Biomolecules

14 pages, 870 KiB

Open AccessEditor’s ChoiceReview

by Patricija van Oosten-Hawle

Biomolecules 2023, 13(2), 251; https://doi.org/10.3390/biom13020251 - 29 Jan 2023

Cited by 5 | Viewed by 2045

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation [...] Read more.

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation to environmental stresses. Emerging research shows that Hsp90 function in an organism goes well beyond intracellular proteostasis. In metazoans, Hsp90, as an environmentally responsive chaperone, is involved in inter-tissue stress signaling responses that coordinate and safeguard cell nonautonomous proteostasis and organismal health. In this way, Hsp90 has the capacity to influence evolution and aging, and effect behavioral responses to facilitate tissue-defense systems that ensure organismal survival. In this review, I summarize the literature on the organismal roles of Hsp90 uncovered in multicellular organisms, from plants to invertebrates and mammals. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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13 pages, 2560 KiB

Open AccessEditor’s ChoiceArticle

Identification of Inhibitors of Tubulin Polymerization Using a CRISPR-Edited Cell Line with Endogenous Fluorescent Tagging of β-Tubulin and Histone H1

by Harutyun Khachatryan, Bartlomiej Olszowy, Carlos A. Barrero, John Gordon and Oscar Perez-Leal

Biomolecules 2023, 13(2), 249; https://doi.org/10.3390/biom13020249 - 29 Jan 2023

Cited by 6 | Viewed by 6560

Abstract

Tubulin is a protein that plays a critical role in maintaining cellular structure and facilitating cell division. Inhibiting tubulin polymerization has been shown to be an effective strategy for inhibiting the proliferation of cancer cells. In the past, identifying compounds that could inhibit [...] Read more.

Tubulin is a protein that plays a critical role in maintaining cellular structure and facilitating cell division. Inhibiting tubulin polymerization has been shown to be an effective strategy for inhibiting the proliferation of cancer cells. In the past, identifying compounds that could inhibit tubulin polymerization has required the use of in vitro assays utilizing purified tubulin or immunofluorescence of fixed cells. This study presents a novel approach for identifying tubulin polymerization inhibitors using a CRISPR-edited cell line that expresses fluorescently tagged β-tubulin and a nuclear protein, enabling the visualization of tubulin polymerization dynamics via high-content imaging analysis (HCI). The cells were treated with known tubulin polymerization inhibitors, colchicine, and vincristine, and the resulting phenotypic changes indicative of tubulin polymerization inhibition were confirmed using HCI. Furthermore, a library of 429 kinase inhibitors was screened, resulting in the identification of three compounds (ON-01910, HMN-214, and KX2-391) that inhibit tubulin polymerization. Live cell tracking analysis confirmed that compound treatment leads to rapid tubulin depolymerization. These findings suggest that CRISPR-edited cells with fluorescently tagged endogenous β-tubulin can be utilized to screen large compound libraries containing diverse chemical families for the identification of novel tubulin polymerization inhibitors. Full article

(This article belongs to the Section Molecular Biology)

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14 pages, 2704 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Pathway Analysis: Advantages and Pitfalls for the Functional Interpretation of Metabolomics and Lipidomics Data

by Sofia Tsouka and Mojgan Masoodi

Biomolecules 2023, 13(2), 244; https://doi.org/10.3390/biom13020244 - 27 Jan 2023

Cited by 5 | Viewed by 3921

Abstract

Over the past decades, pathway analysis has become one of the most commonly used approaches for the functional interpretation of metabolomics data. Although the approach is widely used, it is not well standardized and the impact of different methodologies on the functional outcome [...] Read more.

Over the past decades, pathway analysis has become one of the most commonly used approaches for the functional interpretation of metabolomics data. Although the approach is widely used, it is not well standardized and the impact of different methodologies on the functional outcome is not well understood. Using four publicly available datasets, we investigated two main aspects of topological pathway analysis, namely the consideration of non-human native enzymatic reactions (e.g., from microbiota) and the interconnectivity of individual pathways. The exclusion of non-human native reactions led to detached and poorly represented reaction networks and to loss of information. The consideration of connectivity between pathways led to better emphasis of certain central metabolites in the network; however, it occasionally overemphasized the hub compounds. We proposed and examined a penalization scheme to diminish the effect of such compounds in the pathway evaluation. In order to compare and assess the results between different methodologies, we also performed over-representation analysis of the same datasets. We believe that our findings will raise awareness on both the capabilities and shortcomings of the currently used pathway analysis practices in metabolomics. Additionally, it will provide insights on various methodologies and strategies that should be considered for the analysis and interpretation of metabolomics data. Full article

(This article belongs to the Collection Metabolomics and Integrated Multi-Omics in Health and Disease)

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16 pages, 3321 KiB

Open AccessEditor’s ChoiceArticle

The Role of the Hydrogen Bond Network in Maintaining Heme Pocket Stability and Protein Function Specificity of C. diphtheriae Coproheme Decarboxylase

by Federico Sebastiani, Chiara Baroni, Gaurav Patil, Andrea Dali, Maurizio Becucci, Stefan Hofbauer and Giulietta Smulevich

Biomolecules 2023, 13(2), 235; https://doi.org/10.3390/biom13020235 - 25 Jan 2023

Cited by 4 | Viewed by 3603

Abstract

Monoderm bacteria accumulate heme b via the coproporphyrin-dependent biosynthesis pathway. In the final step, in the presence of two molecules of H₂O₂, the propionate groups of coproheme at positions 2 and 4 are decarboxylated to form vinyl groups by [...] Read more.

Monoderm bacteria accumulate heme b via the coproporphyrin-dependent biosynthesis pathway. In the final step, in the presence of two molecules of H₂O₂, the propionate groups of coproheme at positions 2 and 4 are decarboxylated to form vinyl groups by coproheme decarboxylase (ChdC), in a stepwise process. Decarboxylation of propionate 2 produces an intermediate that rotates by 90° inside the protein pocket, bringing propionate 4 near the catalytic tyrosine, to allow the second decarboxylation step. The active site of ChdCs is stabilized by an extensive H-bond network involving water molecules, specific amino acid residues, and the propionate groups of the porphyrin. To evaluate the role of these H-bonds in the pocket stability and enzyme functionality, we characterized, via resonance Raman and electronic absorption spectroscopies, single and double mutants of the actinobacterial pathogen Corynebacterium diphtheriae ChdC complexed with coproheme and heme b. The selective elimination of the H-bond interactions between propionates 2, 4, 6, and 7 and the polar residues of the pocket allowed us to establish the role of each H-bond in the catalytic reaction and to follow the changes in the interactions from the substrate to the product. Full article

(This article belongs to the Special Issue Hemoproteins and Proteolytic Enzymes: Variations on the Theme of Functional Modulation: A Themed Issue in Honor of Professor Massimo Coletta)

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27 pages, 2700 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Mitochondrial Modulators: The Defender

by Emmanuel Makinde, Linlin Ma, George D. Mellick and Yunjiang Feng

Biomolecules 2023, 13(2), 226; https://doi.org/10.3390/biom13020226 - 24 Jan 2023

Cited by 7 | Viewed by 2936

Abstract

Mitochondria are widely considered the “power hub” of the cell because of their pivotal roles in energy metabolism and oxidative phosphorylation. However, beyond the production of ATP, which is the major source of chemical energy supply in eukaryotes, mitochondria are also central to [...] Read more.

Mitochondria are widely considered the “power hub” of the cell because of their pivotal roles in energy metabolism and oxidative phosphorylation. However, beyond the production of ATP, which is the major source of chemical energy supply in eukaryotes, mitochondria are also central to calcium homeostasis, reactive oxygen species (ROS) balance, and cell apoptosis. The mitochondria also perform crucial multifaceted roles in biosynthetic pathways, serving as an important source of building blocks for the biosynthesis of fatty acid, cholesterol, amino acid, glucose, and heme. Since mitochondria play multiple vital roles in the cell, it is not surprising that disruption of mitochondrial function has been linked to a myriad of diseases, including neurodegenerative diseases, cancer, and metabolic disorders. In this review, we discuss the key physiological and pathological functions of mitochondria and present bioactive compounds with protective effects on the mitochondria and their mechanisms of action. We highlight promising compounds and existing difficulties limiting the therapeutic use of these compounds and potential solutions. We also provide insights and perspectives into future research windows on mitochondrial modulators. Full article

(This article belongs to the Special Issue Advances in the Role of Mitochondria in Regulated Cell Death Dysfunctions Associated with Human Pathologies)

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15 pages, 3130 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Hazard Assessment of Polystyrene Nanoplastics in Primary Human Nasal Epithelial Cells, Focusing on the Autophagic Effects

by Balasubramanyam Annangi, Aliro Villacorta, Montserrat López-Mesas, Victor Fuentes-Cebrian, Ricard Marcos and Alba Hernández

Biomolecules 2023, 13(2), 220; https://doi.org/10.3390/biom13020220 - 23 Jan 2023

Cited by 9 | Viewed by 2437

Abstract

The human health risks posed by micro/nanoplastics (MNPLs), as emerging pollutants of environmental/health concern, need to be urgently addressed as part of a needed hazard assessment. The routes of MNPL exposure in humans could mainly come from oral, inhalation, or dermal means. Among [...] Read more.

The human health risks posed by micro/nanoplastics (MNPLs), as emerging pollutants of environmental/health concern, need to be urgently addressed as part of a needed hazard assessment. The routes of MNPL exposure in humans could mainly come from oral, inhalation, or dermal means. Among them, inhalation exposure to MNPLs is the least studied area, even though their widespread presence in the air is dramatically increasing. In this context, this study focused on the potential hazard of polystyrene nanoplastics (PSNPLs with sizes 50 and 500 nm) in human primary nasal epithelial cells (HNEpCs), with the first line of cells acting as a physical and immune barrier in the respiratory system. Primarily, cellular internalization was evaluated by utilizing laboratory-labeled fluorescence PSNPLs with iDye, a commercial, pink-colored dye, using confocal microscopy, and found PSNPLs to be significantly internalized by HNEpCs. After, various cellular effects, such as the induction of intracellular reactive oxygen species (iROS), the loss of mitochondrial membrane potential (MMP), and the modulation of the autophagy pathway in the form of the accumulation of autophagosomes (LC3-II) and p62 markers (a ubiquitin involved in the clearance of cell debris), were evaluated after cell exposure. The data demonstrated significant increases in iROS, a decrease in MMP, as well as a greater accumulation of LC3-II and p62 in the presence of PSNPLs. Notably, the autophagic effects did indicate the implications of PSNPLs in defective or insufficient autophagy. This is the first study showing the autophagy pathway as a possible target for PSNPL-induced adverse effects in HNEpCs. When taken together, this study proved the cellular effects of PSNPLs in HNEpCs and adds value to the existing studies as a part of the respiratory risk assessment of MNPLs. Full article

(This article belongs to the Special Issue How Environmental Plastic Particles and Their Adsorbed Contaminants Interact with Biomolecules?)

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13 pages, 2207 KiB

Open AccessEditor’s ChoiceArticle

Aquaporin-1 and Aquaporin-4 Expression in Ependyma, Choroid Plexus and Surrounding Transition Zones in the Human Brain

by Ronja Bihlmaier, Felix Deffner, Ulrich Mattheus, Peter H. Neckel, Bernhard Hirt and Andreas F. Mack

Biomolecules 2023, 13(2), 212; https://doi.org/10.3390/biom13020212 - 22 Jan 2023

Cited by 3 | Viewed by 2106

Abstract

The choroid plexus (CP) is a structure in the brain ventricles that produces the main part of the cerebrospinal fluid (CSF). It is covered with specialized cells which show epithelial characteristics and are the site of the blood–CSF barrier. These cells form a [...] Read more.

The choroid plexus (CP) is a structure in the brain ventricles that produces the main part of the cerebrospinal fluid (CSF). It is covered with specialized cells which show epithelial characteristics and are the site of the blood–CSF barrier. These cells form a contiguous cell sheet with ventricle-lining ependymal cells which are known to express aquaporin-4 (AQP4). In contrast, CP epithelial cells express aquaporin-1 (AQP1) apically. We investigated the expression patterns of aquaporins in the CP-ependyma transition from human body donors using immunofluorescence and electron microscopy. Ependymal cells and subependymal astrocytes at the base of the CP showed a particularly high AQP4 immunoreactivity. Astrocytic processes formed a dense meshwork or glial plate around the blood vessels entering the CP. Interestingly, some of these astrocytic processes were in direct contact with the CP stroma, which contains fenestrated blood vessels, separated only by a basal lamina. Electron microscopy confirmed the continuity of the subastrocytic basal lamina with the CP epithelium. We also probed for components of the AQP4 anchoring dystrophin–dystroglycan complex. Immunolabeling for dystrophin and AQP4 showed an overlapping staining pattern in the glial plate but not in previously reported AQP4-positive CP epithelial cells. In contrast, dystroglycan expression was associated with laminin staining in the glial plate and the CP epithelium. This suggests different mechanisms for AQP4 anchoring in the cell membrane. The high AQP4 density in the connecting glial plate might facilitate the transport of water in and out of the CP stroma and could possibly serve as a drainage and clearing pathway for metabolites. Full article

(This article belongs to the Special Issue Aquaporins in the CNS–in Honor of the 30th Anniversary of the Discovery of Aquaporins)

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21 pages, 2060 KiB

Open AccessEditor’s ChoiceArticle

Updated Virophage Taxonomy and Distinction from Polinton-like Viruses

by Simon Roux, Matthias G. Fischer, Thomas Hackl, Laura A. Katz, Frederik Schulz and Natalya Yutin

Biomolecules 2023, 13(2), 204; https://doi.org/10.3390/biom13020204 - 19 Jan 2023

Cited by 11 | Viewed by 4019

Abstract

Virophages are small dsDNA viruses that hijack the machinery of giant viruses during the co-infection of a protist (i.e., microeukaryotic) host and represent an exceptional case of “hyperparasitism” in the viral world. While only a handful of virophages have been isolated, a vast [...] Read more.

Virophages are small dsDNA viruses that hijack the machinery of giant viruses during the co-infection of a protist (i.e., microeukaryotic) host and represent an exceptional case of “hyperparasitism” in the viral world. While only a handful of virophages have been isolated, a vast diversity of virophage-like sequences have been uncovered from diverse metagenomes. Their wide ecological distribution, idiosyncratic infection and replication strategy, ability to integrate into protist and giant virus genomes and potential role in antiviral defense have made virophages a topic of broad interest. However, one limitation for further studies is the lack of clarity regarding the nomenclature and taxonomy of this group of viruses. Specifically, virophages have been linked in the literature to other “virophage-like” mobile genetic elements and viruses, including polinton-like viruses (PLVs), but there are no formal demarcation criteria and proper nomenclature for either group, i.e., virophage or PLVs. Here, as part of the ICTV Virophage Study Group, we leverage a large set of genomes gathered from published datasets as well as newly generated protist genomes to propose delineation criteria and classification methods at multiple taxonomic ranks for virophages ‘sensu stricto’, i.e., genomes related to the prototype isolates Sputnik and mavirus. Based on a combination of comparative genomics and phylogenetic analyses, we show that this group of virophages forms a cohesive taxon that we propose to establish at the class level and suggest a subdivision into four orders and seven families with distinctive ecogenomic features. Finally, to illustrate how the proposed delineation criteria and classification method would be used, we apply these to two recently published datasets, which we show include both virophages and other virophage-related elements. Overall, we see this proposed classification as a necessary first step to provide a robust taxonomic framework in this area of the virosphere, which will need to be expanded in the future to cover other virophage-related viruses such as PLVs. Full article

(This article belongs to the Special Issue Virology 130 Years After Ivanovsky—A Theme Issue Commemorating the Discovery of Viruses by Dmitri Ivanovsky)

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13 pages, 2656 KiB

Open AccessEditor’s ChoiceArticle

Chronic Exposure to Low-Molecular-Weight Polycyclic Aromatic Hydrocarbons Promotes Lipid Accumulation and Metabolic Inflammation

by Asia Bright, Fenfen Li, Miranda Movahed, Hang Shi and Bingzhong Xue

Biomolecules 2023, 13(2), 196; https://doi.org/10.3390/biom13020196 - 18 Jan 2023

Cited by 8 | Viewed by 1823

Abstract

2-naphthol is a low-molecular-weight (LMW) polycyclic aromatic hydrocarbon (PAH) and air pollutant associated with childhood obesity. There has been a recent emergence of studies on the consequences of PAHs on human health. Current epidemiological reports suggest LMW-PAHs may contribute to obesity incidences in [...] Read more.

2-naphthol is a low-molecular-weight (LMW) polycyclic aromatic hydrocarbon (PAH) and air pollutant associated with childhood obesity. There has been a recent emergence of studies on the consequences of PAHs on human health. Current epidemiological reports suggest LMW-PAHs may contribute to obesity incidences in children, yet most studies focus on high-molecular-weight PAHs. This study explores 2-naphthol’s impact on obesity and obesity-associated metabolic disorders. To investigate 2-naphthol’s effect on lipid metabolism and inflammation, we employed 3T3-L1 and BAT1 cell lines to model white and brown adipocytes, respectively, alongside a murine macrophage cell line (RAW264.7). We found that 2-naphthol increased the expression of key adipogenic and lipogenic genes while decreasing lipolytic gene expression in chronically treated 3T3-L1 and BAT1 adipocytes. In addition, chronic 2-naphthol treatment also suppressed adrenergic-stimulated thermogenic gene expression in BAT1 brown adipocytes. In consistence, an increase in lipid accumulation was demonstrated in BODIPY and Oil Red O-stained adipocytes. Additionally, 3T3-L1 adipocytes and RAW264.7 macrophages chronically exposed to 2-naphthol showed upregulated mRNA expression of major inflammatory cytokines (e.g., tumor necrosis factor α (Tnfα), interleukin-1β (Il-1β), and Il-6). In summary, chronic exposure to 2-naphthol stimulates lipid accumulation in adipocytes and inflammation in adipocytes and macrophages. These findings support previous research that demonstrates 2-naphthol has obesogenic potential. Full article

(This article belongs to the Collection Molecular Mechanisms of Obesity, Diabetes, Inflammation and Aging)

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22 pages, 958 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Type 2 Diabetes and Alzheimer’s Disease: The Emerging Role of Cellular Lipotoxicity

by Nicola Marrano, Giuseppina Biondi, Anna Borrelli, Martina Rella, Tommaso Zambetta, Ludovico Di Gioia, Mariangela Caporusso, Giancarlo Logroscino, Sebastio Perrini, Francesco Giorgino and Annalisa Natalicchio

Biomolecules 2023, 13(1), 183; https://doi.org/10.3390/biom13010183 - 16 Jan 2023

Cited by 10 | Viewed by 4360

Abstract

Type 2 diabetes (T2D) and Alzheimer’s diseases (AD) represent major health issues that have reached alarming levels in the last decades. Although growing evidence demonstrates that AD is a significant comorbidity of T2D, and there is a ~1.4–2-fold increase in the risk of [...] Read more.

Type 2 diabetes (T2D) and Alzheimer’s diseases (AD) represent major health issues that have reached alarming levels in the last decades. Although growing evidence demonstrates that AD is a significant comorbidity of T2D, and there is a ~1.4–2-fold increase in the risk of developing AD among T2D patients, the involvement of possible common triggers in the pathogenesis of these two diseases remains largely unknown. Of note, recent mechanistic insights suggest that lipotoxicity could represent the missing ring in the pathogenetic mechanisms linking T2D to AD. Indeed, obesity, which represents the main cause of lipotoxicity, has been recognized as a major risk factor for both pathological conditions. Lipotoxicity can lead to inflammation, insulin resistance, oxidative stress, ceramide and amyloid accumulation, endoplasmic reticulum stress, ferroptosis, and autophagy, which are shared biological events in the pathogenesis of T2D and AD. In the current review, we try to provide a critical and comprehensive view of the common molecular pathways activated by lipotoxicity in T2D and AD, attempting to summarize how these mechanisms can drive future research and open the way to new therapeutic perspectives. Full article

(This article belongs to the Special Issue Role of Fatty Acid-Induced Multi-Organ Damage on Diabetes Onset and Progression: Implications for Therapeutic Strategies)

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15 pages, 1822 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Is Glial Dysfunction the Key Pathogenesis of LRRK2-Linked Parkinson’s Disease?

by Tatou Iseki, Yuzuru Imai and Nobutaka Hattori

Biomolecules 2023, 13(1), 178; https://doi.org/10.3390/biom13010178 - 15 Jan 2023

Cited by 5 | Viewed by 2943

Abstract

Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson’s disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with [...] Read more.

Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson’s disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with LRRK2 mutations indicate a varied pathology, and the molecular functions of LRRK2 and its relationship to PD pathogenesis are largely unknown. Recently, non-autonomous neurodegeneration associated with glial cell dysfunction has attracted attention as a possible mechanism of dopaminergic neurodegeneration. Molecular studies of LRRK2 in astrocytes and microglia have also suggested that LRRK2 is involved in the regulation of lysosomal and other organelle dynamics and inflammation. In this review, we describe the proposed functions of LRRK2 in glial cells and discuss its involvement in the pathomechanisms of PD. Full article

(This article belongs to the Special Issue Pathological Roles of LRRK2)

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26 pages, 1670 KiB

Open AccessEditor’s ChoiceReview

The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging

by Nekane Romero-García, Javier Huete-Acevedo, Cristina Mas-Bargues, Jorge Sanz-Ros, Mar Dromant and Consuelo Borrás

Biomolecules 2023, 13(1), 165; https://doi.org/10.3390/biom13010165 - 13 Jan 2023

Cited by 4 | Viewed by 2765

Abstract

The exponential growth in the elderly population and their associated socioeconomic burden have recently brought aging research into the spotlight. To integrate current knowledge and guide potential interventions, nine biochemical pathways are summarized under the term hallmarks of aging. These hallmarks are deeply [...] Read more.

The exponential growth in the elderly population and their associated socioeconomic burden have recently brought aging research into the spotlight. To integrate current knowledge and guide potential interventions, nine biochemical pathways are summarized under the term hallmarks of aging. These hallmarks are deeply inter-related and act together to drive the aging process. Altered intercellular communication is particularly relevant since it explains how damage at the cellular level translates into age-related loss of function at the organismal level. As the main effectors of intercellular communication, extracellular vesicles (EVs) might play a key role in the aggravation or mitigation of the hallmarks of aging. This review aims to summarize this role and to provide context for the multiple emerging EV-based gerotherapeutic strategies that are currently under study. Full article

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15 pages, 1926 KiB

Open AccessEditor’s ChoiceArticle

Glycosylated Lipopeptides—Synthesis and Evaluation of Antimicrobial Activity and Cytotoxicity

by Karol Sikora, Marta Bauer, Sylwia Bartoszewska, Damian Neubauer and Wojciech Kamysz

Biomolecules 2023, 13(1), 172; https://doi.org/10.3390/biom13010172 - 13 Jan 2023

Cited by 1 | Viewed by 1825

Abstract

Ultrashort cationic lipopeptides (USCLs) are promising antimicrobial agents that may be used to combat pathogens such as bacteria and fungi. USCLs consist of a few basic amino acid residues and at least one lipid moiety, usually a fatty acid chain. Generally, USCLs are [...] Read more.

Ultrashort cationic lipopeptides (USCLs) are promising antimicrobial agents that may be used to combat pathogens such as bacteria and fungi. USCLs consist of a few basic amino acid residues and at least one lipid moiety, usually a fatty acid chain. Generally, USCLs are potent antimicrobials but their major shortcoming is a relatively high cytotoxicity and hemolytic activity. Glycopeptide antibiotics (e.g. vancomycin) are essential in combating bacterial infections and are popular in medicinal practice. However, literature concerning the effect of glycosylation of peptides on their antimicrobial activity is rather scarce. For the first time, this study highlights the effect of USCLs glycosylation on in vitro biological activity. The aim of this study was to evaluate the impact of glycosylation of a series of USCLs on antimicrobial activity, cytotoxicity and hemolytic activity. Straight-chain fatty acids (C14, C16, C18) were attached to the N-terminal amino group of tripeptides—SRR-NH₂, RSR-NH₂ and RRS-NH₂. Two groups of the lipopeptides were synthetized, the first with unmodified L-serine (USCLs) and the other with L-serine O-glycosylated by N-acetyl-β-d-glucosamine to produce new class of glycosylated ultrashort cationic lipopeptide (gUSCLs). Both USCLs and gUSCLs were tested against planktonic and biofilm cultures of ESKAPE strains (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) and Candida glabrata, and hemolytic activity on human erythrocytes and cytotoxicity against the HaCaT cell line was examined. Generally, USCLs and gUSCLs proved to be active against all the tested strains. The highest activity displayed was by lipopeptides containing the C18 fatty acid. Antimicrobial, hemolytic and cytotoxic activities were mainly correlated with amino acid sequence (position of serine/glycosylated serine) and hydrophobicity of molecule and were found to be highly strain-dependent. In general, glycosylation did not guarantee an increased antimicrobial activity or a decreased hemolytic and cytotoxic activities. However, in some cases, gUSCLs proved to be superior to their USCLs analogs. The most pronounced differences were found for peptides with C18 fatty acid and serine at the first and second position against both planktonic cells and biofilm of C. glabrata, as well as the second and third position against S. aureus. It is noteworthy that gUSCLs were also more active against biofilm than were USCLs. Full article

(This article belongs to the Special Issue Nature Inspired Peptides in Medical Sciences)

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12 pages, 2632 KiB

Open AccessEditor’s ChoiceArticle

Sub-Millisecond Photoinduced Dynamics of Free and EL222-Bound FMN by Stimulated Raman and Visible Absorption Spectroscopies

by Yingliang Liu, Aditya S. Chaudhari, Aditi Chatterjee, Prokopis C. Andrikopoulos, Alessandra Picchiotti, Mateusz Rebarz, Miroslav Kloz, Victor A. Lorenz-Fonfria, Bohdan Schneider and Gustavo Fuertes

Biomolecules 2023, 13(1), 161; https://doi.org/10.3390/biom13010161 - 12 Jan 2023

Cited by 1 | Viewed by 2235

Abstract

Time-resolved femtosecond-stimulated Raman spectroscopy (FSRS) provides valuable information on the structural dynamics of biomolecules. However, FSRS has been applied mainly up to the nanoseconds regime and above 700 cm⁻¹, which covers only part of the spectrum of biologically relevant time scales [...] Read more.

Time-resolved femtosecond-stimulated Raman spectroscopy (FSRS) provides valuable information on the structural dynamics of biomolecules. However, FSRS has been applied mainly up to the nanoseconds regime and above 700 cm⁻¹, which covers only part of the spectrum of biologically relevant time scales and Raman shifts. Here we report on a broadband (~200–2200 cm⁻¹) dual transient visible absorption (visTA)/FSRS set-up that can accommodate time delays from a few femtoseconds to several hundreds of microseconds after illumination with an actinic pump. The extended time scale and wavenumber range allowed us to monitor the complete excited-state dynamics of the biological chromophore flavin mononucleotide (FMN), both free in solution and embedded in two variants of the bacterial light-oxygen-voltage (LOV) photoreceptor EL222. The observed lifetimes and intermediate states (singlet, triplet, and adduct) are in agreement with previous time-resolved infrared spectroscopy experiments. Importantly, we found evidence for additional dynamical events, particularly upon analysis of the low-frequency Raman region below 1000 cm⁻¹. We show that fs-to-sub-ms visTA/FSRS with a broad wavenumber range is a useful tool to characterize short-lived conformationally excited states in flavoproteins and potentially other light-responsive proteins. Full article

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

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15 pages, 3374 KiB

Open AccessEditor’s ChoiceArticle

Combining Semi-Targeted Metabolomics and Machine Learning to Identify Metabolic Alterations in the Serum and Urine of Hospitalized Patients with COVID-19

by Gerard Baiges-Gaya, Simona Iftimie, Helena Castañé, Elisabet Rodríguez-Tomàs, Andrea Jiménez-Franco, Ana F. López-Azcona, Antoni Castro, Jordi Camps and Jorge Joven

Biomolecules 2023, 13(1), 163; https://doi.org/10.3390/biom13010163 - 12 Jan 2023

Cited by 7 | Viewed by 2265

Abstract

Viral infections cause metabolic dysregulation in the infected organism. The present study used metabolomics techniques and machine learning algorithms to retrospectively analyze the alterations of a broad panel of metabolites in the serum and urine of a cohort of 126 patients hospitalized with [...] Read more.

Viral infections cause metabolic dysregulation in the infected organism. The present study used metabolomics techniques and machine learning algorithms to retrospectively analyze the alterations of a broad panel of metabolites in the serum and urine of a cohort of 126 patients hospitalized with COVID-19. Results were compared with those of 50 healthy subjects and 45 COVID-19-negative patients but with bacterial infectious diseases. Metabolites were analyzed by gas chromatography coupled to quadrupole time-of-flight mass spectrometry. The main metabolites altered in the sera of COVID-19 patients were those of pentose glucuronate interconversion, ascorbate and fructose metabolism, nucleotide sugars, and nucleotide and amino acid metabolism. Alterations in serum maltose, mannonic acid, xylitol, or glyceric acid metabolites segregated positive patients from the control group with high diagnostic accuracy, while succinic acid segregated positive patients from those with other disparate infectious diseases. Increased lauric acid concentrations were associated with the severity of infection and death. Urine analyses could not discriminate between groups. Targeted metabolomics and machine learning algorithms facilitated the exploration of the metabolic alterations underlying COVID-19 infection, and to identify the potential biomarkers for the diagnosis and prognosis of the disease. Full article

(This article belongs to the Special Issue Metabolic Pathways and COVID-19: Mechanisms and Clinical Implications)

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25 pages, 1260 KiB

Open AccessEditor’s ChoiceReview

The Challenges and Prospects of p53-Based Therapies in Ovarian Cancer

by Bryce Wallis, Katherine Redd Bowman, Phong Lu and Carol S. Lim

Biomolecules 2023, 13(1), 159; https://doi.org/10.3390/biom13010159 - 12 Jan 2023

Cited by 11 | Viewed by 5130

Abstract

It has been well established that mutations in the tumor suppressor gene, p53, occur readily in a vast majority of cancer tumors, including ovarian cancer. Typically diagnosed in stages three or four, ovarian cancer is the fifth leading cause of death in women, [...] Read more.

It has been well established that mutations in the tumor suppressor gene, p53, occur readily in a vast majority of cancer tumors, including ovarian cancer. Typically diagnosed in stages three or four, ovarian cancer is the fifth leading cause of death in women, despite accounting for only 2.5% of all female malignancies. The overall 5-year survival rate for ovarian cancer is around 47%; however, this drops to an abysmal 29% for the most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC). HGSOC has upwards of 96% of cases expressing mutations in p53. Therefore, wild-type (WT) p53 and p53-based therapies have been explored as treatment options via a plethora of drug delivery vehicles including nanoparticles, viruses, polymers, and liposomes. However, previous p53 therapeutics have faced many challenges, which have resulted in their limited translational success to date. This review highlights a selection of these historical p53-targeted therapeutics for ovarian cancer, why they failed, and what the future could hold for a new generation of this class of therapies. Full article

(This article belongs to the Collection p53 Function and Dysfunction in Human Health and Diseases)

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17 pages, 26388 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Improving Protein–Ligand Interaction Modeling with cryo-EM Data, Templates, and Deep Learning in 2021 Ligand Model Challenge

by Nabin Giri and Jianlin Cheng

Biomolecules 2023, 13(1), 132; https://doi.org/10.3390/biom13010132 - 09 Jan 2023

Cited by 9 | Viewed by 3149

Abstract

Elucidating protein–ligand interaction is crucial for studying the function of proteins and compounds in an organism and critical for drug discovery and design. The problem of protein–ligand interaction is traditionally tackled by molecular docking and simulation, which is based on physical forces and [...] Read more.

Elucidating protein–ligand interaction is crucial for studying the function of proteins and compounds in an organism and critical for drug discovery and design. The problem of protein–ligand interaction is traditionally tackled by molecular docking and simulation, which is based on physical forces and statistical potentials and cannot effectively leverage cryo-EM data and existing protein structural information in the protein–ligand modeling process. In this work, we developed a deep learning bioinformatics pipeline (DeepProLigand) to predict protein–ligand interactions from cryo-EM density maps of proteins and ligands. DeepProLigand first uses a deep learning method to predict the structure of proteins from cryo-EM maps, which is averaged with a reference (template) structure of the proteins to produce a combined structure to add ligands. The ligands are then identified and added into the structure to generate a protein–ligand complex structure, which is further refined. The method based on the deep learning prediction and template-based modeling was blindly tested in the 2021 EMDataResource Ligand Challenge and was ranked first in fitting ligands to cryo-EM density maps. These results demonstrate that the deep learning bioinformatics approach is a promising direction for modeling protein–ligand interactions on cryo-EM data using prior structural information. Full article

(This article belongs to the Collection Feature Papers in Bioinformatics and Systems Biology Section)

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20 pages, 3979 KiB

Open AccessEditor’s ChoiceArticle

Selenium-Substituted Monomethine Cyanine Dyes as Selective G-Quadruplex Spectroscopic Probes with Theranostic Potential

by Ivana Fabijanić, Atanas Kurutos, Ana Tomašić Paić, Vanja Tadić, Fadhil S. Kamounah, Lucija Horvat, Anamaria Brozovic, Ivo Crnolatac and Marijana Radić Stojković

Biomolecules 2023, 13(1), 128; https://doi.org/10.3390/biom13010128 - 07 Jan 2023

Cited by 4 | Viewed by 2689

Abstract

The binding interactions of six ligands, neutral and monocationic asymmetric monomethine cyanine dyes comprising benzoselenazolyl moiety with duplex DNA and RNA and G-quadruplex structures were evaluated using fluorescence, UV/Vis (thermal melting) and circular dichroism (CD) spectroscopy. The main objective was to assess the [...] Read more.

The binding interactions of six ligands, neutral and monocationic asymmetric monomethine cyanine dyes comprising benzoselenazolyl moiety with duplex DNA and RNA and G-quadruplex structures were evaluated using fluorescence, UV/Vis (thermal melting) and circular dichroism (CD) spectroscopy. The main objective was to assess the impact of different substituents (methyl vs. sulfopropyl vs. thiopropyl/thioethyl) on the nitrogen atom of the benzothiazolyl chromophore on various nucleic acid structures. The monomethine cyanine dyes with methyl substituents showed a 100-fold selectivity for G-quadruplex versus duplex DNA. Study results indicate that cyanines bind with G-quadruplex via end π-π stacking interactions and possible additional interactions with nucleobases/phosphate backbone of grooves or loop bases. Cyanine with thioethyl substituent distinguishes duplex DNA and RNA and G-quadruplex structures by distinctly varying ICD signals. Furthermore, cell viability assay reveals the submicromolar activity of cyanines with methyl substituents against all tested human cancer cell lines. Confocal microscopy analysis shows preferential accumulation of cyanines with sulfopropyl and thioethyl substituents in mitochondria and indicates localization of cyanines with methyl in nucleus, particularly nucleolus. This confirms the potential of examined cyanines as theranostic agents, possessing both fluorescent properties and cell viability inhibitory effect. Full article

(This article belongs to the Special Issue Polynucleotides)

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12 pages, 687 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Insulin Resistance in Mitochondrial Diabetes

by Chika Takano, Erika Ogawa and Satoshi Hayakawa

Biomolecules 2023, 13(1), 126; https://doi.org/10.3390/biom13010126 - 07 Jan 2023

Cited by 8 | Viewed by 4181

Abstract

Mitochondrial diabetes (MD) is generally classified as a genetic defect of β-cells. The main pathophysiology is insulin secretion failure in pancreatic β-cells due to impaired mitochondrial ATP production. However, several reports have mentioned the presence of insulin resistance (IR) as a clinical feature [...] Read more.

Mitochondrial diabetes (MD) is generally classified as a genetic defect of β-cells. The main pathophysiology is insulin secretion failure in pancreatic β-cells due to impaired mitochondrial ATP production. However, several reports have mentioned the presence of insulin resistance (IR) as a clinical feature of MD. As mitochondrial dysfunction is one of the important factors causing IR, we need to focus on IR as another pathophysiology of MD. In this special issue, we first briefly summarized the insulin signaling and molecular mechanisms of IR. Second, we overviewed currently confirmed pathogenic mitochondrial DNA (mtDNA) mutations from the MITOMAP database. The variants causing diabetes were mostly point mutations in the transfer RNA (tRNA) of the mitochondrial genome. Third, we focused on these variants leading to the recently described “tRNA modopathies” and reviewed the clinical features of patients with diabetes. Finally, we discussed the pathophysiology of MD caused by mtDNA mutations and explored the possible mechanism underlying the development of IR. This review should be beneficial to all clinicians involved in diagnostics and therapeutics related to diabetes and mitochondrial diseases. Full article

(This article belongs to the Special Issue Insulin Resistance: Metabolic Mechanisms and Consequences Both In Vivo and Vitro)

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27 pages, 3169 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Archaea as a Model System for Molecular Biology and Biotechnology

by Federica De Lise, Roberta Iacono, Marco Moracci, Andrea Strazzulli and Beatrice Cobucci-Ponzano

Biomolecules 2023, 13(1), 114; https://doi.org/10.3390/biom13010114 - 06 Jan 2023

Cited by 6 | Viewed by 3487

Abstract

Archaea represents the third domain of life, displaying a closer relationship with eukaryotes than bacteria. These microorganisms are valuable model systems for molecular biology and biotechnology. In fact, nowadays, methanogens, halophiles, thermophilic euryarchaeota, and crenarchaeota are the four groups of archaea for which [...] Read more.

Archaea represents the third domain of life, displaying a closer relationship with eukaryotes than bacteria. These microorganisms are valuable model systems for molecular biology and biotechnology. In fact, nowadays, methanogens, halophiles, thermophilic euryarchaeota, and crenarchaeota are the four groups of archaea for which genetic systems have been well established, making them suitable as model systems and allowing for the increasing study of archaeal genes’ functions. Furthermore, thermophiles are used to explore several aspects of archaeal biology, such as stress responses, DNA replication and repair, transcription, translation and its regulation mechanisms, CRISPR systems, and carbon and energy metabolism. Extremophilic archaea also represent a valuable source of new biomolecules for biological and biotechnological applications, and there is growing interest in the development of engineered strains. In this review, we report on some of the most important aspects of the use of archaea as a model system for genetic evolution, the development of genetic tools, and their application for the elucidation of the basal molecular mechanisms in this domain of life. Furthermore, an overview on the discovery of new enzymes of biotechnological interest from archaea thriving in extreme environments is reported. Full article

(This article belongs to the Special Issue Theme Issue Honoring Scientist Louis Pasteur on His 200th Birthday)

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15 pages, 3524 KiB

Open AccessEditor’s ChoiceArticle

The Placentas of Women Who Suffer an Episode of Psychosis during Pregnancy Have Increased Lipid Peroxidation with Evidence of Ferroptosis

by Miguel A. Ortega, Oscar Fraile-Martinez, Cielo García-Montero, Rosa M. Funes Moñux, Sonia Rodriguez-Martín, Coral Bravo, Juan A. De Leon-Luis, Jose V. Saz, Miguel A. Saez, Luis G. Guijarro, Guillermo Lahera, Fernando Mora, Sonia Fernandez-Rojo, Javier Quintero, Jorge Monserrat, Natalio García-Honduvilla, Julia Bujan, Melchor Alvarez-Mon and Miguel Angel Alvarez-Mon

Biomolecules 2023, 13(1), 120; https://doi.org/10.3390/biom13010120 - 06 Jan 2023

Cited by 10 | Viewed by 2409

Abstract

Psychosis is a complex entity characterized by psychological, behavioral, and motor alterations resulting in a loss of contact with reality. Although it is not common, pregnancy can be a period in which a first episode of psychosis can manifest, entailing detrimental consequences for [...] Read more.

Psychosis is a complex entity characterized by psychological, behavioral, and motor alterations resulting in a loss of contact with reality. Although it is not common, pregnancy can be a period in which a first episode of psychosis can manifest, entailing detrimental consequences for both the fetus and the mother. The pathophysiological basis and study of maternofetal wellbeing need to be further elucidated. Lipid peroxidation and ferroptosis are two phenomena that are tightly linked to the placental dysfunction commonly observed in different complications of pregnancy. In the present study, we aim to explore the histopathological and gene expression of different markers of lipid peroxidation and ferroptosis in the placentas of women who underwent a first episode of psychosis during their pregnancy (n = 22). The aim is to then compare them with healthy pregnant women (n = 20). In order to achieve this goal, iron deposits were studied using Prussian Blue staining. In addition, the protein/gene expression of a transferrin receptor (TFRC), as well as an acyl-CoA synthetase long-chain family member 4 (ACSL-4), arachidonate lipoxygenase-5 (ALOX-5), malondialdehyde (MDA), and glutathione peroxidase 4 (GPX4) were all analyzed through gene expression (RT-qPCR) and immunohistochemical procedures. Our results demonstrate an increased presence of iron deposits that are accompanied by a further expression of TFRC, ACSL-4, ALOX-5, MDA, and GPX4—all of which are observed in the placenta tissue of women who have suffered from a first episode of psychosis. Therefore, in our study, a histopathological increase in lipid peroxidation and ferroptosis markers in the affected women is suggested. However, further studies are needed in order to validate our results and to establish possible consequences for the reported alterations. Full article

(This article belongs to the Special Issue Placental-Related Disorders of Pregnancy)

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21 pages, 2757 KiB

Open AccessEditor’s ChoiceArticle

Effects of Chronic Caffeine Consumption on Synaptic Function, Metabolism and Adenosine Modulation in Different Brain Areas

by Cátia R. Lopes, Andreia Oliveira, Ingride Gaspar, Matilde S. Rodrigues, Joana Santos, Eszter Szabó, Henrique B. Silva, Ângelo R. Tomé, Paula M. Canas, Paula Agostinho, Rui A. Carvalho, Rodrigo A. Cunha, Ana Patrícia Simões, João Pedro Lopes and Samira G. Ferreira

Biomolecules 2023, 13(1), 106; https://doi.org/10.3390/biom13010106 - 04 Jan 2023

Cited by 3 | Viewed by 4575

Abstract

Adenosine receptors mainly control synaptic function, and excessive activation of adenosine receptors may worsen the onset of many neurological disorders. Accordingly, the regular intake of moderate doses of caffeine antagonizes adenosine receptors and affords robust neuroprotection. Although caffeine intake alters brain functional connectivity [...] Read more.

Adenosine receptors mainly control synaptic function, and excessive activation of adenosine receptors may worsen the onset of many neurological disorders. Accordingly, the regular intake of moderate doses of caffeine antagonizes adenosine receptors and affords robust neuroprotection. Although caffeine intake alters brain functional connectivity and multi-omics analyses indicate that caffeine intake modifies synaptic and metabolic processes, it is unclear how caffeine intake affects behavior, synaptic plasticity and its modulation by adenosine. We now report that male mice drinking caffeinated water (0.3 g/L) for 2 weeks were behaviorally indistinguishable (locomotion, mood, memory) from control mice (drinking water) and displayed superimposable synaptic plasticity (long-term potentiation) in different brain areas (hippocampus, prefrontal cortex, amygdala). Moreover, there was a general preservation of the efficiency of adenosine A₁ and A_2A receptors to control synaptic transmission and plasticity, although there was a tendency for lower levels of endogenous adenosine ensuring A₁ receptor-mediated inhibition. In spite of similar behavioral and neurophysiological function, caffeine intake increased the energy charge and redox state of cortical synaptosomes. This increased metabolic competence likely involved a putative increase in the glycolytic rate in synapses and a prospective greater astrocyte–synapse lactate shuttling. It was concluded that caffeine intake does not trigger evident alterations of behavior or of synaptic plasticity but increases the metabolic competence of synapses, which might be related with the previously described better ability of animals consuming caffeine to cope with deleterious stimuli triggering brain dysfunction. Full article

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16 pages, 596 KiB

Open AccessEditor’s ChoiceReview

HDL Functions—Current Status and Future Perspectives

by Yasuhiro Endo, Masanori Fujita and Katsunori Ikewaki

Biomolecules 2023, 13(1), 105; https://doi.org/10.3390/biom13010105 - 04 Jan 2023

Cited by 13 | Viewed by 2961

Abstract

Cardiovascular disease (CVD) is the leading cause of death in Western countries. A low HDL-C is associated with the development of CVD. However, recent epidemiology studies have shown U-shaped curves between HDL-C and CVD mortality, with paradoxically increased CVD mortality in patients with [...] Read more.

Cardiovascular disease (CVD) is the leading cause of death in Western countries. A low HDL-C is associated with the development of CVD. However, recent epidemiology studies have shown U-shaped curves between HDL-C and CVD mortality, with paradoxically increased CVD mortality in patients with extremely high HDL-C levels. Furthermore, HDL-C raising therapy using nicotinic acids or CETP inhibitors mostly failed to reduce CVD events. Based on this background, HDL functions rather than HDL-C could be a novel biomarker; research on the clinical utility of HDL functionality is ongoing. In this review, we summarize the current status of HDL functions and their future perspectives from the findings of basic research and clinical trials. Full article

(This article belongs to the Special Issue Lipids in Atherosclerosis)

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11 pages, 839 KiB

Open AccessEditor’s ChoiceReview

Efavirenz: History, Development and Future

by Bárbara Costa and Nuno Vale

Biomolecules 2023, 13(1), 88; https://doi.org/10.3390/biom13010088 - 31 Dec 2022

Cited by 9 | Viewed by 2936

Abstract

Efavirenz (Sustiva^®) is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) used to treat human immunodeficiency virus (HIV) type 1 infection or to prevent the spread of HIV. In 1998, the FDA authorized efavirenz for the treatment of HIV-1 infection. Patients formerly [...] Read more.

Efavirenz (Sustiva^®) is a first-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) used to treat human immunodeficiency virus (HIV) type 1 infection or to prevent the spread of HIV. In 1998, the FDA authorized efavirenz for the treatment of HIV-1 infection. Patients formerly required three 200 mg efavirenz capsules daily, which was rapidly updated to a 600 mg tablet that only required one tablet per day. However, when given 600 mg once daily, plasma efavirenz concentrations were linked not only to poor HIV suppression but also to toxicity. Clinical data suggested that the standard dose of efavirenz could be reduced without compromising its effectiveness, resulting in a reduction in side effects and making the drug more affordable. Therefore, ENCORE1 was performed to compare the efficiency and safeness of a reduced dose of efavirenz (400 mg) with the standard dose (600 mg) plus two NRTI in antiretroviral-naïve HIV-infected individuals. Nowadays, due to the emergence of integrase strand transfer inhibitors (INSTIs), some consider that it is time to stop using efavirenz as a first-line treatment on a global scale, in the parts of the world where that is possible. Efavirenz has been a primary first-line antiviral drug for more than 15 years. However, at this moment, the best use for efavirenz could be for pre-exposure prophylaxis (PrEP) and repurposing in medicine. Full article

(This article belongs to the Special Issue New Advances in Drug Repurposing for Oncology)

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12 pages, 1886 KiB

Open AccessEditor’s ChoiceArticle

Lack of Epileptogenic Effects of the Creatine Precursor Guanidinoacetic Acid on Neuronal Cultures In Vitro

by Fabio Poggio, Martina Brofiga, Mariateresa Tedesco, Paolo Massobrio, Enrico Adriano and Maurizio Balestrino

Biomolecules 2023, 13(1), 74; https://doi.org/10.3390/biom13010074 - 30 Dec 2022

Cited by 1 | Viewed by 1822

Abstract

The creatine precursor Guanidinoacetic Acid (GAA) accumulates in the genetic deficiency of the GuanidinoAcetate Methyl Transferase (GAMT) enzyme and it is believed to cause the seizures that often occur in this condition. However, evidence that it is indeed epileptogenic is scarce and we [...] Read more.

The creatine precursor Guanidinoacetic Acid (GAA) accumulates in the genetic deficiency of the GuanidinoAcetate Methyl Transferase (GAMT) enzyme and it is believed to cause the seizures that often occur in this condition. However, evidence that it is indeed epileptogenic is scarce and we previously found that it does not cause neuronal hyperexcitation in in vitro brain slices. Here, we used Micro-Electrode Arrays (MEAs) to further investigate the electrophysiological effects of its acute and chronic administration in the networks of cultured neurons, either neocortical or hippocampal. We found that: (1) GAA at the 1 µM concentration, comparable to its concentration in normal cerebrospinal fluid, does not modify any of the parameters we investigated in either neuronal type; (2) at the 10 µM concentration, very similar to that found in the GAMT deficiency, it did not affect any of the parameters we tested except the bursting rate of neocortical networks and the burst duration of hippocampal networks, both of which were decreased, a change pointing in a direction opposite to epileptogenesis; (3) at the very high and unphysiological 100 µM concentration, it caused a decrease in all parameters, a change that again goes in the direction opposite to epileptogenesis. Our results confirm that GAA is not epileptogenic. Full article

(This article belongs to the Collection Feature Papers in Chemical Biology)

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45 pages, 2307 KiB

Open AccessEditor’s ChoiceReview

Cancer-Associated Fibroblast Heterogeneity, Activation and Function: Implications for Prostate Cancer

by Jasmine S. Owen, Aled Clayton and Helen B. Pearson

Biomolecules 2023, 13(1), 67; https://doi.org/10.3390/biom13010067 - 29 Dec 2022

Cited by 11 | Viewed by 4587

Abstract

The continuous remodeling of the tumor microenvironment (TME) during prostate tumorigenesis is emerging as a critical event that facilitates cancer growth, progression and drug-resistance. Recent advances have identified extensive communication networks that enable tumor–stroma cross-talk, and emphasized the functional importance of diverse, heterogeneous [...] Read more.

The continuous remodeling of the tumor microenvironment (TME) during prostate tumorigenesis is emerging as a critical event that facilitates cancer growth, progression and drug-resistance. Recent advances have identified extensive communication networks that enable tumor–stroma cross-talk, and emphasized the functional importance of diverse, heterogeneous stromal fibroblast populations during malignant growth. Cancer-associated fibroblasts (CAFs) are a vital component of the TME, which mediate key oncogenic events including angiogenesis, immunosuppression, metastatic progression and therapeutic resistance, thus presenting an attractive therapeutic target. Nevertheless, how fibroblast heterogeneity, recruitment, cell-of-origin and differential functions contribute to prostate cancer remains to be fully delineated. Developing our molecular understanding of these processes is fundamental to developing new therapies and biomarkers that can ultimately improve clinical outcomes. In this review, we explore the current challenges surrounding fibroblast identification, discuss new mechanistic insights into fibroblast functions during normal prostate tissue homeostasis and tumorigenesis, and illustrate the diverse nature of fibroblast recruitment and CAF generation. We also highlight the promise of CAF-targeted therapies for the treatment of prostate cancer. Full article

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19 pages, 2948 KiB

Open AccessEditor’s ChoiceArticle

Carrying Temoporfin with Human Serum Albumin: A New Perspective for Photodynamic Application in Head and Neck Cancer

by Edoardo Jun Mattioli, Luca Ulfo, Alessia Marconi, Valentina Pellicioni, Paolo Emidio Costantini, Tainah Dorina Marforio, Matteo Di Giosia, Alberto Danielli, Carmela Fimognari, Eleonora Turrini and Matteo Calvaresi

Biomolecules 2023, 13(1), 68; https://doi.org/10.3390/biom13010068 - 29 Dec 2022

Cited by 8 | Viewed by 2543

Abstract

Temoporfin (mTHPC) is approved in Europe for the photodynamic treatment of head and neck squamous cell carcinoma (HNSCC). Although it has a promising profile, its lipophilic character hampers the full exploitation of its potential due to high tendency of aggregation and a reduced [...] Read more.

Temoporfin (mTHPC) is approved in Europe for the photodynamic treatment of head and neck squamous cell carcinoma (HNSCC). Although it has a promising profile, its lipophilic character hampers the full exploitation of its potential due to high tendency of aggregation and a reduced ROS generation that compromise photodynamic therapy (PDT) efficacy. Moreover, for its clinical administration, mTHPC requires the presence of ethanol and propylene glycol as solvents, often causing adverse effects in the site of injection. In this paper we explored the efficiency of a new mTHPC formulation that uses human serum albumin (HSA) to disperse the photosensitizer in solution (mTHPC@HSA), investigating its anticancer potential in two HNSCC cell lines. Through a comprehensive characterization, we demonstrated that mTHPC@HSA is stable in physiological environment, does not aggregate, and is extremely efficient in PDT performance, due to its high singlet oxygen generation and the high dispersion as monomolecular form in HSA. This is supported by the computational identification of the specific binding pocket of mTHPC in HSA. Moreover, mTHPC@HSA-PDT induces cytotoxicity in both HNSCC cell lines, increasing intracellular ROS generation and the number of γ-H2AX foci, a cellular event involved in the global response to cellular stress. Taken together these results highlight the promising phototoxic profile of the complex, prompting further studies to assess its clinical potential. Full article

(This article belongs to the Special Issue Involvement of Oxidative Stress Signalling Pathways in Cell Death)

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13 pages, 2222 KiB

Open AccessEditor’s ChoiceArticle

Iron Deprivation by Oral Deferoxamine Application Alleviates Acute Campylobacteriosis in a Clinical Murine Campylobacter jejuni Infection Model

by Stefan Bereswill, Soraya Mousavi, Dennis Weschka, Agnes Buczkowski, Sebastian Schmidt and Markus M. Heimesaat

Biomolecules 2023, 13(1), 71; https://doi.org/10.3390/biom13010071 - 29 Dec 2022

Cited by 6 | Viewed by 1408

Abstract

The progressively rising food-borne Campylobacter jejuni infections pose serious health problems and socioeconomic burdens. Given that antibiotic therapy is not recommended for most campylobacteriosis patients, novel treatment options include strategies targeting iron homeostasis that impacts both C. jejuni virulence and inflammatory cell damage [...] Read more.

The progressively rising food-borne Campylobacter jejuni infections pose serious health problems and socioeconomic burdens. Given that antibiotic therapy is not recommended for most campylobacteriosis patients, novel treatment options include strategies targeting iron homeostasis that impacts both C. jejuni virulence and inflammatory cell damage caused by toxic oxygen species. In our preclinical intervention study, we tested potential disease-alleviating effects upon prophylactic oral application of the iron-chelating compound desferoxamine (DESF) in acute murine campylobacteriosis. Therefore, microbiota-depleted IL-10^−/− mice received synthetic DESF via the drinking water starting seven days before oral infection with C. jejuni strain 81-176. Results revealed that the DESF application did not reduce gastrointestinal pathogen loads but significantly improved the clinical outcome of infected mice at day 6 post-infection. This was accompanied by less pronounced colonic epithelial cell apoptosis, attenuated accumulation of neutrophils in the infected large intestines and abolished intestinal IFN-γ and even systemic MCP-1 secretion. In conclusion, our study highlights the applied murine campylobacteriosis model as suitable for investigating the role of iron in C. jejuni infection in vivo as demonstrated by the disease-alleviating effects of specific iron binding by oral DESF application in acute C. jejuni induced enterocolitis. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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10 pages, 1616 KiB

Open AccessEditor’s ChoiceArticle

Age- and Sex-Dependent Behavioral and Neurochemical Alterations in hLRRK2-G2019S BAC Mice

by Ning Yao, Olga Skiteva and Karima Chergui

Biomolecules 2023, 13(1), 51; https://doi.org/10.3390/biom13010051 - 27 Dec 2022

Cited by 1 | Viewed by 1407

Abstract

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with late-onset Parkinson’s disease (PD). Although PD affects men and women differently, longitudinal studies examining sex- and age-dependent alterations in mice carrying the G2019S mutation are limited. We [...] Read more.

The G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene is associated with late-onset Parkinson’s disease (PD). Although PD affects men and women differently, longitudinal studies examining sex- and age-dependent alterations in mice carrying the G2019S mutation are limited. We examined if behavioral and neurochemical dysfunctions, as well as neurodegeneration, occur in male and female BAC LRRK2-hG2019S (G2019S) mice, compared to their age-matched wild type littermates, at four age ranges. In the open field test, hyperlocomotion was observed in 10–12 month old male and 2–4.5 months old female G2019S mice. In the pole test, motor coordination was impaired in male G2019S mice from 15 months of age and in 20–21 months old female G2019S mice. In the striatum of G2019S male and female mice, the amounts of tyrosine hydroxylase (TH), measured with Western blotting, were unaltered. However, we found a decreased expression of the dopamine transporter in 20–21 month old male G2019S mice. The number of TH-positive neurons in the substantia nigra compacta was unaltered in 20–21 month old male and female G2019S mice. These results identify sex- and age-dependent differences in the occurrence of motor and neurochemical deficits in BAC LRRK2-hG2019S mice, and no degeneration of DA neurons. Full article

(This article belongs to the Special Issue Pathological Roles of LRRK2)

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31 pages, 3181 KiB

Open AccessEditor’s ChoiceReview

Advances and Innovations of 3D Bioprinting Skin

by Moon Sung Kang, Jinju Jang, Hyo Jung Jo, Won-Hyeon Kim, Bongju Kim, Heoung-Jae Chun, Dohyung Lim and Dong-Wook Han

Biomolecules 2023, 13(1), 55; https://doi.org/10.3390/biom13010055 - 27 Dec 2022

Cited by 8 | Viewed by 4207

Abstract

Three-dimensional (3D) bioprinted skin equivalents are highlighted as the new gold standard for alternative models to animal testing, as well as full-thickness wound healing. In this review, we focus on the advances and innovations of 3D bioprinting skin for skin regeneration, within the [...] Read more.

Three-dimensional (3D) bioprinted skin equivalents are highlighted as the new gold standard for alternative models to animal testing, as well as full-thickness wound healing. In this review, we focus on the advances and innovations of 3D bioprinting skin for skin regeneration, within the last five years. After a brief introduction to skin anatomy, 3D bioprinting methods and the remarkable features of recent studies are classified as advances in materials, structures, and functions. We will discuss several ways to improve the clinical potential of 3D bioprinted skin, with state-of-the-art printing technology and novel biomaterials. After the breakthrough in the bottleneck of the current studies, highly developed skin can be fabricated, comprising stratified epidermis, dermis, and hypodermis with blood vessels, nerves, muscles, and skin appendages. We hope that this review will be priming water for future research and clinical applications, that will guide us to break new ground for the next generation of skin regeneration. Full article

(This article belongs to the Special Issue 3D Printing Biological and Medical Application)

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16 pages, 17434 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Tuning Liposome Stability in Biological Environments and Intracellular Drug Release Kinetics

by Keni Yang, Karolina Tran and Anna Salvati

Biomolecules 2023, 13(1), 59; https://doi.org/10.3390/biom13010059 - 27 Dec 2022

Cited by 2 | Viewed by 3372

Abstract

Ideal drug carriers should be stable in biological environments but eventually release their drug load once inside the targeted cells. These two aspects can be in contrast with each other, thus they need to be carefully tuned in order to achieve the desired [...] Read more.

Ideal drug carriers should be stable in biological environments but eventually release their drug load once inside the targeted cells. These two aspects can be in contrast with each other, thus they need to be carefully tuned in order to achieve the desired properties for specific applications. Quantifying drug release profiles in biological environments or inside cells can be highly challenging, and standard methods to determine drug release kinetics in many cases cannot be applied to complex biological environments or cells. Within this context, the present work combined kinetic studies by flow cytometry with aging experiments in biological fluids and size-exclusion chromatography to determine drug release profiles in biological environments and inside cells. To this purpose, anionic and zwitterionic liposomes were used as model nanomedicines. By changing lipid composition, liposome stability in serum and intracellular release kinetics could be tuned and formulations with very different properties could be obtained. The methods presented can be used to characterize liposome release profiles in complex biological media, as well as inside cells. In this way, liposome composition can be tuned in order to achieve formulations with optimal balance between stability and release kinetics for specific applications. Full article

(This article belongs to the Special Issue Liposomes for Drug Delivery: Recent Advances and Discoveries)

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19 pages, 1931 KiB

Open AccessEditor’s ChoiceReview

Biological Effects of Human Exposure to Environmental Cadmium

by Massimiliano Peana, Alessio Pelucelli, Christos T. Chasapis, Spyros P. Perlepes, Vlasoula Bekiari, Serenella Medici and Maria Antonietta Zoroddu

Biomolecules 2023, 13(1), 36; https://doi.org/10.3390/biom13010036 - 24 Dec 2022

Cited by 49 | Viewed by 7611

Abstract

Cadmium (Cd) is a toxic metal for the human organism and for all ecosystems. Cd is naturally found at low levels; however, higher amounts of Cd in the environment result from human activities as it spreads into the air and water in the [...] Read more.

Cadmium (Cd) is a toxic metal for the human organism and for all ecosystems. Cd is naturally found at low levels; however, higher amounts of Cd in the environment result from human activities as it spreads into the air and water in the form of micropollutants as a consequence of industrial processes, pollution, waste incineration, and electronic waste recycling. The human body has a limited ability to respond to Cd exposure since the metal does not undergo metabolic degradation into less toxic species and is only poorly excreted. The extremely long biological half-life of Cd essentially makes it a cumulative toxin; chronic exposure causes harmful effects from the metal stored in the organs. The present paper considers exposure and potential health concerns due to environmental cadmium. Exposure to Cd compounds is primarily associated with an elevated risk of lung, kidney, prostate, and pancreatic cancer. Cd has also been linked to cancers of the breast, urinary system, and bladder. The multiple mechanisms of Cd-induced carcinogenesis include oxidative stress with the inhibition of antioxidant enzymes, the promotion of lipid peroxidation, and interference with DNA repair systems. Cd²⁺ can also replace essential metal ions, including redox-active ones. A total of 12 cancer types associated with specific genes coding for the Cd-metalloproteome were identified in this work. In addition, we summarize the proper treatments of Cd poisoning, based on the use of selected Cd detoxifying agents and chelators, and the potential for preventive approaches to counteract its chronic exposure. Full article

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

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16 pages, 3451 KiB

Open AccessEditor’s ChoiceArticle

Thrombin-Mediated Formation of Globular Adiponectin Promotes an Increase in Adipose Tissue Mass

by Peter Zahradka, Carla G. Taylor, Leslee Tworek, Raissa Perrault, Sofia M’Seffar, Megha Murali, Tara Loader and Jeffrey T. Wigle

Biomolecules 2023, 13(1), 30; https://doi.org/10.3390/biom13010030 - 23 Dec 2022

Cited by 2 | Viewed by 1914

Abstract

A decrease in the circulating levels of adiponectin in obesity increases the risk of metabolic complications, but the role of globular adiponectin, a truncated form produced by proteolytic cleavage, has not been defined. The objective of this investigation was to determine how globular [...] Read more.

A decrease in the circulating levels of adiponectin in obesity increases the risk of metabolic complications, but the role of globular adiponectin, a truncated form produced by proteolytic cleavage, has not been defined. The objective of this investigation was to determine how globular adiponectin is generated and to determine whether this process impacts obesity. The cleavage of recombinant full-length adiponectin into globular adiponectin by plasma in vitro was used to identify Gly-93 as the N-terminal residue after proteolytic processing. The amino acid sequence of the cleavage site suggested thrombin was the protease responsible for cleavage, and inhibitors confirmed its likely involvement. The proteolytic site was modified, and this thrombin-resistant mutant protein was infused for 4 weeks into obese adiponectin-knockout mice that had been on a high-fat diet for 8 weeks. The mutation of the cleavage site ensured that globular adiponectin was not generated, and thus did not confound the actions of the full-length adiponectin. Mice infused with the mutant adiponectin accumulated less fat and had smaller adipocytes compared to mice treated with globular adiponectin, and concurrently had elevated fasting glucose. The data demonstrate that generation of globular adiponectin through the action of thrombin increases both adipose tissue mass and adipocyte size, but it has no effect on fasting glucose levels in the context of obesity. Full article

(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)

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19 pages, 1215 KiB

Open AccessEditor’s ChoiceReview

Message in a Scaffold: Natural Biomaterials for Three-Dimensional (3D) Bioprinting of Human Brain Organoids

by Pierre Layrolle, Pierre Payoux and Stéphane Chavanas

Biomolecules 2023, 13(1), 25; https://doi.org/10.3390/biom13010025 - 22 Dec 2022

Cited by 5 | Viewed by 2806

Abstract

Brain organoids are invaluable tools for pathophysiological studies or drug screening, but there are still challenges to overcome in making them more reproducible and relevant. Recent advances in three-dimensional (3D) bioprinting of human neural organoids is an emerging approach that may overcome the [...] Read more.

Brain organoids are invaluable tools for pathophysiological studies or drug screening, but there are still challenges to overcome in making them more reproducible and relevant. Recent advances in three-dimensional (3D) bioprinting of human neural organoids is an emerging approach that may overcome the limitations of self-organized organoids. It requires the development of optimal hydrogels, and a wealth of research has improved our knowledge about biomaterials both in terms of their intrinsic properties and their relevance on 3D culture of brain cells and tissue. Although biomaterials are rarely biologically neutral, few articles have reviewed their roles on neural cells. We here review the current knowledge on unmodified biomaterials amenable to support 3D bioprinting of neural organoids with a particular interest in their impact on cell homeostasis. Alginate is a particularly suitable bioink base for cell encapsulation. Gelatine is a valuable helper agent for 3D bioprinting due to its viscosity. Collagen, fibrin, hyaluronic acid and laminin provide biological support to adhesion, motility, differentiation or synaptogenesis and optimize the 3D culture of neural cells. Optimization of specialized hydrogels to direct differentiation of stem cells together with an increased resolution in phenotype analysis will further extend the spectrum of possible bioprinted brain disease models. Full article

(This article belongs to the Special Issue 3D Printing Biological and Medical Application)

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20 pages, 5119 KiB

Open AccessEditor’s ChoiceReview

Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia

by Teresa Zalewska, Paulina Pawelec, Karolina Ziabska and Malgorzata Ziemka-Nalecz

Biomolecules 2023, 13(1), 26; https://doi.org/10.3390/biom13010026 - 22 Dec 2022

Cited by 7 | Viewed by 2679

Abstract

Epidemiological studies and clinical observations show evidence of sexual dimorphism in brain responses to several neurological conditions. It is suggested that sex-related differences between men and women may have profound effects on disease susceptibility, pathophysiology, and progression. Sexual differences of the brain are [...] Read more.

Epidemiological studies and clinical observations show evidence of sexual dimorphism in brain responses to several neurological conditions. It is suggested that sex-related differences between men and women may have profound effects on disease susceptibility, pathophysiology, and progression. Sexual differences of the brain are achieved through the complex interplay of several factors contributing to this phenomenon, such as sex hormones, as well as genetic and epigenetic differences. Despite recent advances, the precise link between these factors and brain disorders is incompletely understood. This review aims to briefly outline the most relevant aspects that differ between men and women in ischemia and neurodegenerative disorders (AD, PD, HD, ALS, and SM). Recognition of disparities between both sexes could aid the development of individual approaches to ameliorate or slow the progression of intractable disorders. Full article

(This article belongs to the Special Issue Signaling Biomolecules in the Central Nervous System (CNS)—At the Nexus of Neuropsychiatric and Neurodegenerative Disorders)

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17 pages, 1119 KiB

Open AccessEditor’s ChoiceReview

NRF2 in the Epidermal Pigmentary System

by Tatsuya Ogawa and Yosuke Ishitsuka

Biomolecules 2023, 13(1), 20; https://doi.org/10.3390/biom13010020 - 22 Dec 2022

Cited by 2 | Viewed by 2311

Abstract

Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox) governs pigmentary responses, for which coordination among epidermal resident cells is indispensable. Here, we review the current understanding of melanocyte [...] Read more.

Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox) governs pigmentary responses, for which coordination among epidermal resident cells is indispensable. Here, we review the current understanding of melanocyte biology with a particular focus on the “master regulator” of oxidative stress responses (i.e., the Kelch-like erythroid cell-derived protein with cap‘n’collar homology-associated protein 1-nuclear factor erythroid-2-related factor 2 system) and the autoimmune pigment disorder vitiligo. Our investigation revealed that the former is essential in pigmentogenesis, whereas the latter results from unbalanced redox homeostasis and/or defective intercellular communication in the interfollicular epidermis (IFE). Finally, we propose a model in which keratinocytes provide a “niche” for differentiated melanocytes and may “imprint” IFE pigmentation. Full article

(This article belongs to the Special Issue Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches II)

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13 pages, 758 KiB

Open AccessEditor’s ChoiceReview

Use of Insect Promoters in Genetic Engineering to Control Mosquito-Borne Diseases

by Vanessa Bottino-Rojas and Anthony A. James

Biomolecules 2023, 13(1), 16; https://doi.org/10.3390/biom13010016 - 21 Dec 2022

Cited by 4 | Viewed by 3802

Abstract

Mosquito transgenesis and gene-drive technologies provide the basis for developing promising new tools for vector-borne disease prevention by either suppressing wild mosquito populations or reducing their capacity from transmitting pathogens. Many studies of the regulatory DNA and promoters of genes with robust sex-, [...] Read more.

Mosquito transgenesis and gene-drive technologies provide the basis for developing promising new tools for vector-borne disease prevention by either suppressing wild mosquito populations or reducing their capacity from transmitting pathogens. Many studies of the regulatory DNA and promoters of genes with robust sex-, tissue- and stage-specific expression profiles have supported the development of new tools and strategies that could bring mosquito-borne diseases under control. Although the list of regulatory elements available is significant, only a limited set of those can reliably drive spatial–temporal expression. Here, we review the advances in our ability to express beneficial and other genes in mosquitoes, and highlight the information needed for the development of new mosquito-control and anti-disease strategies. Full article

(This article belongs to the Special Issue Contributions of Promoters to the Physiology, Biochemistry and Molecular Biology Processes of Insects)

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12 pages, 10293 KiB

Open AccessEditor’s ChoiceArticle

Metabolomics and a Breath Sensor Identify Acetone as a Biomarker for Heart Failure

by Patrick A. Gladding, Maxine Cooper, Renee Young, Suzanne Loader, Kevin Smith, Erica Zarate, Saras Green, Silas G. Villas Boas, Phillip Shepherd, Purvi Kakadiya, Eric Thorstensen, Christine Keven, Margaret Coe, Mia Jüllig, Edmond Zhang and Todd T. Schlegel

Biomolecules 2023, 13(1), 13; https://doi.org/10.3390/biom13010013 - 21 Dec 2022

Cited by 4 | Viewed by 2676

Abstract

Background: Multi-omics delivers more biological insight than targeted investigations. We applied multi-omics to patients with heart failure with reduced ejection fraction (HFrEF). Methods: 46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LC-MS/GC-MS) and solid-phase microextraction (SPME) [...] Read more.

Background: Multi-omics delivers more biological insight than targeted investigations. We applied multi-omics to patients with heart failure with reduced ejection fraction (HFrEF). Methods: 46 patients with HFrEF and 20 controls underwent metabolomic profiling, including liquid/gas chromatography mass spectrometry (LC-MS/GC-MS) and solid-phase microextraction (SPME) volatilomics in plasma and urine. HFrEF was defined using left ventricular global longitudinal strain, ejection fraction and NTproBNP. A consumer breath acetone (BrACE) sensor validated results in n = 73. Results: 28 metabolites were identified by GCMS, 35 by LCMS and 4 volatiles by SPME in plasma and urine. Alanine, aspartate and glutamate, citric acid cycle, arginine biosynthesis, glyoxylate and dicarboxylate metabolism were altered in HFrEF. Plasma acetone correlated with NT-proBNP (r = 0.59, 95% CI 0.4 to 0.7), 2-oxovaleric and cis-aconitic acid, involved with ketone metabolism and mitochondrial energetics. BrACE > 1.5 ppm discriminated HF from other cardiac pathology (AUC 0.8, 95% CI 0.61 to 0.92, p < 0.0001). Conclusion: Breath acetone discriminated HFrEF from other cardiac pathology using a consumer sensor, but was not cardiac specific. Full article

(This article belongs to the Special Issue Omic Approaches in Human Disease: Impact on Therapeutics and Diagnostics)

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16 pages, 2554 KiB

Open AccessEditor’s ChoiceArticle

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT₆R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

by Vittorio Canale, Wojciech Trybała, Séverine Chaumont-Dubel, Paulina Koczurkiewicz-Adamczyk, Grzegorz Satała, Ophélie Bento, Klaudia Blicharz-Futera, Xavier Bantreil, Elżbieta Pękala, Andrzej J. Bojarski, Frédéric Lamaty, Philippe Marin and Paweł Zajdel

Biomolecules 2023, 13(1), 12; https://doi.org/10.3390/biom13010012 - 21 Dec 2022

Cited by 3 | Viewed by 2022

Abstract

In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT₆R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active [...] Read more.

In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT₆R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT₆R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT₆R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g, which behaves as a neutral antagonist at the 5-HT₆R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT₆R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases. Full article

(This article belongs to the Special Issue Recent Advances on 5-HT6 Receptors)

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14 pages, 2262 KiB

Open AccessEditor’s ChoiceArticle

The Effect of Novel Selenopolysaccharide Isolated from Lentinula edodes Mycelium on Human T Lymphocytes Activation, Proliferation, and Cytokines Synthesis

by Aleksander Roszczyk, Michał Zych, Katarzyna Zielniok, Natalia Krata, Jadwiga Turło, Marzenna Klimaszewska, Radosław Zagożdżon and Beata Kaleta

Biomolecules 2022, 12(12), 1900; https://doi.org/10.3390/biom12121900 - 19 Dec 2022

Cited by 2 | Viewed by 1723

Abstract

Polysaccharides isolated from Lentinula edodes are bioactive compounds with immunomodulatory properties. In our previous studies from L. edodes mycelium, we have isolated a selenium(Se)-enriched fraction (named Se-Le-30), a mixture of linear 1,4-α-glucan and linear 1,3-β- and 1,6-β-glucans. In this study, we analyzed the [...] Read more.

Polysaccharides isolated from Lentinula edodes are bioactive compounds with immunomodulatory properties. In our previous studies from L. edodes mycelium, we have isolated a selenium(Se)-enriched fraction (named Se-Le-30), a mixture of linear 1,4-α-glucan and linear 1,3-β- and 1,6-β-glucans. In this study, we analyzed the effects of Se-Le-30 on the activation and proliferation of human T lymphocytes stimulated by anti-CD3 and anti-CD3/CD28 antibodies (Abs) and on the production of cytokines by peripheral blood mononuclear cells (PBMCs). Se-Le-30 had effects on T cell proliferation induced by Abs against CD3 and CD28. It significantly inhibited the proliferation of CD3-stimulated CD4⁺ and CD8⁺ T cells and enhanced the proliferation of CD4⁺ T cells stimulated with anti-CD3/CD28 Ab. Moreover, Se-Le-30 downregulated the number of CD3-stimulated CD4⁺CD69⁺ cells, CD4⁺CD25⁺ cells, as well as CD8⁺CD25⁺ cells, and upregulated the expression of CD25 marker on CD4+ and CD8+ T cells activated with anti-CD3/CD28 Abs. Furthermore, Se-Le-30 enhanced the synthesis of IFN-γ by the unstimulated and anti-CD3/CD28-stimulated PBMCs, inhibited synthesis of IL-2 and IL-4 by CD3-stimulated cells, and augmented the synthesis of IL-6 and IL-10 by unstimulated, CD3-stimulated, and CD3/CD28-stimulated PBMCs. Together, we demonstrated that Se-Le-30 exerts immunomodulatory effects on human T lymphocytes. These observations are of importance for the prospective use of Se-Le-30 in research or as a therapeutic compound. Full article

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13 pages, 1469 KiB

Open AccessEditor’s ChoiceReview

Oxidative Stress and Phototherapy in Atopic Dermatitis: Mechanisms, Role, and Future Perspectives

by Francesco Borgia, Federica Li Pomi, Mario Vaccaro, Clara Alessandrello, Vincenzo Papa and Sebastiano Gangemi

Biomolecules 2022, 12(12), 1904; https://doi.org/10.3390/biom12121904 - 19 Dec 2022

Cited by 13 | Viewed by 2607

Abstract

Atopic dermatitis is a chronic inflammatory skin disease in which the overproduction of reactive oxygen species plays a pivotal role in the pathogenesis and persistence of inflammatory lesions. Phototherapy represents one of the most used therapeutic options, with benefits in the clinical picture. [...] Read more.

Atopic dermatitis is a chronic inflammatory skin disease in which the overproduction of reactive oxygen species plays a pivotal role in the pathogenesis and persistence of inflammatory lesions. Phototherapy represents one of the most used therapeutic options, with benefits in the clinical picture. Studies have demonstrated the immunomodulatory effect of phototherapy and its role in reducing molecule hallmarks of oxidative stress. In this review, we report the data present in literature dealing with the main signaling molecular pathways involved in oxidative stress after phototherapy to target atopic dermatitis-affected cells. Since oxidative stress plays a pivotal role in the pathogenesis of atopic dermatitis and its flare-up, new research lines could be opened to study new drugs that act on this mechanism, perhaps in concert with phototherapy. Full article

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24 pages, 853 KiB

Open AccessFeature PaperEditor’s ChoiceReview

One-Carbon and Polyamine Metabolism as Cancer Therapy Targets

by Anowarul Islam, Zeeshan Shaukat, Rashid Hussain and Stephen L. Gregory

Biomolecules 2022, 12(12), 1902; https://doi.org/10.3390/biom12121902 - 19 Dec 2022

Cited by 4 | Viewed by 3246

Abstract

Cancer metabolic reprogramming is essential for maintaining cancer cell survival and rapid replication. A common target of this metabolic reprogramming is one-carbon metabolism which is notable for its function in DNA synthesis, protein and DNA methylation, and antioxidant production. Polyamines are a key [...] Read more.

Cancer metabolic reprogramming is essential for maintaining cancer cell survival and rapid replication. A common target of this metabolic reprogramming is one-carbon metabolism which is notable for its function in DNA synthesis, protein and DNA methylation, and antioxidant production. Polyamines are a key output of one-carbon metabolism with widespread effects on gene expression and signaling. As a result of these functions, one-carbon and polyamine metabolism have recently drawn a lot of interest for their part in cancer malignancy. Therapeutic inhibitors that target one-carbon and polyamine metabolism have thus been trialed as anticancer medications. The significance and future possibilities of one-carbon and polyamine metabolism as a target in cancer therapy are discussed in this review. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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12 pages, 2742 KiB

Open AccessEditor’s ChoiceArticle

Effects of the Myokine Irisin on Stromal Cells from Swine Adipose Tissue

by Giuseppina Basini, Simona Bussolati, Stefano Grolli, Priscilla Berni, Rosanna Di Lecce and Francesca Grasselli

Biomolecules 2022, 12(12), 1895; https://doi.org/10.3390/biom12121895 - 17 Dec 2022

Cited by 3 | Viewed by 1339

Abstract

Irisin is a hormone able to reproduce some of the positive effects of physical activity and diet. Recently, we demonstrated the presence of Irisin at the ovarian level as a potential physiological regulator of follicular function. Adipose tissue is crucial for reproductive function [...] Read more.

Irisin is a hormone able to reproduce some of the positive effects of physical activity and diet. Recently, we demonstrated the presence of Irisin at the ovarian level as a potential physiological regulator of follicular function. Adipose tissue is crucial for reproductive function through its metabolic activity and the production of adipokines. At present, the exact nature of adipocyte precursors is still under debate, but an important role has been assigned to the population of adipose tissue mesenchymal stromal cells (ASCs) of perivascular origin. It should be noted that, when appropriately stimulated, ASCs can differentiate into preadipocytes and, subsequently, adipocytes. Therefore, this present study was undertaken to explore the potential effect of Irisin on ASCs, known for their high differentiative potential. Since Irisin expression in ASCs was confirmed by PCR, we tested its potential effects on the main functional activities of these cells, including proliferation (BrdU uptake); metabolic activity (ATP production); redox status, evaluated as the generation of free molecules such as superoxide anion and nitric oxide; and scavenger activities, assessed as both enzymatic (superoxide dismutase) and non-enzymatic antioxidant power. Moreover, we tested the effect of Irisin on ASCs adipogenic differentiation. BrdU uptake was significantly (p < 0.001) inhibited by Irisin, while ATP production was significantly (p < 0.05) increased. Both superoxide anion and nitric oxide generation were significantly increased (p < 0.001) by Irisin, while scavenger activity was significantly reduced (p < 0.05). Irisin was found to significantly (p < 0.05) inhibit ASCs adipogenic differentiation. Taken together, the present results suggest a potential local role of Irisin in the regulation of adipose tissue function. Full article

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13 pages, 2282 KiB

Open AccessEditor’s ChoiceReview

Calcium Overload and Mitochondrial Metabolism

by Lauren L. Walkon, Jasiel O. Strubbe-Rivera and Jason N. Bazil

Biomolecules 2022, 12(12), 1891; https://doi.org/10.3390/biom12121891 - 17 Dec 2022

Cited by 19 | Viewed by 3365

Abstract

Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming the mitochondrial calcium retention capacity leads to loss of mitochondrial function. In moderate amounts, however, ATP synthesis rates [...] Read more.

Mitochondria calcium is a double-edged sword. While low levels of calcium are essential to maintain optimal rates of ATP production, extreme levels of calcium overcoming the mitochondrial calcium retention capacity leads to loss of mitochondrial function. In moderate amounts, however, ATP synthesis rates are inhibited in a calcium-titratable manner. While the consequences of extreme calcium overload are well-known, the effects on mitochondrial function in the moderately loaded range remain enigmatic. These observations are associated with changes in the mitochondria ultrastructure and cristae network. The present mini review/perspective follows up on previous studies using well-established cryo–electron microscopy and poses an explanation for the observable depressed ATP synthesis rates in mitochondria during calcium-overloaded states. The results presented herein suggest that the inhibition of oxidative phosphorylation is not caused by a direct decoupling of energy metabolism via the opening of a calcium-sensitive, proteinaceous pore but rather a separate but related calcium-dependent phenomenon. Such inhibition during calcium-overloaded states points towards mitochondrial ultrastructural modifications, enzyme activity changes, or an interplay between both events. Full article

(This article belongs to the Special Issue Computational Insights into Calcium Signaling)

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18 pages, 3145 KiB

Open AccessEditor’s ChoiceArticle

Palmitoylethanolamide Mitigates Paclitaxel Toxicity in Primary Dorsal Root Ganglion Neurons

by Amira Elfarnawany and Faramarz Dehghani

Biomolecules 2022, 12(12), 1873; https://doi.org/10.3390/biom12121873 - 14 Dec 2022

Cited by 4 | Viewed by 2489

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of several chemotherapeutic agents, such as Paclitaxel. The main symptoms of CIPN are pain and numbness in the hands and feet. Paclitaxel is believed to accumulate in the dorsal root ganglia and free nerve [...] Read more.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of several chemotherapeutic agents, such as Paclitaxel. The main symptoms of CIPN are pain and numbness in the hands and feet. Paclitaxel is believed to accumulate in the dorsal root ganglia and free nerve endings. Novel therapeutic agents might help to mitigate or prevent Paclitaxel toxicity on dorsal root ganglion (DRG) neurons. Thus, we used primary DRG neurons as a model to investigate the potential neuroprotective effects of the endocannabinoid-like substance, palmitoylethanolamide (PEA). DRG neurons were isolated from cervical to sacral segments of spinal nerves of Wister rats (6–8 weeks old). After isolation and purification of neuronal cell populations, different concentrations of Paclitaxel (0.01–10 µM) or PEA (0.1–10 µM) or their combination were tested on cell viability by MTT assay at 24 h, 48, and 72 h post-treatment. Furthermore, morphometric analyses of neurite length and soma size for DRG neurons were performed. Adverse Paclitaxel effects on cell viability were apparent at 72 h post-treatment whereas Paclitaxel significantly reduced the neurite length in a concentration-dependent manner nearly at all investigated time points. However, Paclitaxel significantly increased the size of neuronal cell bodies at all time windows. These phenotypic effects were significantly reduced in neurons additionally treated with PEA, indicating the neuroprotective effect of PEA. PEA alone led to a significant increase in neuron viability regardless of PEA concentrations, apparent improvements in neurite outgrowth as well as a significant decrease in soma size of neurons at different investigated time points. Taken together, PEA showed promising protective effects against Paclitaxel-related toxicity on DRG neurons. Full article

(This article belongs to the Special Issue To Go Where Nature Leads: Focus on Palmitoylethanolamide and Related ALIAmides As Innovative Approach to Neuroinflammatory and Pain-Related Disease States in Honor of Doctor Francesco Della Valle)

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18 pages, 1489 KiB

Open AccessEditor’s ChoiceReview

The Effect of Electrical Stimulation on Nerve Regeneration Following Peripheral Nerve Injury

by Luke Juckett, Tiam Mana Saffari, Benjamin Ormseth, Jenna-Lynn Senger and Amy M. Moore

Biomolecules 2022, 12(12), 1856; https://doi.org/10.3390/biom12121856 - 12 Dec 2022

Cited by 18 | Viewed by 7740

Abstract

Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from [...] Read more.

Peripheral nerve injuries (PNI) are common and often result in lifelong disability. The peripheral nervous system has an inherent ability to regenerate following injury, yet complete functional recovery is rare. Despite advances in the diagnosis and repair of PNIs, many patients suffer from chronic pain, and sensory and motor dysfunction. One promising surgical adjunct is the application of intraoperative electrical stimulation (ES) to peripheral nerves. ES acts through second messenger cyclic AMP to augment the intrinsic molecular pathways of regeneration. Decades of animal studies have demonstrated that 20 Hz ES delivered post-surgically accelerates axonal outgrowth and end organ reinnervation. This work has been translated clinically in a series of randomized clinical trials, which suggest that ES can be used as an efficacious therapy to improve patient outcomes following PNIs. The aim of this review is to discuss the cellular physiology and the limitations of regeneration after peripheral nerve injuries. The proposed mechanisms of ES protocols and how they facilitate nerve regeneration depending on timing of administration are outlined. Finally, future directions of research that may provide new perspectives on the optimal delivery of ES following PNI are discussed. Full article

(This article belongs to the Special Issue Peripheral Nerve Plasticity: Development and Regeneration)

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12 pages, 305 KiB

Open AccessEditor’s ChoiceReview

Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction

by Francesca Bianco, Giulia Lattanzio, Luca Lorenzini, Maurizio Mazzoni, Paolo Clavenzani, Laura Calzà, Luciana Giardino, Catia Sternini, Anna Costanzini, Elena Bonora and Roberto De Giorgio

Biomolecules 2022, 12(12), 1849; https://doi.org/10.3390/biom12121849 - 10 Dec 2022

Cited by 9 | Viewed by 2094

Abstract

Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is [...] Read more.

Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is a typical clinical phenotype of severe gut dysmotility. This syndrome occurs due to changes altering the morpho-functional integrity of the intrinsic (enteric) innervation and extrinsic nerve supply (hence neuropathy), the interstitial cells of Cajal (ICC) (mesenchymopathy), and smooth muscle cells (myopathy). In the last years, several genes have been identified in different subsets of CIPO patients. The focus of this review is to cover the most recent update on enteric dysmotility related to CIPO, highlighting (a) forms with predominant underlying neuropathy, (b) forms with predominant myopathy, and (c) mitochondrial disorders with a clear gut dysfunction as part of their clinical phenotype. We will provide a thorough description of the genes that have been proven through recent evidence to cause neuro-(ICC)-myopathies leading to abnormal gut contractility patterns in CIPO. The discovery of susceptibility genes for this severe condition may pave the way for developing target therapies for enteric neuro-(ICC)-myopathies underlying CIPO and other forms of gut dysmotility. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

22 pages, 8765 KiB

Open AccessEditor’s ChoiceArticle

Oxidative Stress-Induced HMGB1 Translocation in Myenteric Neurons Contributes to Neuropathy in Colitis

by Rhian Stavely, Lauren Sahakian, Rhiannon T. Filippone, Vanesa Stojanovska, Joel C. Bornstein, Samy Sakkal and Kulmira Nurgali

Biomolecules 2022, 12(12), 1831; https://doi.org/10.3390/biom12121831 - 07 Dec 2022

Cited by 5 | Viewed by 1941

Abstract

High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern released by dying cells to stimulate the immune response. During cell death, HMGB1 is translocated from the nucleus to the cytoplasm and passively released. High levels of secreted HMGB1 are observed in the [...] Read more.

High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern released by dying cells to stimulate the immune response. During cell death, HMGB1 is translocated from the nucleus to the cytoplasm and passively released. High levels of secreted HMGB1 are observed in the faeces of inflammatory bowel disease (IBD) patients, indicating its role in IBD pathophysiology and potential as a non-invasive IBD biomarker. HMGB1 is important in regulating neuronal damage in the central nervous system; its pathological activity is intertwined with oxidative stress and inflammation. In this study, HMGB1 expression in the enteric nervous system and its relevance to intestinal neuroinflammation is explored in organotypic cultures of the myenteric plexus exposed to oxidative stimuli and in Winnie mice with spontaneous chronic colitis. Oxidative stimuli induced cytoplasmic translocation of HMGB1 in myenteric neurons in organotypic preparations. HMGB1 translocation correlated with enteric neuronal loss and oxidative stress in the myenteric ganglia of Winnie mice. Inhibition of HMGB1 by glycyrrhizic acid ameliorated HMGB1 translocation and myenteric neuronal loss in Winnie mice. These data highlight modulation of HMGB1 signalling as a therapeutic strategy to reduce the consequences of enteric neuroinflammation in colitis, warranting the exploration of therapeutics acting on the HMGB1 pathway as an adjunct treatment with current anti-inflammatory agents. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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22 pages, 1999 KiB

Open AccessEditor’s ChoiceArticle

Transcriptomics and Metabolomics of Reactive Oxygen Species Modulation in Near-Null Magnetic Field-Induced Arabidopsis thaliana

by Ambra S. Parmagnani, Giuseppe Mannino and Massimo E. Maffei

Biomolecules 2022, 12(12), 1824; https://doi.org/10.3390/biom12121824 - 06 Dec 2022

Cited by 7 | Viewed by 2171

Abstract

The geomagnetic field (GMF) is a natural component of Earth’s biosphere. GMF reduction to near-null values (NNMF) induces gene expression modulation that generates biomolecular, morphological, and developmental changes. Here, we evaluate the effect of NNMF on gene expression and reactive oxygen species (ROS) [...] Read more.

The geomagnetic field (GMF) is a natural component of Earth’s biosphere. GMF reduction to near-null values (NNMF) induces gene expression modulation that generates biomolecular, morphological, and developmental changes. Here, we evaluate the effect of NNMF on gene expression and reactive oxygen species (ROS) production in time-course experiments on Arabidopsis thaliana. Plants exposed to NNMF in a triaxial Helmholtz coils system were sampled from 10 min to 96 h to evaluate differentially expressed genes (DEGs) of oxidative stress responses by gene microarray. In 24–96 h developing stages, H₂O₂ and polyphenols were also analyzed from roots and shoots. A total of 194 DEGs involved in oxidative reactions were selected, many of which showed a fold change ≥±2 in at least one timing point. Heatmap clustering showed DEGs both between roots/shoots and among the different time points. NNMF induced a lower H₂O₂ than GMF, in agreement with the expression of ROS-related genes. Forty-four polyphenols were identified, the content of which progressively decreased during NNMF exposition time. The comparison between polyphenols content and DEGs showed overlapping patterns. These results indicate that GMF reduction induces metabolomic and transcriptomic modulation of ROS-scavenging enzymes and H₂O₂ production in A. thaliana, which is paralleled by the regulation of antioxidant polyphenols. Full article

(This article belongs to the Special Issue Functional Plant Metabolism 2.0)

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18 pages, 1921 KiB

Open AccessEditor’s ChoiceReview

The Emerging Role of Deubiquitinases in Cell Death

by Zhuan Zhou, Xinxin Song, Rui Kang and Daolin Tang

Biomolecules 2022, 12(12), 1825; https://doi.org/10.3390/biom12121825 - 06 Dec 2022

Cited by 2 | Viewed by 2652

Abstract

Regulated cell death (RCD) is a signal-controlled process that not only eliminates infected, damaged, or aged cells but is also implicated in a variety of pathological conditions. The process of RCD is regulated by intracellular proteins that undergo varying levels of post-translational modifications, [...] Read more.

Regulated cell death (RCD) is a signal-controlled process that not only eliminates infected, damaged, or aged cells but is also implicated in a variety of pathological conditions. The process of RCD is regulated by intracellular proteins that undergo varying levels of post-translational modifications, including mono- or polyubiquitination. Functionally, ubiquitination can affect protein abundance, localization, and activity. Like other post-translational modifications, ubiquitination is a dynamic and reversible process mediated by deubiquitinases, a large class of proteases that cleave ubiquitin from proteins and other substrates. The balance between ubiquitination and deubiquitination machinery determines cell fate under stressful conditions. Here, we review the latest advances in our understanding of the role of deubiquitinases in regulating the main types of RCD, including apoptosis, necroptosis, pyroptosis, and ferroptosis. This knowledge may contribute to identifying new protein degradation-related prognostic markers and therapeutic targets for human disease. Full article

(This article belongs to the Special Issue Deubiquitinating Enzymes in Health and Disease)

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