known as NETosis, is a regulated cell [...] Read more.

Neutrophil extracellular traps (NETs) are intricate, DNA-based, web-like structures adorned with cytotoxic proteins. They play a crucial role in antimicrobial defense but are also implicated in autoimmune diseases and tissue injury. The process of NET formation, known as NETosis, is a regulated cell death mechanism that involves the release of these structures and is unique to neutrophils. NETosis is heavily dependent on the production of reactive oxygen species (ROS), which can be generated either through NADPH oxidase (NOX) or mitochondrial pathways, leading to NOX-dependent or NOX-independent NETosis, respectively. Recent research has revealed an intricate interplay between ROS production, DNA repair, and NET formation in different contexts. UV radiation can trigger a combined process of NETosis and apoptosis, known as apoNETosis, driven by mitochondrial ROS and DNA repair. Similarly, in calcium ionophore-induced NETosis, both ROS and DNA repair are key components, but only play a partial role. In the case of bacterial infections, the early stages of DNA repair are pivotal. Interestingly, in serum-free conditions, spontaneous NETosis occurs through NOX-derived ROS, with early-stage DNA repair inhibition halting the process, while late-stage inhibition increases it. The intricate balance between DNA repair processes and ROS production appears to be a critical factor in regulating NET formation, with different pathways being activated depending on the nature of the stimulus. These findings not only deepen our understanding of the mechanisms behind NETosis but also suggest potential therapeutic targets for conditions where NETs contribute to disease pathology. Full article

(This article belongs to the Section Cellular Biochemistry)

► Show Figures

Figure 1

20 pages, 904 KiB

Open AccessReview

Evaluating Circulating Biomarkers for Diagnosis, Prognosis, and Tumor Monitoring in Pediatric Sarcomas: Recent Advances and Future Directions

by Joaquín J. Maqueda, Alessandra De Feo and Katia Scotlandi

Biomolecules 2024, 14(10), 1306; https://doi.org/10.3390/biom14101306 - 16 Oct 2024

Viewed by 389

Abstract

Pediatric sarcomas present a significant challenge in oncology. There is an urgent need for improved therapeutic strategies for high-risk patients and better management of long-term side effects for those who survive the disease. Liquid biopsy is emerging as a promising tool to optimize [...] Read more.

Pediatric sarcomas present a significant challenge in oncology. There is an urgent need for improved therapeutic strategies for high-risk patients and better management of long-term side effects for those who survive the disease. Liquid biopsy is emerging as a promising tool to optimize treatment in these patients by offering non-invasive, repeatable assessments of disease status. Circulating biomarkers can provide valuable insights into tumor genetics and treatment response, potentially facilitating early diagnosis and dynamic disease monitoring. This review examines the potential of liquid biopsies, focusing on circulating biomarkers in the most common pediatric sarcomas, i.e., osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma. We also highlight the current research efforts and the necessary advancements required before these technologies can be widely adopted in clinical practice. Full article

(This article belongs to the Special Issue Genetic and Genomic Biomarkers of Cancer)

► Show Figures

Figure 1

19 pages, 21163 KiB

Open AccessArticle

Metabolic and Proteomic Profiling of Coronary Microvascular Dysfunction: Insights from Rat Models

by Yan Lu, Yuying Wang, Qiqi Xin, Rong Yuan, Keji Chen, Jianfeng Chu and Weihong Cong

Biomolecules 2024, 14(10), 1305; https://doi.org/10.3390/biom14101305 - 16 Oct 2024

Viewed by 330

Abstract

Coronary microvascular dysfunction (CMD) represents a principal etiological factor in ischemic heart disease. Nonetheless, a considerable subset of CMD patients experiences diagnostic delays attributable to the inadequacy of current diagnostic methodologies; which in turn results in deferred therapeutic interventions and elevated mortality rates. [...] Read more.

Coronary microvascular dysfunction (CMD) represents a principal etiological factor in ischemic heart disease. Nonetheless, a considerable subset of CMD patients experiences diagnostic delays attributable to the inadequacy of current diagnostic methodologies; which in turn results in deferred therapeutic interventions and elevated mortality rates. This study seeks to elucidate the distinct metabolic profile associated with CMD in rat models and to identify specific diagnostic markers that could enhance the diagnostic accuracy for CMD. In this study, 18 Wistar rats were randomly allocated into two groups: the sham group and the CMD group. The CMD group received injections of embolic microspheres into the left ventricle to establish a CMD model. Subsequently, non-targeted metabolomics and acetylated proteomics analyses were conducted. Machine-learning techniques were employed to identify the co-diagnostic markers of the disease. This study identified 53 key proteins through differential expression proteins (DEPs) and modular proteins analysis. Subsequently, four core proteins (Emc1; Ank1; Fbln2; and Hp) were determined as diagnostic markers for CMD using lasso regression, support vector machine, and random forest methodologies. Receiver operating characteristic curve analysis further demonstrated robust diagnostic performance. Gene ontology and kyoto encyclopedia of genes and genome enrichment analyses indicated that the DEPs were predominantly associated with metabolic pathways. Ultimately, the integrative analysis of proteomics and metabolomics suggested that the central metabolic mechanism underlying CMD pathogenesis may be linked to the tricarboxylic acid cycle. This study revealed specific changes in the proteomic and metabolic profiles of CMD rats and identified four diagnostic markers, which are proteins and metabolites that could be potential diagnostic biomarkers for CMD. Full article

► Show Figures

Figure 1

28 pages, 3458 KiB

Open AccessReview

Decoding Cancer through Silencing the Mitochondrial Gatekeeper VDAC1

by Tasleem Arif, Anna Shteinfer-Kuzmine and Varda Shoshan-Barmatz

Biomolecules 2024, 14(10), 1304; https://doi.org/10.3390/biom14101304 - 15 Oct 2024

Viewed by 267

Abstract

Mitochondria serve as central hubs for regulating numerous cellular processes that include metabolism, apoptosis, cell cycle progression, proliferation, differentiation, epigenetics, immune signaling, and aging. The voltage-dependent anion channel 1 (VDAC1) functions as a crucial mitochondrial gatekeeper, controlling the flow of ions, such as [...] Read more.

Mitochondria serve as central hubs for regulating numerous cellular processes that include metabolism, apoptosis, cell cycle progression, proliferation, differentiation, epigenetics, immune signaling, and aging. The voltage-dependent anion channel 1 (VDAC1) functions as a crucial mitochondrial gatekeeper, controlling the flow of ions, such as Ca²⁺, nucleotides, and metabolites across the outer mitochondrial membrane, and is also integral to mitochondria-mediated apoptosis. VDAC1 functions in regulating ATP production, Ca²⁺ homeostasis, and apoptosis, which are essential for maintaining mitochondrial function and overall cellular health. Most cancer cells undergo metabolic reprogramming, often referred to as the “Warburg effect”, supplying tumors with energy and precursors for the biosynthesis of nucleic acids, phospholipids, fatty acids, cholesterol, and porphyrins. Given its multifunctional nature and overexpression in many cancers, VDAC1 presents an attractive target for therapeutic intervention. Our research has demonstrated that silencing VDAC1 expression using specific siRNA in various tumor types leads to a metabolic rewiring of the malignant cancer phenotype. This results in a reversal of oncogenic properties that include reduced tumor growth, invasiveness, stemness, epithelial–mesenchymal transition. Additionally, VDAC1 depletion alters the tumor microenvironment by reducing angiogenesis and modifying the expression of extracellular matrix- and structure-related genes, such as collagens and glycoproteins. Furthermore, VDAC1 depletion affects several epigenetic-related enzymes and substrates, including the acetylation-related enzymes SIRT1, SIRT6, and HDAC2, which in turn modify the acetylation and methylation profiles of histone 3 and histone 4. These epigenetic changes can explain the altered expression levels of approximately 4000 genes that are associated with reversing cancer cells oncogenic properties. Given VDAC1’s critical role in regulating metabolic and energy processes, targeting it offers a promising strategy for anti-cancer therapy. We also highlight the role of VDAC1 expression in various disease pathologies, including cardiovascular, neurodegenerative, and viral and bacterial infections, as explored through siRNA targeting VDAC1. Thus, this review underscores the potential of targeting VDAC1 as a strategy for addressing high-energy-demand cancers. By thoroughly understanding VDAC1’s diverse roles in metabolism, energy regulation, mitochondrial functions, and other cellular processes, silencing VDAC1 emerges as a novel and strategic approach to combat cancer. Full article

(This article belongs to the Special Issue The Central Role of Mitochondrial Protein VDAC1 in Human Diseases – Honorary Special Issue Commemorating the Work of Prof. Varda Shoshan-Barmatz)

► Show Figures

Figure 1

13 pages, 1145 KiB

Open AccessReview

Future Perspective: Harnessing the Power of Artificial Intelligence in the Generation of New Peptide Drugs

by Nour Nissan, Mitchell C. Allen, David Sabatino and Kyle K. Biggar

Biomolecules 2024, 14(10), 1303; https://doi.org/10.3390/biom14101303 - 15 Oct 2024

Viewed by 517

Abstract

The expansive field of drug discovery is continually seeking innovative approaches to identify and develop novel peptide-based therapeutics. With the advent of artificial intelligence (AI), there has been a transformative shift in the generation of new peptide drugs. AI offers a range of [...] Read more.

The expansive field of drug discovery is continually seeking innovative approaches to identify and develop novel peptide-based therapeutics. With the advent of artificial intelligence (AI), there has been a transformative shift in the generation of new peptide drugs. AI offers a range of computational tools and algorithms that enables researchers to accelerate the therapeutic peptide pipeline. This review explores the current landscape of AI applications in peptide drug discovery, highlighting its potential, challenges, and ethical considerations. Additionally, it presents case studies and future prospectives that demonstrate the impact of AI on the generation of new peptide drugs. Full article

(This article belongs to the Section Molecular Medicine)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Biomolecules, Volume 14, Issue 10 (October 2024) – 134 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI