Biomolecules

18 pages, 1194 KiB

Open AccessEditor’s ChoiceReview

Electroceuticals and Magnetoceuticals in Gastroenterology

by Gengqing Song, Roberta Sclocco, Amol Sharma, Ingrid Guerrero-López and Braden Kuo

Biomolecules 2024, 14(7), 760; https://doi.org/10.3390/biom14070760 - 26 Jun 2024

Cited by 6 | Viewed by 2898

In the realm of gastroenterology, the inadequacy of current medical treatments for gastrointestinal (GI) motility disorders and inflammatory bowel disease (IBD), coupled with their potential side effects, necessitates novel therapeutic approaches. Neuromodulation, targeting the nervous system’s control of GI functions, emerges as a [...] Read more.

In the realm of gastroenterology, the inadequacy of current medical treatments for gastrointestinal (GI) motility disorders and inflammatory bowel disease (IBD), coupled with their potential side effects, necessitates novel therapeutic approaches. Neuromodulation, targeting the nervous system’s control of GI functions, emerges as a promising alternative. This review explores the promising effects of vagal nerve stimulation (VNS), magnetic neuromodulation, and acupuncture in managing these challenging conditions. VNS offers targeted modulation of GI motility and inflammation, presenting a potential solution for patients not fully relieved from traditional medications. Magnetic neuromodulation, through non-invasive means, aims to enhance neurophysiological processes, showing promise in improving GI function and reducing inflammation. Acupuncture and electroacupuncture, grounded in traditional medicine yet validated by modern science, exert comprehensive effects on GI physiology via neuro-immune-endocrine mechanisms, offering relief from motility and inflammatory symptoms. This review highlights the need for further research to refine these interventions, emphasizing their prospective role in advancing patient-specific management strategies for GI motility disorders and IBD, thus paving the way for a new therapeutic paradigm. Full article

(This article belongs to the Special Issue Pathogenesis and Potential Treatments of Neurointestinal Diseases)

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15 pages, 2548 KiB

Open AccessEditor’s ChoiceArticle

Extracellular Vesicle-Mediated Modulation of Stem-like Phenotype in Breast Cancer Cells under Fluid Shear Stress

by Spenser R. Brown, Margaret E. Radcliffe, Joseph T. Danner, Wilmer J. Andújar Cruz, Kimberly H. Lackey, Han-A Park, Steven T. Weinman and Yonghyun Kim

Biomolecules 2024, 14(7), 757; https://doi.org/10.3390/biom14070757 - 25 Jun 2024

Cited by 1 | Viewed by 2447

Abstract

Circulating tumor cells (CTCs) are some of the key culprits that cause cancer metastasis and metastasis-related deaths. These cells exist in a dynamic microenvironment where they experience fluid shear stress (FSS), and the CTCs that survive FSS are considered to be highly metastatic [...] Read more.

Circulating tumor cells (CTCs) are some of the key culprits that cause cancer metastasis and metastasis-related deaths. These cells exist in a dynamic microenvironment where they experience fluid shear stress (FSS), and the CTCs that survive FSS are considered to be highly metastatic and stem cell-like. Biophysical stresses such as FSS are also known to cause the production of extracellular vesicles (EVs) that can facilitate cell–cell communication by carrying biomolecular cargos such as microRNAs. Here, we hypothesized that physiological FSS will impact the yield of EV production, and that these EVs will have biomolecules that transform the recipient cells. The EVs were isolated using direct flow filtration with and without FSS from the MDA-MB-231 cancer cell line, and the expression of key stemness-related genes and microRNAs was characterized. There was a significantly increased yield of EVs under FSS. These EVs also contained significantly increased levels of miR-21, which was previously implicated to promote metastatic progression and chemotherapeutic resistance. When these EVs from FSS were introduced to MCF-7 cancer cells, the recipient cells had a significant increase in their stem-like gene expression and CD44⁺/CD24⁻ cancer stem cell-like subpopulation. There was also a correlated increased proliferation along with an increased ATP production. Together, these findings indicate that the presence of physiological FSS can directly influence the EVs’ production and their contents, and that the EV-mediated transfer of miR-21 can have an important role in FSS-existing contexts, such as in cancer metastasis. Full article

(This article belongs to the Special Issue Advances in Nano-Based Drug Delivery: Unveiling the Next Frontier)

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22 pages, 24995 KiB

Open AccessEditor’s ChoiceArticle

Expression Proteomics and Histone Analysis Reveal Extensive Chromatin Network Changes and a Role for Histone Tail Trimming during Cellular Differentiation

by Giorgio Oliviero, Kieran Wynne, Darrell Andrews, John Crean, Walter Kolch and Gerard Cagney

Biomolecules 2024, 14(7), 747; https://doi.org/10.3390/biom14070747 - 24 Jun 2024

Cited by 2 | Viewed by 2552

Abstract

In order to understand the coordinated proteome changes associated with differentiation of a cultured cell pluripotency model, protein expression changes induced by treatment of NT2 embryonal carcinoma cells with retinoic acid were monitored by mass spectrometry. The relative levels of over 5000 proteins [...] Read more.

In order to understand the coordinated proteome changes associated with differentiation of a cultured cell pluripotency model, protein expression changes induced by treatment of NT2 embryonal carcinoma cells with retinoic acid were monitored by mass spectrometry. The relative levels of over 5000 proteins were mapped across distinct cell fractions. Analysis of the chromatin fraction revealed major abundance changes among chromatin proteins and epigenetic pathways between the pluripotent and differentiated states. Protein complexes associated with epigenetic regulation of gene expression, chromatin remodelling (e.g., SWI/SNF, NuRD) and histone-modifying enzymes (e.g., Polycomb, MLL) were found to be extensively regulated. We therefore investigated histone modifications before and after differentiation, observing changes in the global levels of lysine acetylation and methylation across the four canonical histone protein families, as well as among variant histones. We identified the set of proteins with affinity to peptides housing the histone marks H3K4me3 and H3K27me3, and found increased levels of chromatin-associated histone H3 tail trimming following differentiation that correlated with increased expression levels of cathepsin proteases. We further found that inhibition of cathepsins B and D reduces histone H3 clipping. Overall, the work reveals a global reorganization of the cell proteome congruent with differentiation, highlighting the key role of multiple epigenetic pathways, and demonstrating a direct link between cathepsin B and D activity and histone modification. Full article

(This article belongs to the Section Molecular Biology)

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19 pages, 1670 KiB

Open AccessEditor’s ChoiceReview

Exploring the Link between Varicella-Zoster Virus, Autoimmune Diseases, and the Role of Recombinant Zoster Vaccine

by Ryuhei Ishihara, Ryu Watanabe, Mayu Shiomi, Masao Katsushima, Kazuo Fukumoto, Shinsuke Yamada, Tadashi Okano and Motomu Hashimoto

Biomolecules 2024, 14(7), 739; https://doi.org/10.3390/biom14070739 - 22 Jun 2024

Cited by 6 | Viewed by 5286

Abstract

The varicella-zoster virus (VZV) is a human neurotropic herpes virus responsible for varicella and herpes zoster (HZ). Following primary infection in childhood, VZV manifests as varicella (chickenpox) and enters a period of latency within the dorsal root ganglion. A compromised cellular immune response [...] Read more.

The varicella-zoster virus (VZV) is a human neurotropic herpes virus responsible for varicella and herpes zoster (HZ). Following primary infection in childhood, VZV manifests as varicella (chickenpox) and enters a period of latency within the dorsal root ganglion. A compromised cellular immune response due to aging or immunosuppression triggers viral reactivation and the development of HZ (shingles). Patients with autoimmune diseases have a higher risk of developing HZ owing to the immunodeficiency associated with the disease itself and/or the use of immunosuppressive agents. The introduction of new immunosuppressive agents with unique mechanisms has expanded the treatment options for autoimmune diseases but has also increased the risk of HZ. Specifically, Janus kinase (JAK) inhibitors and anifrolumab have raised concerns regarding HZ. Despite treatment advances, a substantial number of patients suffer from complications such as postherpetic neuralgia for prolonged periods. The adjuvanted recombinant zoster vaccine (RZV) is considered safe and effective even in immunocompromised patients. The widespread adoption of RZV may reduce the health and socioeconomic burdens of HZ patients. This review covers the link between VZV and autoimmune diseases, assesses the risk of HZ associated with immunosuppressant use, and discusses the benefits and risks of using RZV in patients with autoimmune diseases. Full article

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17 pages, 2727 KiB

Open AccessEditor’s ChoiceArticle

Concept of Normativity in Multi-Omics Analysis of Axon Regeneration

by Isabella Moceri, Sean Meehan, Emily Gonzalez, Kevin K. Park, Abigail Hackam, Richard K. Lee and Sanjoy Bhattacharya

Biomolecules 2024, 14(7), 735; https://doi.org/10.3390/biom14070735 - 21 Jun 2024

Cited by 2 | Viewed by 1727

Abstract

Transcriptomes and proteomes can be normalized with a handful of RNAs or proteins (or their peptides), such as GAPDH, β-actin, RPBMS, and/or GAP43. Even with hundreds of standards, normalization cannot be achieved across different molecular mass ranges for small molecules, such as lipids [...] Read more.

Transcriptomes and proteomes can be normalized with a handful of RNAs or proteins (or their peptides), such as GAPDH, β-actin, RPBMS, and/or GAP43. Even with hundreds of standards, normalization cannot be achieved across different molecular mass ranges for small molecules, such as lipids and metabolites, due to the non-linearity of mass by charge ratio for even the smallest part of the spectrum. We define the amount (or range of amounts) of metabolites and/or lipids per a defined amount of a protein, consistently identified in all samples of a multiple-model organism comparison, as the normative level of that metabolite or lipid. The defined protein amount (or range) is a normalized value for one cohort of complete samples for which intrasample relative protein quantification is available. For example, the amount of citrate (a metabolite) per µg of aconitate hydratase (normalized protein amount) identified in the proteome is the normative level of citrate with aconitase. We define normativity as the amount of metabolites (or amount range) detected when compared to normalized protein levels. We use axon regeneration as an example to illustrate the need for advanced approaches to the normalization of proteins. Comparison across different pharmacologically induced axon regeneration mouse models entails the comparison of axon regeneration, studied at different time points in several models designed using different agents. For the normalization of the proteins across different pharmacologically induced models, we perform peptide doping (fixed amounts of known peptides) in each sample to normalize the proteome across the samples. We develop Regen V peptides, divided into Regen III (SEB, LLO, CFP) and II (HH4B, A1315), for pre- and post-extraction comparisons, performed with the addition of defined, digested peptides (bovine serum albumin tryptic digest) for protein abundance normalization beyond commercial labeled relative quantification (for example, 18-plex tandem mass tags). We also illustrate the concept of normativity by using this normalization technique on regenerative metabolome/lipidome profiles. As normalized protein amounts are different in different biological states (control versus axon regeneration), normative metabolite or lipid amounts are expected to be different for specific biological states. These concepts and standardization approaches are important for the integration of different datasets across different models of axon regeneration. Full article

(This article belongs to the Special Issue Advances in Neuroproteomics)

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25 pages, 1930 KiB

Open AccessEditor’s ChoiceReview

Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects

by Jesús I. Gil-Chinchilla, Agustín G. Zapata, Jose M. Moraleda and David García-Bernal

Biomolecules 2024, 14(7), 734; https://doi.org/10.3390/biom14070734 - 21 Jun 2024

Cited by 7 | Viewed by 3635

Abstract

Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit [...] Read more.

Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy. Full article

(This article belongs to the Special Issue Applications of Mesenchymal Stem/Stromal Cells in Immuno-Oncology Therapy and The Priming Ways to Boost Their Functions)

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12 pages, 1884 KiB

Open AccessEditor’s ChoiceArticle

Macrophage Phenotype Induced by Circulating Small Extracellular Vesicles from Women with Endometriosis

by María Angeles Martínez-Zamora, Olga Armengol-Badia, Lara Quintas-Marquès, Francisco Carmona and Daniel Closa

Biomolecules 2024, 14(7), 737; https://doi.org/10.3390/biom14070737 - 21 Jun 2024

Cited by 3 | Viewed by 1994

Abstract

Evidence suggests that immune system dysfunction and macrophages are involved in the disease establishment and progression of endometriosis. Among the factors involved in this alteration in macrophage activity, Small Extracellular Vesicles (sEVs) have been described to play a role favoring the switch to [...] Read more.

Evidence suggests that immune system dysfunction and macrophages are involved in the disease establishment and progression of endometriosis. Among the factors involved in this alteration in macrophage activity, Small Extracellular Vesicles (sEVs) have been described to play a role favoring the switch to a specific phenotype with controversial results. This study aims to investigate the potential effect of circulating sEVs in the plasma of well-characterized patients with endometriosis on the polarization of macrophages. sEVs were isolated from the plasma of patients diagnosed with endometriosis confirmed by histopathological analysis. Two groups of patients were recruited: the endometriosis group consisted of patients diagnosed with endometriosis by imaging testing (gynecological ultrasonography and/or magnetic resonance imaging), confirmed by histopathologic study (n = 12), and the control group included patients who underwent laparoscopy for tubal sterilization without presurgical suspicion of endometriosis and without endometriosis or signs of any inflammatory pelvic condition during surgery (n = 12). Human THP1 monocytic cells were differentiated into macrophages, and the effect of sEVs on cell uptake and macrophage polarization was evaluated by fluorescent labeling and measurement of the IL1B, TNF, ARG1, and MRC1 expression, respectively. Although no changes in cell uptake were detected, sEVs from endometriosis induced a polarization of macrophages toward an M2 phenotype, characterized by lower IL1B and TNF expression and a tendency to increase MRC1 and ARG1 levels. When macrophages were stimulated with lipopolysaccharides, less activation was also detected after treatment with endometriosis sEVs. Finally, endometriosis sEVs also induced the expression of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARG); however, treatment with rosiglitazone, a PPARG agonist, had no effect on the change in macrophage phenotype. We conclude that circulating sEVs in women with endometriosis have a certain capacity to shift the activation state of macrophages toward an M2 phenotype, but this does not modify the uptake level or the response to PPARG ligands. Full article

(This article belongs to the Topic The Role of Extracellular Vesicles as Modulators of the Tumor Microenvironment)

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25 pages, 2521 KiB

Open AccessEditor’s ChoiceReview

New Insights into the Role of PPARγ in Skin Physiopathology

by Stefania Briganti, Sarah Mosca, Anna Di Nardo, Enrica Flori and Monica Ottaviani

Biomolecules 2024, 14(6), 728; https://doi.org/10.3390/biom14060728 - 19 Jun 2024

Cited by 15 | Viewed by 4144

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for [...] Read more.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor expressed in many tissues, including skin, where it is essential for maintaining skin barrier permeability, regulating cell proliferation/differentiation, and modulating antioxidant and inflammatory responses upon ligand binding. Therefore, PPARγ activation has important implications for skin homeostasis. Over the past 20 years, with increasing interest in the role of PPARs in skin physiopathology, considerable effort has been devoted to the development of PPARγ ligands as a therapeutic option for skin inflammatory disorders. In addition, PPARγ also regulates sebocyte differentiation and lipid production, making it a potential target for inflammatory sebaceous disorders such as acne. A large number of studies suggest that PPARγ also acts as a skin tumor suppressor in both melanoma and non-melanoma skin cancers, but its role in tumorigenesis remains controversial. In this review, we have summarized the current state of research into the role of PPARγ in skin health and disease and how this may provide a starting point for the development of more potent and selective PPARγ ligands with a low toxicity profile, thereby reducing unwanted side effects. Full article

(This article belongs to the Special Issue Peroxisome Proliferator-Activated Receptors (PPARs): A Themed Issue in Honor of Prof. Walter Wahli)

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15 pages, 3824 KiB

Open AccessEditor’s ChoiceArticle

The Structural Basis of the Activity Cliff in Modafinil-Based Dopamine Transporter Inhibitors

by Kuo-Hao Lee, Gisela Andrea Camacho-Hernandez, Amy Hauck Newman and Lei Shi

Biomolecules 2024, 14(6), 713; https://doi.org/10.3390/biom14060713 - 17 Jun 2024

Cited by 2 | Viewed by 2354

Abstract

Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is [...] Read more.

Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT. Full article

(This article belongs to the Collection Molecular Biology: Feature Papers)

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25 pages, 501 KiB

Open AccessEditor’s ChoiceReview

The Role of Zinc in Developed Countries in Pediatric Patients: A 360-Degree View

by Flavia Padoan, Elena Piccoli, Angelo Pietrobelli, Luis A. Moreno, Giorgio Piacentini and Luca Pecoraro

Biomolecules 2024, 14(6), 718; https://doi.org/10.3390/biom14060718 - 17 Jun 2024

Cited by 3 | Viewed by 3597

Abstract

Zinc is an important trace element for growth and health at pediatric ages. Zinc is fundamental in inflammatory pathways, oxidative balance, and immune function. Zinc exhibits anti-inflammatory properties by modulating Nuclear Factor-kappa (NF-κB) activity and reducing histamine release from basophils, leukocytes, and mast [...] Read more.

Zinc is an important trace element for growth and health at pediatric ages. Zinc is fundamental in inflammatory pathways, oxidative balance, and immune function. Zinc exhibits anti-inflammatory properties by modulating Nuclear Factor-kappa (NF-κB) activity and reducing histamine release from basophils, leukocytes, and mast cells. Furthermore, its antioxidant activity protects against oxidative damage and chronic diseases. Finally, zinc improves the ability to trigger effective immune responses against pathogens by contributing to the maturation of lymphocytes, the production of cytokines, and the regulation of apoptosis. Given these properties, zinc can be considered an adjunctive therapy in treating and preventing respiratory, nephrological, and gastrointestinal diseases, both acute and chronic. This review aims to deepen the role and metabolism of zinc, focusing on the role of supplementation in developed countries in pediatric diseases. Full article

(This article belongs to the Special Issue Zinc in Health and Disease Conditions: 2nd Edition)

18 pages, 2574 KiB

Open AccessEditor’s ChoiceArticle

Aromatic Characterisation of Moscato Giallo by GC-MS/MS and Validation of Stable Isotopic Ratio Analysis of the Major Volatile Compounds

by Mauro Paolini, Alberto Roncone, Lorenzo Cucinotta, Danilo Sciarrone, Luigi Mondello, Federica Camin, Sergio Moser, Roberto Larcher and Luana Bontempo

Biomolecules 2024, 14(6), 710; https://doi.org/10.3390/biom14060710 - 16 Jun 2024

Cited by 4 | Viewed by 2048

Abstract

Among the Moscato grapes, Moscato Giallo is a winegrape variety characterised by a high content of free and glycosylated monoterpenoids, which gives wines very intense notes of ripe fruit and flowers. The aromatic bouquet of Moscato Giallo is strongly influenced by the high [...] Read more.

Among the Moscato grapes, Moscato Giallo is a winegrape variety characterised by a high content of free and glycosylated monoterpenoids, which gives wines very intense notes of ripe fruit and flowers. The aromatic bouquet of Moscato Giallo is strongly influenced by the high concentration of linalool, geraniol, linalool oxides, limonene, α-terpineol, citronellol, hotrienol, diendiols, trans/cis-8-hydroxy linalool, geranic acid and myrcene, that give citrus, rose, and peach notes. Except for quali-quantitative analysis, no investigations regarding the isotopic values of the target volatile compounds in grapes and wines are documented in the literature. Nevertheless, the analysis of the stable isotope ratio represents a modern and powerful tool used by the laboratories responsible for official consumer protection, for food quality and genuineness assessment. To this aim, the aromatic compounds extracted from grapes and wine were analysed both by GC-MS/MS, to define the aroma profiles, and by GC-C/Py-IRMS, for a preliminary isotope compound-specific investigation. Seventeen samples of Moscato Giallo grapes were collected during the harvest season in 2021 from two Italian regions renowned for the cultivation of this aromatic variety, Trentino Alto Adige and Veneto, and the corresponding wines were produced at micro-winery scale. The GC-MS/MS analysis confirmed the presence of the typical terpenoids both in glycosylated and free forms, responsible for the characteristic aroma of the Moscato Giallo variety, while the compound-specific isotope ratio analysis allowed us to determine the carbon (δ¹³C) and hydrogen (δ²H) isotopic signatures of the major volatile compounds for the first time. Full article

(This article belongs to the Special Issue 2nd Edition: Biochemistry of Wine and Beer)

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26 pages, 4510 KiB

Open AccessEditor’s ChoiceReview

Paradoxes: Cholesterol and Hypoxia in Preeclampsia

by Nancy R. Hart

Biomolecules 2024, 14(6), 691; https://doi.org/10.3390/biom14060691 - 13 Jun 2024

Cited by 9 | Viewed by 2469

Abstract

Preeclampsia, a hypertensive disease of pregnancy of unknown etiology, is intensely studied as a model of cardiovascular disease (CVD) not only due to multiple shared pathologic elements but also because changes that develop over decades in CVD appear and resolve within days in [...] Read more.

Preeclampsia, a hypertensive disease of pregnancy of unknown etiology, is intensely studied as a model of cardiovascular disease (CVD) not only due to multiple shared pathologic elements but also because changes that develop over decades in CVD appear and resolve within days in preeclampsia. Those affected by preeclampsia and their offspring experience increased lifetime risks of CVD. At the systemic level, preeclampsia is characterized by increased cellular, membrane, and blood levels of cholesterol; however, cholesterol-dependent signaling, such as canonical Wnt/βcatenin, Hedgehog, and endothelial nitric oxide synthase, is downregulated indicating a cholesterol deficit with the upregulation of cholesterol synthesis and efflux. Hypoxia-related signaling in preeclampsia also appears to be paradoxical with increased Hypoxia-Inducible Factors in the placenta but measurably increased oxygen in maternal blood in placental villous spaces. This review addresses the molecular mechanisms by which excessive systemic cholesterol and deficient cholesterol-dependent signaling may arise from the effects of dietary lipid variance and environmental membrane modifiers causing the cellular hypoxia that characterizes preeclampsia. Full article

(This article belongs to the Special Issue Lipids Metabolism in Cardiovascular Disease)

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14 pages, 2204 KiB

Open AccessEditor’s ChoiceArticle

Haloperidol, Olanzapine, and Risperidone Induce Morphological Changes in an In Vitro Model of Human Hippocampal Neurogenesis

by Bálint Jezsó, Sára Kálmán, Kiara Gitta Farkas, Edit Hathy, Katalin Vincze, Dzsenifer Kovács-Schoblocher, Julianna Lilienberg, Csongor Tordai, Zsófia Nemoda, László Homolya, Ágota Apáti and János M. Réthelyi

Biomolecules 2024, 14(6), 688; https://doi.org/10.3390/biom14060688 - 13 Jun 2024

Cited by 2 | Viewed by 2133

Abstract

Background: Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs). Methods: Proliferation and [...] Read more.

Background: Induced pluripotent stem cell (iPSC) based neuronal differentiation is valuable for studying neuropsychiatric disorders and pharmacological mechanisms at the cellular level. We aimed to examine the effects of typical and atypical antipsychotics on human iPSC-derived neural progenitor cells (NPCs). Methods: Proliferation and neurite outgrowth were measured by live cell imaging, and gene expression levels related to neuronal identity were analyzed by RT-QPCR and immunocytochemistry during differentiation into hippocampal dentate gyrus granule cells following treatment of low- and high-dose antipsychotics (haloperidol, olanzapine, and risperidone). Results: Antipsychotics did not modify the growth properties of NPCs after 3 days of treatment. However, the characteristics of neurite outgrowth changed significantly in response to haloperidol and olanzapine. After three weeks of differentiation, mRNA expression levels of the selected neuronal markers increased (except for MAP2), while antipsychotics caused only subtle changes. Additionally, we found no changes in MAP2 or GFAP protein expression levels as a result of antipsychotic treatment. Conclusions: Altogether, antipsychotic medications promoted neurogenesis in vitro by influencing neurite outgrowth rather than changing cell survival or gene expression. This study provides insights into the effects of antipsychotics on neuronal differentiation and highlights the importance of considering neurite outgrowth as a potential target of action. Full article

(This article belongs to the Special Issue Molecular Insights into the Mechanism of Antipsychotic Drugs)

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15 pages, 1033 KiB

Open AccessEditor’s ChoiceReview

Implications of GLP-1 Receptor Agonist on Thyroid Function: A Literature Review of Its Effects on Thyroid Volume, Risk of Cancer, Functionality and TSH Levels

by Stefania Capuccio, Sabrina Scilletta, Francesca La Rocca, Nicoletta Miano, Maurizio Di Marco, Giosiana Bosco, Francesco Di Giacomo Barbagallo, Roberto Scicali, Salvatore Piro and Antonino Di Pino

Biomolecules 2024, 14(6), 687; https://doi.org/10.3390/biom14060687 - 13 Jun 2024

Cited by 13 | Viewed by 5981

Abstract

The increasing utilization of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in managing type 2 diabetes mellitus has raised interest regarding their impact on thyroid function. In fact, while these agents are well known for their efficacy in glycemic control and weight management, their [...] Read more.

The increasing utilization of Glucagon-like Peptide-1 receptor agonists (GLP-1 RAs) in managing type 2 diabetes mellitus has raised interest regarding their impact on thyroid function. In fact, while these agents are well known for their efficacy in glycemic control and weight management, their association with thyroid disorders requires clarification due to the complex interplay between thyroid hormones and metabolic pathways. Thyroid dysfunction commonly co-occurs with metabolic conditions such as diabetes and obesity, suggesting a profound interconnection between these systems. This review aims to contribute to a deeper understanding of the interaction between GLP-1 RAs and thyroid dysfunction and to clarify the safety of GLP-1 RAs in diabetic patients with thyroid disorders. By synthesizing existing evidence, this review highlights that, despite various studies exploring this topic, current evidence is inconclusive, with conflicting results. It is important to note that these drugs are relatively recent, and longer-term studies with larger sample sizes are likely needed to draw clearer conclusions. Currently, no existing guidelines provide definitive directions on this clinical issue; however, it is advisable to include thyroid function tests in the routine screening of diabetic patients, particularly those treated with GLP-1 Ras, with the goal of optimizing patient care and management. Full article

(This article belongs to the Special Issue New Insights into Mechanisms and Therapeutics for Cardiovascular Disorders)

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37 pages, 9291 KiB

Open AccessEditor’s ChoiceArticle

New Heterostilbene and Triazole Oximes as Potential CNS-Active and Cholinesterase-Targeted Therapeutics

by Milena Mlakić, Tena Čadež, Goran Šinko, Irena Škorić and Zrinka Kovarik

Biomolecules 2024, 14(6), 679; https://doi.org/10.3390/biom14060679 - 11 Jun 2024

Viewed by 1971

Abstract

New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite [...] Read more.

New furan, thiophene, and triazole oximes were synthesized through several-step reaction paths to investigate their potential for the development of central nervous systems (CNS)-active and cholinesterase-targeted therapeutics in organophosphorus compound (OP) poisonings. Treating patients with acute OP poisoning is still a challenge despite the development of a large number of oxime compounds that should have the capacity to reactivate acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The activity of these two enzymes, crucial for neurotransmission, is blocked by OP, which has the consequence of disturbing normal cholinergic nerve signal transduction in the peripheral and CNS, leading to a cholinergic crisis. The oximes in use have one or two pyridinium rings and cross the brain–blood barrier poorly due to the quaternary nitrogen. Following our recent study on 2-thienostilbene oximes, in this paper, we described the synthesis of 63 heterostilbene derivatives, of which 26 oximes were tested as inhibitors and reactivators of AChE and BChE inhibited by OP nerve agents–sarin and cyclosarin. While the majority of oximes were potent inhibitors of both enzymes in the micromolar range, we identified several oximes as BChE or AChE selective inhibitors with the potential for drug development. Furthermore, the oximes were poor reactivators of AChE; four heterocyclic derivatives reactivated cyclosarin-inhibited BChE up to 70%, and cis,trans-5 [2-((Z)-2-(5-((E)-(hydroxyimino)methyl)thiophen-2-yl)vinyl)benzonitrile] had a reactivation efficacy comparable to the standard oxime HI-6. In silico analysis and molecular docking studies, including molecular dynamics simulation, connected kinetic data to the structural features of these oximes and confirmed their productive interactions with the active site of cyclosarin-inhibited BChE. Based on inhibition and reactivation and their ADMET properties regarding lipophilicity, CNS activity, and hepatotoxicity, these compounds could be considered for further development of CNS-active reactivators in OP poisoning as well as cholinesterase-targeted therapeutics in neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Full article

(This article belongs to the Special Issue The Role of Cholinesterases in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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15 pages, 1446 KiB

Open AccessEditor’s ChoiceArticle

Perimenopause Decreases SERCA2a Activity in the Hearts of a Mouse Model of Ovarian Failure

by Ciara Barry, Sarah Rouhana, Jessica L. Braun, Mia S. Geromella, Val A. Fajardo and W. Glen Pyle

Biomolecules 2024, 14(6), 675; https://doi.org/10.3390/biom14060675 - 9 Jun 2024

Cited by 3 | Viewed by 2325

Abstract

Risk of cardiovascular disease mortality rises in women after menopause. While increased cardiovascular risk is largely attributed to postmenopausal declines in estrogens, the molecular changes in the heart that contribute to risk are poorly understood. Disruptions in intracellular calcium handling develop in ovariectomized [...] Read more.

Risk of cardiovascular disease mortality rises in women after menopause. While increased cardiovascular risk is largely attributed to postmenopausal declines in estrogens, the molecular changes in the heart that contribute to risk are poorly understood. Disruptions in intracellular calcium handling develop in ovariectomized mice and have been implicated in cardiac dysfunction. Using a mouse model of menopause in which ovarian failure occurs over 120 days, we sought to determine if perimenopause impacted calcium removal mechanisms in the heart and identify the molecular mechanisms. Mice were injected with 4-vinylcyclohexene diepoxide (VCD) to induce ovarian failure over 120 days, mimicking perimenopause. Hearts were removed at 60 and 120 days after VCD injections, representing the middle and end of perimenopause. SERCA2a function was significantly diminished at the end of perimenopause. Neither SERCA2a nor phospholamban expression changed at either time point, but phospholamban phosphorylation at S16 and T17 was dynamically altered. Intrinsic SERCA inhibitors sarcolipin and myoregulin increased >4-fold at day 60, as did the native activator DWORF. At the end of perimenopause, sarcolipin and myoregulin returned to baseline levels while DWORF was significantly reduced below controls. Sodium–calcium exchanger expression was significantly increased at the end of perimenopause. These results show that the foundation for increased cardiovascular disease mortality develops in the heart during perimenopause and that regulators of calcium handling exhibit significant fluctuations over time. Understanding the temporal development of cardiovascular risk associated with menopause and the underlying mechanisms is critical to developing interventions that mitigate the rise in cardiovascular mortality that arises after menopause. Full article

(This article belongs to the Special Issue Heart Diseases: Molecular Mechanisms and New Therapies)

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18 pages, 336 KiB

Open AccessEditor’s ChoiceReview

Molecular Genetics of Acquired Temporal Lobe Epilepsy

by Anne-Marie Neumann and Stefan Britsch

Biomolecules 2024, 14(6), 669; https://doi.org/10.3390/biom14060669 - 7 Jun 2024

Cited by 3 | Viewed by 2319

Abstract

An epilepsy diagnosis reduces a patient’s quality of life tremendously, and it is a fate shared by over 50 million people worldwide. Temporal lobe epilepsy (TLE) is largely considered a nongenetic or acquired form of epilepsy that develops in consequence of neuronal trauma [...] Read more.

An epilepsy diagnosis reduces a patient’s quality of life tremendously, and it is a fate shared by over 50 million people worldwide. Temporal lobe epilepsy (TLE) is largely considered a nongenetic or acquired form of epilepsy that develops in consequence of neuronal trauma by injury, malformations, inflammation, or a prolonged (febrile) seizure. Although extensive research has been conducted to understand the process of epileptogenesis, a therapeutic approach to stop its manifestation or to reliably cure the disease has yet to be developed. In this review, we briefly summarize the current literature predominately based on data from excitotoxic rodent models on the cellular events proposed to drive epileptogenesis and thoroughly discuss the major molecular pathways involved, with a focus on neurogenesis-related processes and transcription factors. Furthermore, recent investigations emphasized the role of the genetic background for the acquisition of epilepsy, including variants of neurodevelopmental genes. Mutations in associated transcription factors may have the potential to innately increase the vulnerability of the hippocampus to develop epilepsy following an injury—an emerging perspective on the epileptogenic process in acquired forms of epilepsy. Full article

(This article belongs to the Special Issue New Insight into the Molecular Genetics of Neurodevelopmental Disorders)

18 pages, 3012 KiB

Open AccessEditor’s ChoiceArticle

Smoking-Induced DNA Hydroxymethylation Signature Is Less Pronounced than True DNA Methylation: The Population-Based KORA Fit Cohort

by Liye Lai, Pamela R. Matías-García, Anja Kretschmer, Christian Gieger, Rory Wilson, Jakob Linseisen, Annette Peters and Melanie Waldenberger

Biomolecules 2024, 14(6), 662; https://doi.org/10.3390/biom14060662 - 5 Jun 2024

Cited by 1 | Viewed by 1850

Abstract

Despite extensive research on 5-methylcytosine (5mC) in relation to smoking, there has been limited exploration into the interaction between smoking and 5-hydroxymethylcytosine (5hmC). In this study, total DNA methylation (5mC+5hmC), true DNA methylation (5mC) and hydroxymethylation (5hmC) levels were profiled utilizing conventional bisulphite [...] Read more.

Despite extensive research on 5-methylcytosine (5mC) in relation to smoking, there has been limited exploration into the interaction between smoking and 5-hydroxymethylcytosine (5hmC). In this study, total DNA methylation (5mC+5hmC), true DNA methylation (5mC) and hydroxymethylation (5hmC) levels were profiled utilizing conventional bisulphite (BS) and oxidative bisulphite (oxBS) treatment, measured with the Illumina Infinium Methylation EPIC BeadChip. An epigenome-wide association study (EWAS) of 5mC+5hmC methylation revealed a total of 38,575 differentially methylated positions (DMPs) and 2023 differentially methylated regions (DMRs) associated with current smoking, along with 82 DMPs and 76 DMRs associated with former smoking (FDR-adjusted p < 0.05). Additionally, a focused examination of 5mC identified 33 DMPs linked to current smoking and 1 DMP associated with former smoking (FDR-adjusted p < 0.05). In the 5hmC category, eight DMPs related to current smoking and two DMPs tied to former smoking were identified, each meeting a suggestive threshold (p < 1 × 10⁻⁵). The substantial number of recognized DMPs, including 5mC+5hmC (7069/38,575, 2/82), 5mC (0/33, 1/1), and 5hmC (2/8, 0/2), have not been previously reported. Our findings corroborated previously established methylation positions and revealed novel candidates linked to tobacco smoking. Moreover, the identification of hydroxymethylated CpG sites with suggestive links provides avenues for future research. Full article

(This article belongs to the Special Issue DNA Methylation in Human Diseases)

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19 pages, 5414 KiB

Open AccessEditor’s ChoiceArticle

Application of Graph Models to the Identification of Transcriptomic Oncometabolic Pathways in Human Hepatocellular Carcinoma

by Sergio Barace, Eva Santamaría, Stefany Infante, Sara Arcelus, Jesus De La Fuente, Enrique Goñi, Ibon Tamayo, Idoia Ochoa, Miguel Sogbe, Bruno Sangro, Mikel Hernaez, Matias A. Avila and Josepmaria Argemi

Biomolecules 2024, 14(6), 653; https://doi.org/10.3390/biom14060653 - 3 Jun 2024

Cited by 2 | Viewed by 1834

Abstract

Whole-tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly [...] Read more.

Whole-tissue transcriptomic analyses have been helpful to characterize molecular subtypes of hepatocellular carcinoma (HCC). Metabolic subtypes of human HCC have been defined, yet whether these different metabolic classes are clinically relevant or derive in actionable cancer vulnerabilities is still an unanswered question. Publicly available gene sets or gene signatures have been used to infer functional changes through gene set enrichment methods. However, metabolism-related gene signatures are poorly co-expressed when applied to a biological context. Here, we apply a simple method to infer highly consistent signatures using graph-based statistics. Using the Cancer Genome Atlas Liver Hepatocellular cohort (LIHC), we describe the main metabolic clusters and their relationship with commonly used molecular classes, and with the presence of TP53 or CTNNB1 driver mutations. We find similar results in our validation cohort, the LIRI-JP cohort. We describe how previously described metabolic subtypes could not have therapeutic relevance due to their overall downregulation when compared to non-tumoral liver, and identify N-glycan, mevalonate and sphingolipid biosynthetic pathways as the hallmark of the oncogenic shift of the use of acetyl-coenzyme A in HCC metabolism. Finally, using DepMap data, we demonstrate metabolic vulnerabilities in HCC cell lines. Full article

(This article belongs to the Special Issue Signal Transduction to Transcription Factors in Health and Disease—Honorary Special Issue Commemorating the Work of Prof. Athanasios G. Papavassiliou)

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11 pages, 249 KiB

Open AccessEditor’s ChoiceReview

Schnitzler Syndrome: Insights into Its Pathogenesis, Clinical Manifestations, and Current Management

by Antoine Braud and Dan Lipsker

Biomolecules 2024, 14(6), 646; https://doi.org/10.3390/biom14060646 - 31 May 2024

Cited by 6 | Viewed by 2854

Abstract

Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash associated with immunoglobulin M (IgM) monoclonal gammopathy. Schnitzler syndrome shares strong clinicopathologic similarities with monogenic IL-1-mediated autoinflammatory disorders and is now considered an acquired adult-onset autoinflammatory disease. The spectacular effect of [...] Read more.

Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash associated with immunoglobulin M (IgM) monoclonal gammopathy. Schnitzler syndrome shares strong clinicopathologic similarities with monogenic IL-1-mediated autoinflammatory disorders and is now considered an acquired adult-onset autoinflammatory disease. The spectacular effect of interleukin-1 inhibitors demonstrates the key role of this cytokine in the pathogenesis of the disease. However, the physiopathology of Schnitzler syndrome remains elusive, and the main question regarding the relationship between autoinflammatory features and monoclonal gammopathy is still unanswered. The purpose of this narrative review is to describe what is currently known about the pathogenesis of this peculiar disease, as well as to address its diagnosis and management. Full article

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

12 pages, 1208 KiB

Open AccessEditor’s ChoiceReview

Duckweed: Beyond an Efficient Plant Model System

by Doni Thingujam, Karolina M. Pajerowska-Mukhtar and M. Shahid Mukhtar

Biomolecules 2024, 14(6), 628; https://doi.org/10.3390/biom14060628 - 27 May 2024

Cited by 9 | Viewed by 5110

Abstract

Duckweed (Lemnaceae) rises as a crucial model system due to its unique characteristics and wide-ranging utility. The significance of physiological research and phytoremediation highlights the intricate potential of duckweed in the current era of plant biology. Special attention to duckweed has [...] Read more.

Duckweed (Lemnaceae) rises as a crucial model system due to its unique characteristics and wide-ranging utility. The significance of physiological research and phytoremediation highlights the intricate potential of duckweed in the current era of plant biology. Special attention to duckweed has been brought due to its distinctive features of nutrient uptake, ion transport dynamics, detoxification, intricate signaling, and stress tolerance. In addition, duckweed can alleviate environmental pollutants and enhance sustainability by participating in bioremediation processes and wastewater treatment. Furthermore, insights into the genomic complexity of Lemnaceae species and the flourishing field of transgenic development highlight the opportunities for genetic manipulation and biotechnological innovations. Novel methods for the germplasm conservation of duckweed can be adopted to preserve genetic diversity for future research endeavors and breeding programs. This review centers around prospects in duckweed research promoting interdisciplinary collaborations and technological advancements to drive its full potential as a model organism. Full article

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23 pages, 6190 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Functional Significance of High Cysteine Content in Eye Lens γ-Crystallins

by Eugene Serebryany, Rachel W. Martin and Gemma R. Takahashi

Biomolecules 2024, 14(5), 594; https://doi.org/10.3390/biom14050594 - 17 May 2024

Cited by 4 | Viewed by 3103

Abstract

Cataract disease is strongly associated with progressively accumulating oxidative damage to the extremely long-lived crystallin proteins of the lens. Cysteine oxidation affects crystallin folding, interactions, and light-scattering aggregation especially strongly due to the formation of disulfide bridges. Minimizing crystallin aggregation is crucial for [...] Read more.

Cataract disease is strongly associated with progressively accumulating oxidative damage to the extremely long-lived crystallin proteins of the lens. Cysteine oxidation affects crystallin folding, interactions, and light-scattering aggregation especially strongly due to the formation of disulfide bridges. Minimizing crystallin aggregation is crucial for lifelong lens transparency, so one might expect the ubiquitous lens crystallin superfamilies (α and βγ) to contain little cysteine. Yet, the Cys content of γ-crystallins is well above the average for human proteins. We review literature relevant to this longstanding puzzle and take advantage of expanding genomic databases and improved machine learning tools for protein structure prediction to investigate it further. We observe remarkably low Cys conservation in the βγ-crystallin superfamily; however, in γ-crystallin, the spatial positioning of Cys residues is clearly fine-tuned by evolution. We propose that the requirements of long-term lens transparency and high lens optical power impose competing evolutionary pressures on lens βγ-crystallins, leading to distinct adaptations: high Cys content in γ-crystallins but low in βB-crystallins. Aquatic species need more powerful lenses than terrestrial ones, which explains the high methionine content of many fish γ- (and even β-) crystallins. Finally, we discuss synergies between sulfur-containing and aromatic residues in crystallins and suggest future experimental directions. Full article

(This article belongs to the Special Issue Physiological and Pathological Functions of Crystallins)

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24 pages, 2029 KiB

Open AccessEditor’s ChoiceReview

Oncogenic Pathways and Targeted Therapies in Ovarian Cancer

by Carolina Lliberos, Gary Richardson and Antonella Papa

Biomolecules 2024, 14(5), 585; https://doi.org/10.3390/biom14050585 - 15 May 2024

Cited by 15 | Viewed by 4306

Abstract

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. [...] Read more.

Epithelial ovarian cancer (EOC) is one of the most aggressive forms of gynaecological malignancies. Survival rates for women diagnosed with OC remain poor as most patients are diagnosed with advanced disease. Debulking surgery and platinum-based therapies are the current mainstay for OC treatment. However, and despite achieving initial remission, a significant portion of patients will relapse because of innate and acquired resistance, at which point the disease is considered incurable. In view of this, novel detection strategies and therapeutic approaches are needed to improve outcomes and survival of OC patients. In this review, we summarize our current knowledge of the genetic landscape and molecular pathways underpinning OC and its many subtypes. By examining therapeutic strategies explored in preclinical and clinical settings, we highlight the importance of decoding how single and convergent genetic alterations co-exist and drive OC progression and resistance to current treatments. We also propose that core signalling pathways such as the PI3K and MAPK pathways play critical roles in the origin of diverse OC subtypes and can become new targets in combination with known DNA damage repair pathways for the development of tailored and more effective anti-cancer treatments. Full article

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23 pages, 1045 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Risk and Resilience Variants in the Retinoic Acid Metabolic and Developmental Pathways Associated with Risk of FASD Outcomes

by Leo McKay, Berardino Petrelli, Molly Pind, James N. Reynolds, Richard F. Wintle, Albert E. Chudley, Britt Drögemöller, Abraham Fainsod, Stephen W. Scherer, Ana Hanlon-Dearman and Geoffrey G. Hicks

Biomolecules 2024, 14(5), 569; https://doi.org/10.3390/biom14050569 - 10 May 2024

Cited by 1 | Viewed by 2153

Abstract

Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or [...] Read more.

Fetal Alcohol Spectrum Disorder (FASD) is a common neurodevelopmental disorder that affects an estimated 2–5% of North Americans. FASD is induced by prenatal alcohol exposure (PAE) during pregnancy and while there is a clear genetic contribution, few genetic factors are currently identified or understood. In this study, using a candidate gene approach, we performed a genetic variant analysis of retinoic acid (RA) metabolic and developmental signaling pathway genes on whole exome sequencing data of 23 FASD-diagnosed individuals. We found risk and resilience alleles in ADH and ALDH genes known to normally be involved in alcohol detoxification at the expense of RA production, causing RA deficiency, following PAE. Risk and resilience variants were also identified in RA-regulated developmental pathway genes, especially in SHH and WNT pathways. Notably, we also identified significant variants in the causative genes of rare neurodevelopmental disorders sharing comorbidities with FASD, including STRA6 (Matthew–Wood), SOX9 (Campomelic Dysplasia), FDG1 (Aarskog), and 22q11.2 deletion syndrome (TBX1). Although this is a small exploratory study, the findings support PAE-induced RA deficiency as a major etiology underlying FASD and suggest risk and resilience variants may be suitable biomarkers to determine the risk of FASD outcomes following PAE. Full article

(This article belongs to the Special Issue New Insight into the Molecular Genetics of Neurodevelopmental Disorders)

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23 pages, 4279 KiB

Open AccessEditor’s ChoiceArticle

Disruption of Transmembrane Phosphatidylserine Asymmetry by HIV-1 Incorporated SERINC5 Is Not Responsible for Virus Restriction

by Gokul Raghunath, Elizabeth H. Abbott, Mariana Marin, Hui Wu, Judith Mary Reyes Ballista, Melinda A. Brindley and Gregory B. Melikyan

Biomolecules 2024, 14(5), 570; https://doi.org/10.3390/biom14050570 - 10 May 2024

Cited by 3 | Viewed by 1779

Abstract

Host restriction factor SERINC5 (SER5) incorporates into the HIV-1 membrane and inhibits infectivity by a poorly understood mechanism. Recently, SER5 was found to exhibit scramblase-like activity leading to the externalization of phosphatidylserine (PS) on the viral surface, which has been proposed to be [...] Read more.

Host restriction factor SERINC5 (SER5) incorporates into the HIV-1 membrane and inhibits infectivity by a poorly understood mechanism. Recently, SER5 was found to exhibit scramblase-like activity leading to the externalization of phosphatidylserine (PS) on the viral surface, which has been proposed to be responsible for SER5’s antiviral activity. This and other reports that document modulation of HIV-1 infectivity by viral lipid composition prompted us to investigate the role of PS in regulating SER5-mediated HIV-1 restriction. First, we show that the level of SER5 incorporation into virions correlates with an increase in PS levels in the outer leaflet of the viral membrane. We developed an assay to estimate the PS distribution across the viral membrane and found that SER5, but not SER2, which lacks antiviral activity, abrogates PS asymmetry by externalizing this lipid. Second, SER5 incorporation diminished the infectivity of pseudoviruses produced from cells lacking a flippase subunit CDC50a and, therefore, exhibited a higher baseline level of surface-accessible PS. Finally, exogenous manipulation of the viral PS levels utilizing methyl-alpha-cyclodextrin revealed a lack of correlation between external PS and virion infectivity. Taken together, our study implies that the increased PS exposure to SER5-containing virions itself is not directly linked to HIV-1 restriction. Full article

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12 pages, 1148 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Synthesis of the Antimicrobial Peptide Murepavadin Using Novel Coupling Agents

by Júlia García-Gros, Yolanda Cajal, Ana Maria Marqués and Francesc Rabanal

Biomolecules 2024, 14(5), 526; https://doi.org/10.3390/biom14050526 - 27 Apr 2024

Cited by 2 | Viewed by 3555

Abstract

The problem of antimicrobial resistance is becoming a daunting challenge for human society and healthcare systems around the world. Hence, there is a constant need to develop new antibiotics to fight resistant bacteria, among other important social and economic measures. In this regard, [...] Read more.

The problem of antimicrobial resistance is becoming a daunting challenge for human society and healthcare systems around the world. Hence, there is a constant need to develop new antibiotics to fight resistant bacteria, among other important social and economic measures. In this regard, murepavadin is a cyclic antibacterial peptide in development. The synthesis of murepavadin was undertaken in order to optimize the preparative protocol and scale-up, in particular, the use of new activation reagents. In our hands, classical approaches using carbodiimide/hydroxybenzotriazole rendered low yields. The use of novel carbodiimide and reagents based on OxymaPure^® and Oxy-B is discussed together with the proper use of chromatographic conditions for the adequate characterization of peptide crudes. Higher yields and purities were obtained. Finally, the antimicrobial activity of different synthetic batches was tested in three Pseudomonas aeruginosa strains, including highly resistant ones. All murepavadin batches yielded the same highly active MIC values and proved that the chiral integrity of the molecule was preserved throughout the whole synthetic procedure. Full article

(This article belongs to the Special Issue Development, Characterization, and Application of Bioactive Peptides, Diagnostic Biomarkers, and Pharmaceutical Proteins)

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14 pages, 2485 KiB

Open AccessEditor’s ChoiceReview

Caspase-5: Structure, Pro-Inflammatory Activity and Evolution

by Leopold Eckhart and Heinz Fischer

Biomolecules 2024, 14(5), 520; https://doi.org/10.3390/biom14050520 - 26 Apr 2024

Cited by 5 | Viewed by 2970

Abstract

Caspase-5 is a protease that induces inflammation in response to lipopolysaccharide (LPS), a component of the cell envelope of Gram-negative bacteria. The expression level of the CASP5 gene is very low in the basal state, but strongly increases in the presence of LPS. [...] Read more.

Caspase-5 is a protease that induces inflammation in response to lipopolysaccharide (LPS), a component of the cell envelope of Gram-negative bacteria. The expression level of the CASP5 gene is very low in the basal state, but strongly increases in the presence of LPS. Intracellular LPS binds to the caspase activation and recruitment domain (CARD) of caspase-5, leading to the formation of a non-canonical inflammasome. Subsequently, the catalytic domain of caspase-5 cleaves gasdermin D and thereby facilitates the formation of cell membrane pores through which pro-inflammatory cytokines of the interleukin-1 family are released. Caspase-4 is also able to form a non-canonical inflammasome upon binding to LPS, but its expression is less dependent on LPS than the expression of caspase-5. Caspase-4 and caspase-5 have evolved via the duplication of a single ancestral gene in a subclade of primates, including humans. Notably, the main biomedical model species, the mouse, has only one ortholog, namely caspase-11. Here, we review the structural features and the mechanisms of regulation that are important for the pro-inflammatory roles of caspase-5. We summarize the interspecies differences and the evolution of pro-inflammatory caspases in mammals and discuss the potential roles of caspase-5 in the defense against Gram-negative bacteria and in sepsis. Full article

(This article belongs to the Section Cellular Biochemistry)

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18 pages, 806 KiB

Open AccessEditor’s ChoiceReview

The Exploitation of the Glycosylation Pattern in Asthma: How We Alter Ancestral Pathways to Develop New Treatments

by Angelika Muchowicz, Agnieszka Bartoszewicz and Zbigniew Zaslona

Biomolecules 2024, 14(5), 513; https://doi.org/10.3390/biom14050513 - 24 Apr 2024

Cited by 4 | Viewed by 2359

Abstract

Asthma has reached epidemic levels, yet progress in developing specific therapies is slow. One of the main reasons for this is the fact that asthma is an umbrella term for various distinct subsets. Due to its high heterogeneity, it is difficult to establish [...] Read more.

Asthma has reached epidemic levels, yet progress in developing specific therapies is slow. One of the main reasons for this is the fact that asthma is an umbrella term for various distinct subsets. Due to its high heterogeneity, it is difficult to establish biomarkers for each subset of asthma and to propose endotype-specific treatments. This review focuses on protein glycosylation as a process activated in asthma and ways to utilize it to develop novel biomarkers and treatments. We discuss known and relevant glycoproteins whose functions control disease development. The key role of glycoproteins in processes integral to asthma, such as inflammation, tissue remodeling, and repair, justifies our interest and research in the field of glycobiology. Altering the glycosylation states of proteins contributing to asthma can change the pathological processes that we previously failed to inhibit. Special emphasis is placed on chitotriosidase 1 (CHIT1), an enzyme capable of modifying LacNAc- and LacdiNAc-containing glycans. The expression and activity of CHIT1 are induced in human diseased lungs, and its pathological role has been demonstrated by both genetic and pharmacological approaches. We propose that studying the glycosylation pattern and enzymes involved in glycosylation in asthma can help in patient stratification and in developing personalized treatment. Full article

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

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17 pages, 3825 KiB

Open AccessEditor’s ChoiceArticle

Metformin Induces MeCP2 in the Hippocampus of Male Mice with Sex-Specific and Brain-Region-Dependent Molecular Impact

by Khatereh Saei Arezoumand, Chris-Tiann Roberts and Mojgan Rastegar

Biomolecules 2024, 14(4), 505; https://doi.org/10.3390/biom14040505 - 21 Apr 2024

Cited by 3 | Viewed by 2697

Abstract

Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental [...] Read more.

Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder with no cure. RTT patients show disease-associated symptoms within 18 months of age that include developmental regression, progressive loss of useful hand movements, and breathing difficulties, along with neurological impairments, seizures, tremor, and mental disability. Rett Syndrome is also associated with metabolic abnormalities, and the anti-diabetic drug metformin is suggested to be a potential drug of choice with low or no side-effects. Previously, we showed that in vitro exposure of metformin in a human brain cell line induces MECP2E1 transcripts, the dominant isoform of the MECP2 gene in the brain, mutations in which causes RTT. Here, we report the molecular impact of metformin in mice. Protein analysis of specific brain regions in the male and female mice by immunoblotting indicated that metformin induces MeCP2 in the hippocampus, in a sex-dependent manner. Additional experiments confirm that the regulatory role of metformin on the MeCP2 target “BDNF” is brain region-dependent and sex-specific. Measurement of the ribosomal protein S6 (in both phosphorylated and unphosphorylated forms) confirms the sex-dependent role of metformin in the liver. Our results can help foster a better understanding of the molecular impact of metformin in different brain regions of male and female adult mice, while providing some insight towards its potential in therapeutic strategies for the treatment of Rett Syndrome. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor in Health and Diseases)

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14 pages, 2283 KiB

Open AccessEditor’s ChoiceArticle

Conformational Modulation of Tissue Transglutaminase via Active Site Thiol Alkylating Agents: Size Does Not Matter

by Pauline Navals, Alana M. M. Rangaswamy, Petr Kasyanchyk, Maxim V. Berezovski and Jeffrey W. Keillor

Biomolecules 2024, 14(4), 496; https://doi.org/10.3390/biom14040496 - 19 Apr 2024

Cited by 1 | Viewed by 1739

Abstract

TG2 is a unique member of the transglutaminase family as it undergoes a dramatic conformational change, allowing its mutually exclusive function as either a cross-linking enzyme or a G-protein. The enzyme’s dysregulated activity has been implicated in a variety of pathologies (e.g., celiac [...] Read more.

TG2 is a unique member of the transglutaminase family as it undergoes a dramatic conformational change, allowing its mutually exclusive function as either a cross-linking enzyme or a G-protein. The enzyme’s dysregulated activity has been implicated in a variety of pathologies (e.g., celiac disease, fibrosis, cancer), leading to the development of a wide range of inhibitors. Our group has primarily focused on the development of peptidomimetic targeted covalent inhibitors, the nature and size of which were thought to be important features to abolish TG2’s conformational dynamism and ultimately inhibit both its activities. However, we recently demonstrated that the enzyme was unable to bind guanosine triphosphate (GTP) when catalytically inactivated by small molecule inhibitors. In this study, we designed a library of models targeting covalent inhibitors of progressively smaller sizes (15 to 4 atoms in length). We evaluated their ability to inactivate TG2 by measuring their respective kinetic parameters k_inact and K_I. Their impact on the enzyme’s ability to bind GTP was then evaluated and subsequently correlated to the conformational state of the enzyme, as determined via native PAGE and capillary electrophoresis. All irreversible inhibitors evaluated herein locked TG2 in its open conformation and precluded GTP binding. Therefore, we conclude that steric bulk and structural complexity are not necessary factors to consider when designing TG2 inhibitors to abolish G-protein activity. Full article

(This article belongs to the Special Issue Transglutaminases: Regulation, Imaging, and Applications)

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13 pages, 972 KiB

Open AccessEditor’s ChoiceReview

Technical Advances in Circulating Cell-Free DNA Detection and Analysis for Personalized Medicine in Patients’ Care

by Monica Sorbini, Tullia Carradori, Gabriele Maria Togliatto, Tiziana Vaisitti and Silvia Deaglio

Biomolecules 2024, 14(4), 498; https://doi.org/10.3390/biom14040498 - 19 Apr 2024

Cited by 10 | Viewed by 4205

Abstract

Circulating cell-free DNA (cfDNA) refers to small fragments of DNA molecules released after programmed cell death and necrosis in several body fluids such as blood, saliva, urine, and cerebrospinal fluid. The discovery of cfDNA has revolutionized the field of non-invasive diagnostics in the [...] Read more.

Circulating cell-free DNA (cfDNA) refers to small fragments of DNA molecules released after programmed cell death and necrosis in several body fluids such as blood, saliva, urine, and cerebrospinal fluid. The discovery of cfDNA has revolutionized the field of non-invasive diagnostics in the oncologic field, in prenatal testing, and in organ transplantation. Despite the potential of cfDNA and the solid results published in the recent literature, several challenges remain, represented by a low abundance, a need for highly sensitive assays, and analytical issues. In this review, the main technical advances in cfDNA analysis are presented and discussed, with a comprehensive examination of the current available methodologies applied in each field. Considering the potential advantages of cfDNA, this biomarker is increasing its consensus among clinicians, as it allows us to monitor patients’ conditions in an easy and non-invasive way, offering a more personalized care. Nevertheless, cfDNA analysis is still considered a diagnostic marker to be further validated, and very few centers are implementing its analysis in routine diagnostics. As technical improvements are enhancing the performances of cfDNA analysis, its application will transversally improve patients’ quality of life. Full article

(This article belongs to the Special Issue Recent Developments in the Biology of Extracellular or Cell-Free DNA)

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24 pages, 3946 KiB

Open AccessEditor’s ChoiceReview

Adenosine Triphosphate: The Primordial Molecule That Controls Protein Homeostasis and Shapes the Genome–Proteome Interface

by Jianxing Song

Biomolecules 2024, 14(4), 500; https://doi.org/10.3390/biom14040500 - 19 Apr 2024

Cited by 5 | Viewed by 2785

Abstract

Adenosine triphosphate (ATP) acts as the universal energy currency that drives various biological processes, while nucleic acids function to store and transmit genetic information for all living organisms. Liquid–liquid phase separation (LLPS) represents the common principle for the formation of membrane-less organelles (MLOs) [...] Read more.

Adenosine triphosphate (ATP) acts as the universal energy currency that drives various biological processes, while nucleic acids function to store and transmit genetic information for all living organisms. Liquid–liquid phase separation (LLPS) represents the common principle for the formation of membrane-less organelles (MLOs) composed of proteins rich in intrinsically disordered regions (IDRs) and nucleic acids. Currently, while IDRs are well recognized to facilitate LLPS through dynamic and multivalent interactions, the precise mechanisms by which ATP and nucleic acids affect LLPS still remain elusive. This review summarizes recent NMR results on the LLPS of human FUS, TDP-43, and the viral nucleocapsid (N) protein of SARS-CoV-2, as modulated by ATP and nucleic acids, revealing the following: (1) ATP binds to folded domains overlapping with nucleic-acid-binding interfaces; (2) ATP and nucleic acids interplay to biphasically modulate LLPS by competitively binding to overlapping pockets of folded domains and Arg/Lys within IDRs; (3) ATP energy-independently induces protein folding with the highest efficiency known so far. As ATP likely emerged in the prebiotic monomeric world, while LLPS represents a pivotal mechanism to concentrate and compartmentalize rare molecules for forming primordial cells, ATP appears to control protein homeostasis and shape genome–proteome interfaces throughout the evolutionary trajectory, from prebiotic origins to modern cells. Full article

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17 pages, 3733 KiB

Open AccessEditor’s ChoiceArticle

Mitochondrial Transplantation’s Role in Rodent Skeletal Muscle Bioenergetics: Recharging the Engine of Aging

by Tasnim Arroum, Gerald A. Hish, Kyle J. Burghardt, James D. McCully, Maik Hüttemann and Moh H. Malek

Biomolecules 2024, 14(4), 493; https://doi.org/10.3390/biom14040493 - 18 Apr 2024

Cited by 6 | Viewed by 4351

Abstract

Background: Mitochondria are the ‘powerhouses of cells’ and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level [...] Read more.

Background: Mitochondria are the ‘powerhouses of cells’ and progressive mitochondrial dysfunction is a hallmark of aging in skeletal muscle. Although different forms of exercise modality appear to be beneficial to attenuate aging-induced mitochondrial dysfunction, it presupposes that the individual has a requisite level of mobility. Moreover, non-exercise alternatives (i.e., nutraceuticals or pharmacological agents) to improve skeletal muscle bioenergetics require time to be effective in the target tissue and have another limitation in that they act systemically and not locally where needed. Mitochondrial transplantation represents a novel directed therapy designed to enhance energy production of tissues impacted by defective mitochondria. To date, no studies have used mitochondrial transplantation as an intervention to attenuate aging-induced skeletal muscle mitochondrial dysfunction. The purpose of this investigation, therefore, was to determine whether mitochondrial transplantation can enhance skeletal muscle bioenergetics in an aging rodent model. We hypothesized that mitochondrial transplantation would result in sustained skeletal muscle bioenergetics leading to improved functional capacity. Methods: Fifteen female mice (24 months old) were randomized into two groups (placebo or mitochondrial transplantation). Isolated mitochondria from a donor mouse of the same sex and age were transplanted into the hindlimb muscles of recipient mice (quadriceps femoris, tibialis anterior, and gastrocnemius complex). Results: The results indicated significant increases (ranging between ~36% and ~65%) in basal cytochrome c oxidase and citrate synthase activity as well as ATP levels in mice receiving mitochondrial transplantation relative to the placebo. Moreover, there were significant increases (approx. two-fold) in protein expression of mitochondrial markers in both glycolytic and oxidative muscles. These enhancements in the muscle translated to significant improvements in exercise tolerance. Conclusions: This study provides initial evidence showing how mitochondrial transplantation can promote skeletal muscle bioenergetics in an aging rodent model. Full article

(This article belongs to the Special Issue Skeletal Muscle Homeostasis and Regeneration)

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13 pages, 3079 KiB

Open AccessEditor’s ChoiceArticle

Radiolabelled FGF-2 for Imaging Activated Fibroblasts in the Tumor Micro-Environment

by Valeria Bentivoglio, Filippo Galli, Michela Varani, Danilo Ranieri, Pallavi Nayak, Annunziata D’Elia, Andrea Soluri, Roberto Massari, Chiara Lauri and Alberto Signore

Biomolecules 2024, 14(4), 491; https://doi.org/10.3390/biom14040491 - 18 Apr 2024

Cited by 2 | Viewed by 2189

Abstract

Tumor associated fibroblasts (TAFs) play a key role in tumor growth and metastatization. TAFs overexpress different biomarkers that are usually expressed at low levels in physiological conditions. Among them are the fibroblast growth factor receptors (FGFRs) that bind the fibroblast growth factors (FGFs). [...] Read more.

Tumor associated fibroblasts (TAFs) play a key role in tumor growth and metastatization. TAFs overexpress different biomarkers that are usually expressed at low levels in physiological conditions. Among them are the fibroblast growth factor receptors (FGFRs) that bind the fibroblast growth factors (FGFs). In particular, the overexpression of FGFR-2c in tumors has been associated with advanced clinical stages and increased metastatization. Here, we developed a non-invasive tool to evaluate, in vivo, the expression of FGFR-2c in metastatic cancer. This is based on ^99mTc-labelled FGF-2. Methods: ^99mTc-FGF-2 was tested in vitro and in vivo in mice bearing allografts of sarcoma cells. Images of ^99mTc-FGF-2 were acquired using a new portable high-resolution ultra-sensitive gamma camera for small animal imaging. Results: FGF-2 was labeled with high specific activity but low labelling efficiency, thus requiring post-labeling purification by gel-filtration chromatography. In vitro binding to 2C human keratinocytes showed a Kd of 3.36 × 10⁻⁹ M. In mice bearing J774A.1 cell allografts, we observed high and rapid tumor uptake of ^99mTc-FGF-2 with a high Tumor/Blood ratio at 24 h post-injection (26.1 %ID/g and 12.9 %ID) with low kidney activity and moderate liver activity. Conclusions: we labeled FGF-2 with ^99mTc and showed nanomolar Kd in vitro with human keratinocytes expressing FGF-2 receptors. In mice, ^99mTc-FGF-2 rapidly and efficiently accumulated in tumors expressing FGF-2 receptors. This new radiopharmaceutical could be used in humans to image TAFs. Full article

(This article belongs to the Section Molecular Medicine)

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9 pages, 820 KiB

Open AccessEditor’s ChoiceArticle

Development of Improved Spectrophotometric Assays for Biocatalytic Silyl Ether Hydrolysis

by Yuqing Lu, Chisom S. Egedeuzu, Peter G. Taylor and Lu Shin Wong

Biomolecules 2024, 14(4), 492; https://doi.org/10.3390/biom14040492 - 18 Apr 2024

Cited by 2 | Viewed by 1870

Abstract

Reported herein is the development of assays for the spectrophotometric quantification of biocatalytic silicon−oxygen bond hydrolysis. Central to these assays are a series of chromogenic substrates that release highly absorbing phenoxy anions upon cleavage of the sessile bond. These substrates were tested with [...] Read more.

Reported herein is the development of assays for the spectrophotometric quantification of biocatalytic silicon−oxygen bond hydrolysis. Central to these assays are a series of chromogenic substrates that release highly absorbing phenoxy anions upon cleavage of the sessile bond. These substrates were tested with silicatein, an enzyme from a marine sponge that is known to catalyse the hydrolysis and condensation of silyl ethers. It was found that, of the substrates tested, tert-butyldimethyl(2-methyl-4-nitrophenoxy)silane provided the best assay performance, as evidenced by the highest ratio of enzyme catalysed reaction rate compared with the background (uncatalysed) reaction. These substrates were also found to be suitable for detailed enzyme kinetics measurements, as demonstrated by their use to determine the Michaelis−Menten kinetic parameters for silicatein. Full article

(This article belongs to the Section Enzymology)

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56 pages, 3906 KiB

Open AccessEditor’s ChoiceReview

Metabolic Syndrome and Biotherapeutic Activity of Dairy (Cow and Buffalo) Milk Proteins and Peptides: Fast Food-Induced Obesity Perspective—A Narrative Review

by Kenbon Beyene Abdisa, Emőke Szerdahelyi, Máté András Molnár, László Friedrich, Zoltán Lakner, András Koris, Attila Toth and Arijit Nath

Biomolecules 2024, 14(4), 478; https://doi.org/10.3390/biom14040478 - 14 Apr 2024

Cited by 7 | Viewed by 3840

Abstract

Metabolic syndrome (MS) is defined by the outcome of interconnected metabolic factors that directly increase the prevalence of obesity and other metabolic diseases. Currently, obesity is considered one of the most relevant topics of discussion because an epidemic heave of the incidence of [...] Read more.

Metabolic syndrome (MS) is defined by the outcome of interconnected metabolic factors that directly increase the prevalence of obesity and other metabolic diseases. Currently, obesity is considered one of the most relevant topics of discussion because an epidemic heave of the incidence of obesity in both developing and underdeveloped countries has been reached. According to the World Obesity Atlas 2023 report, 38% of the world population are presently either obese or overweight. One of the causes of obesity is an imbalance of energy intake and energy expenditure, where nutritional imbalance due to consumption of high-calorie fast foods play a pivotal role. The dynamic interactions among different risk factors of obesity are highly complex; however, the underpinnings of hyperglycemia and dyslipidemia for obesity incidence are recognized. Fast foods, primarily composed of soluble carbohydrates, non-nutritive artificial sweeteners, saturated fats, and complexes of macronutrients (protein-carbohydrate, starch-lipid, starch-lipid-protein) provide high metabolic calories. Several experimental studies have pointed out that dairy proteins and peptides may modulate the activities of risk factors of obesity. To justify the results precisely, peptides from dairy milk proteins were synthesized under in vitro conditions and their contributions to biomarkers of obesity were assessed. Comprehensive information about the impact of proteins and peptides from dairy milks on fast food-induced obesity is presented in this narrative review article. Full article

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

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13 pages, 682 KiB

Open AccessEditor’s ChoiceReview

Innate Immunity and MASLD

by Moritz Meyer, Julian Schwärzler, Almina Jukic and Herbert Tilg

Biomolecules 2024, 14(4), 476; https://doi.org/10.3390/biom14040476 - 13 Apr 2024

Cited by 16 | Viewed by 3761

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications. Full article

(This article belongs to the Special Issue Honorary Special Issue Dedicated to Prof. Giovanni Targher–the Metabolic Fatty Liver Syndromes: MASLD/MAFLD/NAFLD)

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13 pages, 1564 KiB

Open AccessEditor’s ChoiceArticle

Enhancement of Acetate-Induced Apoptosis of Colorectal Cancer Cells by Cathepsin D Inhibition Depends on Oligomycin A-Sensitive Respiration

by Sara Alves, Cátia Santos-Pereira, Cláudia S. F. Oliveira, Ana Preto, Susana R. Chaves and Manuela Côrte-Real

Biomolecules 2024, 14(4), 473; https://doi.org/10.3390/biom14040473 - 12 Apr 2024

Cited by 2 | Viewed by 1986

Abstract

Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest [...] Read more.

Colorectal cancer (CRC) is a leading cause of death worldwide. Conventional therapies are available with varying effectiveness. Acetate, a short-chain fatty acid produced by human intestinal bacteria, triggers mitochondria-mediated apoptosis preferentially in CRC but not in normal colonocytes, which has spurred an interest in its use for CRC prevention/therapy. We previously uncovered that acetate-induced mitochondrial-mediated apoptosis in CRC cells is significantly enhanced by the inhibition of the lysosomal protease cathepsin D (CatD), which indicates both mitochondria and the lysosome are involved in the regulation of acetate-induced apoptosis. Herein, we sought to determine whether mitochondrial function affects CatD apoptotic function. We found that enhancement of acetate-induced apoptosis by CatD inhibition depends on oligomycin A-sensitive respiration. Mechanistically, the potentiating effect is associated with an increase in cellular and mitochondrial superoxide anion accumulation and mitochondrial mass. Our results provide novel clues into the regulation of CatD function and the effect of tumor heterogeneity in the outcome of combined treatment using acetate and CatD inhibitors. 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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21 pages, 3686 KiB

Open AccessEditor’s ChoiceArticle

Mice Mutated in the First Fibronectin Domain of Adhesion Molecule L1 Show Brain Malformations and Behavioral Abnormalities

by Viviana Granato, Ludovica Congiu, Igor Jakovcevski, Ralf Kleene, Benjamin Schwindenhammer, Luciana Fernandes, Sandra Freitag, Melitta Schachner and Gabriele Loers

Biomolecules 2024, 14(4), 468; https://doi.org/10.3390/biom14040468 - 11 Apr 2024

Cited by 1 | Viewed by 1785

Abstract

The X-chromosome-linked cell adhesion molecule L1 (L1CAM), a glycoprotein mainly expressed by neurons in the central and peripheral nervous systems, has been implicated in many neural processes, including neuronal migration and survival, neuritogenesis, synapse formation, synaptic plasticity and regeneration. L1 consists of extracellular, [...] Read more.

The X-chromosome-linked cell adhesion molecule L1 (L1CAM), a glycoprotein mainly expressed by neurons in the central and peripheral nervous systems, has been implicated in many neural processes, including neuronal migration and survival, neuritogenesis, synapse formation, synaptic plasticity and regeneration. L1 consists of extracellular, transmembrane and cytoplasmic domains. Proteolytic cleavage of L1’s extracellular and transmembrane domains by different proteases generates several L1 fragments with different functions. We found that myelin basic protein (MBP) cleaves L1’s extracellular domain, leading to enhanced neuritogenesis and neuronal survival in vitro. To investigate in vivo the importance of the MBP-generated 70 kDa fragment (L1-70), we generated mice with an arginine to alanine substitution at position 687 (L1/687), thereby disrupting L1’s MBP cleavage site and obliterating L1-70. Young adult L1/687 males showed normal anxiety and circadian rhythm activities but enhanced locomotion, while females showed altered social interactions. Older L1/687 males were impaired in motor coordination. Furthermore, L1/687 male and female mice had a larger hippocampus, with more neurons in the dentate gyrus and more proliferating cells in the subgranular layer, while the thickness of the corpus callosum and the size of lateral ventricles were normal. In summary, subtle mutant morphological changes result in subtle behavioral changes. Full article

(This article belongs to the Section Biological Factors)

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25 pages, 17475 KiB

Open AccessEditor’s ChoiceArticle

Small Spleen Peptides (SSPs) Shape Dendritic Cell Differentiation through Modulation of Extracellular ATP Synthesis Profile

by Viktor Wixler, Rafael Leite Dantas, Georg Varga, Yvonne Boergeling and Stephan Ludwig

Biomolecules 2024, 14(4), 469; https://doi.org/10.3390/biom14040469 - 11 Apr 2024

Cited by 3 | Viewed by 2459

Abstract

Restoring peripheral immune tolerance is crucial for addressing autoimmune diseases. An ancient mechanism in maintaining the balance between inflammation and tolerance is the ratio of extracellular ATP (exATP) and adenosine. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs) in inhibiting [...] Read more.

Restoring peripheral immune tolerance is crucial for addressing autoimmune diseases. An ancient mechanism in maintaining the balance between inflammation and tolerance is the ratio of extracellular ATP (exATP) and adenosine. Our previous research demonstrated the effectiveness of small spleen peptides (SSPs) in inhibiting psoriatic arthritis progression, even in the presence of the pro-inflammatory cytokine TNFα, by transforming dendritic cells (DCs) into tolerogenic cells and fostering regulatory Foxp3⁺ Treg cells. Here, we identified thymosins as the primary constituents of SSPs, but recombinant thymosin peptides were less efficient in inhibiting arthritis than SSPs. Since Tβ4 is an ecto-ATPase-binding protein, we hypothesized that SSPs regulate exATP profiles. Real-time investigation of exATP levels in DCs revealed that tolerogenic stimulation led to robust de novo exATP synthesis followed by significant degradation, while immunogenic stimulation resulted in a less pronounced increase in exATP and less effective degradation. These contrasting exATP profiles were crucial in determining whether DCs entered an inflammatory or tolerogenic state, highlighting the significance of SSPs as natural regulators of peripheral immunological tolerance, with potential therapeutic benefits for autoimmune diseases. Finally, we demonstrated that the tolerogenic phenotype of SSPs is mainly influenced by adenosine receptors, and in vivo administration of SSPs inhibits psoriatic skin inflammation. Full article

(This article belongs to the Special Issue Diet and Immune Response)

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22 pages, 3397 KiB

Open AccessEditor’s ChoiceArticle

Neurosteroid Modulation of Synaptic and Extrasynaptic GABA_A Receptors of the Mouse Nucleus Accumbens

by Scott J. Mitchell, Grant D. Phillips, Becks Tench, Yunkai Li, Delia Belelli, Stephen J. Martin, Jerome D. Swinny, Louise Kelly, John R. Atack, Michael Paradowski and Jeremy J. Lambert

Biomolecules 2024, 14(4), 460; https://doi.org/10.3390/biom14040460 - 9 Apr 2024

Cited by 4 | Viewed by 2914

Abstract

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABA_AR function are clinically effective in this [...] Read more.

The recent approval of formulations of the endogenous neurosteroid allopregnanolone (brexanolone) and the synthetic neuroactive steroid SAGE-217 (zuranolone) to treat postpartum depression (PPD) has encouraged further research to elucidate why these potent enhancers of GABA_AR function are clinically effective in this condition. Dopaminergic projections from the ventral tegmental area (VTA) to the nucleus accumbens are associated with reward/motivation and brain imaging studies report that individuals with PPD show reduced activity of this pathway in response to reward and infant engagement. However, the influence of neurosteroids on GABA-ergic transmission in the nucleus accumbens has received limited attention. Here, we investigate, in the medium spiny neurons (MSNs) of the mouse nucleus accumbens core, the effect of allopregnanolone, SAGE-217 and other endogenous and synthetic steroids of interest on fast phasic and tonic inhibition mediated by synaptic (α1/2βγ2) and extrasynaptic (α4βδ) GABA_ARs, respectively. We present evidence suggesting the resident tonic current results from the spontaneous opening of δ-GABA_ARs, where the steroid-enhanced tonic current is GABA-dependent. Furthermore, we demonstrate local neurosteroid synthesis in the accumbal slice preparation and reveal that GABA-ergic neurotransmission of MSNs is influenced by an endogenous neurosteroid tone. Given the dramatic fluctuations in allopregnanolone levels during pregnancy and postpartum, this neurosteroid-mediated local fine-tuning of GABAergic transmission in the MSNs will probably be perturbed. Full article

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

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11 pages, 1652 KiB

Open AccessEditor’s ChoiceArticle

Applying Machine Learning for Enhanced MicroRNA Analysis: A Companion Risk Tool for Oral Squamous Cell Carcinoma in Standard Care Incisional Biopsy

by Neha Pruthi, Tami Yap, Caroline Moore, Nicola Cirillo and Michael J. McCullough

Biomolecules 2024, 14(4), 458; https://doi.org/10.3390/biom14040458 - 9 Apr 2024

Cited by 2 | Viewed by 2381

Abstract

Machine learning analyses within the realm of oral cancer outcomes are relatively underexplored compared to other cancer types. This study aimed to assess the performance of machine learning algorithms in identifying oral cancer patients, utilizing microRNA expression data. In this study, we implemented [...] Read more.

Machine learning analyses within the realm of oral cancer outcomes are relatively underexplored compared to other cancer types. This study aimed to assess the performance of machine learning algorithms in identifying oral cancer patients, utilizing microRNA expression data. In this study, we implemented this approach using a panel of oral cancer-associated microRNAs sourced from standard incisional biopsy specimens to identify cases of oral squamous cell carcinomas (OSCC). For the model development process, we used a dataset comprising 30 OSCC and 30 histologically normal epithelium (HNE) cases. We initially trained a logistic regression prediction model using 70 percent of the dataset, while reserving the remaining 30 percent for testing. Subsequently, the model underwent hyperparameter tuning resulting in enhanced performance metrics. The hyperparameter-tuned model exhibited high accuracy (0.894) and ROC AUC (0.898) in predicting OSCC. Testing the model on cases of potentially malignant disorders (OPMDs) revealed that leukoplakia with mild dysplasia was predicted as having a high risk of progressing to OSCC, emphasizing machine learning’s advantage over histopathology in detecting early molecular changes. These findings underscore the necessity for further refinement, incorporating a broader set of variables to enhance the model’s predictive capabilities in assessing the risk of oral potentially malignant disorders. Full article

(This article belongs to the Special Issue Biomolecules and Biomarkers in Head and Neck Medicine (Volume II))

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16 pages, 13158 KiB

Open AccessEditor’s ChoiceArticle

Intact Transition Epitope Mapping—Force Interferences by Variable Extensions (ITEM-FIVE)

by Cornelia Koy, Claudia Röwer, Hans-Jürgen Thiesen, Andrei Neamtu and Michael O. Glocker

Biomolecules 2024, 14(4), 454; https://doi.org/10.3390/biom14040454 - 8 Apr 2024

Cited by 1 | Viewed by 1470

Abstract

Investigations on binding strength differences of non-covalent protein complex components were performed by mass spectrometry. T4 fibritin foldon (T4Ff) is a well-studied miniprotein, which together with its biotinylated version served as model system to represent a compactly folded protein to which an Intrinsically [...] Read more.

Investigations on binding strength differences of non-covalent protein complex components were performed by mass spectrometry. T4 fibritin foldon (T4Ff) is a well-studied miniprotein, which together with its biotinylated version served as model system to represent a compactly folded protein to which an Intrinsically Disordered Region (IDR) was attached. The apparent enthalpies of the gas phase dissociation reactions of the homo-trimeric foldon F-F-F and of the homo-trimeric triply biotinylated foldon bF-bF-bF have been determined to be rather similar (3.32 kJ/mol and 3.85 kJ/mol) but quite distinct from those of the singly and doubly biotinylated hetero-trimers F-F-bF and F-bF-bF (1.86 kJ/mol and 1.08 kJ/mol). Molecular dynamics simulations suggest that the ground states of the (biotinylated) T4Ff trimers are highly symmetric and well comparable to each other, indicating that the energy levels of all four (biotinylated) T4Ff trimer ground states are nearly indistinguishable. The experimentally determined differences and/or similarities in enthalpies of the complex dissociation reactions are explained by entropic spring effects, which are noticeable in the T4Ff hetero-trimers but not in the T4Ff homo-trimers. A lowering of the transition state energy levels of the T4Ff hetero-trimers seems likely because the biotin moieties, mimicking intrinsically disordered regions (IDRs), induced asymmetries in the transition states of the biotinylated T4Ff hetero-trimers. This transition state energy level lowering effect is absent in the T4Ff homo-trimer, as well as in the triply biotinylated T4Ff homo-trimer. In the latter, the IDR-associated entropic spring effects on complex stability cancel each other out. ITEM-FIVE enabled semi-quantitative determination of energy differences of complex dissociation reactions, whose differences were modulated by IDRs attached to compactly folded proteins. Full article

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

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24 pages, 908 KiB

Open AccessEditor’s ChoiceReview

Krill Oil and Its Bioactive Components as a Potential Therapy for Inflammatory Bowel Disease: Insights from In Vivo and In Vitro Studies

by Yingying Liu, Ainsley M. Robinson, Xiao Qun Su and Kulmira Nurgali

Biomolecules 2024, 14(4), 447; https://doi.org/10.3390/biom14040447 - 6 Apr 2024

Cited by 2 | Viewed by 4198

Abstract

Krill oil is extracted from krill, a small crustacean in the Antarctic Ocean. It has received growing attention because of krill oil’s unique properties and diverse health benefits. Recent experimental and clinical studies suggest that it has potential therapeutic benefits in preventing the [...] Read more.

Krill oil is extracted from krill, a small crustacean in the Antarctic Ocean. It has received growing attention because of krill oil’s unique properties and diverse health benefits. Recent experimental and clinical studies suggest that it has potential therapeutic benefits in preventing the development of a range of chronic conditions, including inflammatory bowel disease (IBD). Krill oil is enriched with long-chain n-3 polyunsaturated fatty acids, especially eicosapentaenoic and docosahexaenoic acids, and the potent antioxidant astaxanthin, contributing to its therapeutic properties. The possible underlying mechanisms of krill oil’s health benefits include anti-inflammatory and antioxidant actions, maintaining intestinal barrier functions, and modulating gut microbiota. This review aims to provide an overview of the beneficial effects of krill oil and its bioactive components on intestinal inflammation and to discuss the findings on the molecular mechanisms associated with the role of krill oil in IBD prevention and treatment. Full article

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

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25 pages, 3866 KiB

Open AccessEditor’s ChoiceArticle

Morphological Changes Induced by TKS4 Deficiency Can Be Reversed by EZH2 Inhibition in Colorectal Carcinoma Cells

by Mevan Jacksi, Eva Schad and Agnes Tantos

Biomolecules 2024, 14(4), 445; https://doi.org/10.3390/biom14040445 - 5 Apr 2024

Cited by 1 | Viewed by 2495

Abstract

Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phosphorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank–Ter Haar syndrome (FTHS). [...] Read more.

Background: The scaffold protein tyrosine kinase substrate 4 (TKS4) undergoes tyrosine phosphorylation by the epidermal growth factor receptor (EGFR) pathway via Src kinase. The TKS4 deficiency in humans is responsible for the manifestation of a genetic disorder known as Frank–Ter Haar syndrome (FTHS). Based on our earlier investigation, the absence of TKS4 triggers migration, invasion, and epithelial–mesenchymal transition (EMT)-like phenomena while concurrently suppressing cell proliferation in HCT116 colorectal carcinoma cells. This indicates that TKS4 may play a unique role in the progression of cancer. In this study, we demonstrated that the enhancer of zeste homolog 2 (EZH2) and the histone methyltransferase of polycomb repressive complex 2 (PRC2) are involved in the migration, invasion, and EMT-like changes in TKS4-deficient cells (KO). EZH2 is responsible for the maintenance of the trimethylated lysine 27 on histone H3 (H3K27me3). Methods: We performed transcriptome sequencing, chromatin immunoprecipitation, protein and RNA quantitative studies, cell mobility, invasion, and proliferation studies combined with/without the EZH2 activity inhibitor 3-deazanoplanocine (DZNep). Results: We detected an elevation of global H3K27me3 levels in the TKS4 KO cells, which could be reduced with treatment with DZNep, an EZH2 inhibitor. Inhibition of EZH2 activity reversed the phenotypic effects of the knockout of TKS4, reducing the migration speed and wound healing capacity of the cells as well as decreasing the invasion capacity, while the decrease in cell proliferation became stronger. In addition, inhibition of EZH2 activity also reversed most epithelial and mesenchymal markers. We investigated the wider impact of TKS4 deletion on the gene expression profile of colorectal cancer cells using transcriptome sequencing of wild-type and TKS4 knockout cells, particularly before and after treatment with DZNep. Additionally, we observed changes in the expression of several protein-coding genes and long non-coding RNAs that showed a recovery in expression levels following EZH2 inhibition. Conclusions: Our results indicate that the removal of TKS4 causes a notable disruption in the gene expression pattern, leading to the disruption of several signal transduction pathways. Inhibiting the activity of EZH2 can restore most of these transcriptomics and phenotypic effects in colorectal carcinoma cells. Full article

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

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14 pages, 1048 KiB

Open AccessEditor’s ChoiceReview

Emerging Insights into the Role of BDNF on Health and Disease in Periphery

by Mayuko Ichimura-Shimizu, Khuleshwari Kurrey, Misaki Miyata, Takuya Dezawa, Koichi Tsuneyama and Masami Kojima

Biomolecules 2024, 14(4), 444; https://doi.org/10.3390/biom14040444 - 5 Apr 2024

Cited by 5 | Viewed by 3164

Abstract

Brain-derived neurotrophic factor (BDNF) is a growth factor that promotes the survival and growth of developing neurons. It also enhances circuit formation to synaptic transmission for mature neurons in the brain. However, reduced BDNF expression and single nucleotide polymorphisms (SNP) are reported to [...] Read more.

Brain-derived neurotrophic factor (BDNF) is a growth factor that promotes the survival and growth of developing neurons. It also enhances circuit formation to synaptic transmission for mature neurons in the brain. However, reduced BDNF expression and single nucleotide polymorphisms (SNP) are reported to be associated with functional deficit and disease development in the brain, suggesting that BDNF is a crucial molecule for brain health. Interestingly, BDNF is also expressed in the hypothalamus in appetite and energy metabolism. Previous reports demonstrated that BDNF knockout mice exhibited overeating and obesity phenotypes remarkably. Therefore, we could raise a hypothesis that the loss of function of BDNF may be associated with metabolic syndrome and peripheral diseases. In this review, we describe our recent finding that BDNF knockout mice develop metabolic dysfunction-associated steatohepatitis and recent reports demonstrating the role of one of the BDNF receptors, TrkB-T1, in some peripheral organ functions and diseases, and would provide an insight into the role of BDNF beyond the brain. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor in Health and Diseases)

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22 pages, 2432 KiB

Open AccessEditor’s ChoiceReview

The Impact of Inorganic Systems and Photoactive Metal Compounds on Cytochrome P450 Enzymes and Metabolism: From Induction to Inhibition

by Dmytro Havrylyuk, David K. Heidary and Edith C. Glazer

Biomolecules 2024, 14(4), 441; https://doi.org/10.3390/biom14040441 - 4 Apr 2024

Cited by 3 | Viewed by 2617

Abstract

While cytochrome P450 (CYP; P450) enzymes are commonly associated with the metabolism of organic xenobiotics and drugs or the biosynthesis of organic signaling molecules, they are also impacted by a variety of inorganic species. Metallic nanoparticles, clusters, ions, and complexes can alter CYP [...] Read more.

While cytochrome P450 (CYP; P450) enzymes are commonly associated with the metabolism of organic xenobiotics and drugs or the biosynthesis of organic signaling molecules, they are also impacted by a variety of inorganic species. Metallic nanoparticles, clusters, ions, and complexes can alter CYP expression, modify enzyme interactions with reductase partners, and serve as direct inhibitors. This commonly overlooked topic is reviewed here, with an emphasis on understanding the structural and physiochemical basis for these interactions. Intriguingly, while both organometallic and coordination compounds can act as potent CYP inhibitors, there is little evidence for the metabolism of inorganic compounds by CYPs, suggesting a potential alternative approach to evading issues associated with rapid modification and elimination of medically useful compounds. Full article

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

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19 pages, 3153 KiB

Open AccessEditor’s ChoiceArticle

The Antioxidant Drug Edaravone Binds to the Aryl Hydrocarbon Receptor (AHR) and Promotes the Downstream Signaling Pathway Activation

by Caterina Veroni, Stefania Olla, Maria Stefania Brignone, Chiara Siguri, Alessia Formato, Manuela Marra, Rosa Manzoli, Maria Carla Macario, Elena Ambrosini, Enrico Moro and Cristina Agresti

Biomolecules 2024, 14(4), 443; https://doi.org/10.3390/biom14040443 - 4 Apr 2024

Cited by 3 | Viewed by 2518

Abstract

A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention [...] Read more.

A considerable effort has been spent in the past decades to develop targeted therapies for the treatment of demyelinating diseases, such as multiple sclerosis (MS). Among drugs with free radical scavenging activity and oligodendrocyte protecting effects, Edaravone (Radicava) has recently received increasing attention because of being able to enhance remyelination in experimental in vitro and in vivo disease models. While its beneficial effects are greatly supported by experimental evidence, there is a current paucity of information regarding its mechanism of action and main molecular targets. By using high-throughput RNA-seq and biochemical experiments in murine oligodendrocyte progenitors and SH-SY5Y neuroblastoma cells combined with molecular docking and molecular dynamics simulation, we here provide evidence that Edaravone triggers the activation of aryl hydrocarbon receptor (AHR) signaling by eliciting AHR nuclear translocation and the transcriptional-mediated induction of key cytoprotective gene expression. We also show that an Edaravone-dependent AHR signaling transduction occurs in the zebrafish experimental model, associated with a downstream upregulation of the NRF2 signaling pathway. We finally demonstrate that its rapid cytoprotective and antioxidant actions boost increased expression of the promyelinating Olig2 protein as well as of an Olig2:GFP transgene in vivo. We therefore shed light on a still undescribed potential mechanism of action for this drug, providing further support to its therapeutic potential in the context of debilitating demyelinating conditions. Full article

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

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20 pages, 2583 KiB

Open AccessEditor’s ChoiceArticle

A High-Throughput Screening of a Natural Products Library for Mitochondria Modulators

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

Biomolecules 2024, 14(4), 440; https://doi.org/10.3390/biom14040440 - 4 Apr 2024

Cited by 3 | Viewed by 2232

Abstract

Mitochondria, the energy hubs of the cell, are progressively becoming attractive targets in the search for potent therapeutics against neurodegenerative diseases. The pivotal role of mitochondrial dysfunction in the pathogenesis of various diseases, including Parkinson’s disease (PD), underscores the urgency of discovering novel [...] Read more.

Mitochondria, the energy hubs of the cell, are progressively becoming attractive targets in the search for potent therapeutics against neurodegenerative diseases. The pivotal role of mitochondrial dysfunction in the pathogenesis of various diseases, including Parkinson’s disease (PD), underscores the urgency of discovering novel therapeutic strategies. Given the limitations associated with available treatments for mitochondrial dysfunction-associated diseases, the search for new potent alternatives has become imperative. In this report, we embarked on an extensive screening of 4224 fractions from 384 Australian marine organisms and plant samples to identify natural products with protective effects on mitochondria. Our initial screening using PD patient-sourced olfactory neurosphere-derived (hONS) cells with rotenone as a mitochondria stressor resulted in 108 promising fractions from 11 different biota. To further assess the potency and efficacy of these hits, the 11 biotas were subjected to a subsequent round of screening on human neuroblastoma (SH-SY5Y) cells, using 6-hydroxydopamine to induce mitochondrial stress, complemented by a mitochondrial membrane potential assay. This rigorous process yielded 35 active fractions from eight biotas. Advanced analysis using an orbit trap mass spectrophotometer facilitated the identification of the molecular constituents of the most active fraction from each of the eight biotas. This meticulous approach led to the discovery of 57 unique compounds, among which 12 were previously recognized for their mitoprotective effects. Our findings highlight the vast potential of natural products derived from Australian marine organisms and plants in the quest for innovative treatments targeting mitochondrial dysfunction in neurodegenerative diseases. Full article

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

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17 pages, 4125 KiB

Open AccessEditor’s ChoiceArticle

Transient Receptor Potential Canonical 5 (TRPC5): Regulation of Heart Rate and Protection against Pathological Cardiac Hypertrophy

by Pratish Thakore, James E. Clark, Aisah A. Aubdool, Dibesh Thapa, Anna Starr, Paul A. Fraser, Keith Farrell-Dillon, Elizabeth S. Fernandes, Ian McFadzean and Susan D. Brain

Biomolecules 2024, 14(4), 442; https://doi.org/10.3390/biom14040442 - 4 Apr 2024

Cited by 1 | Viewed by 2218

Abstract

TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters [...] Read more.

TRPC5 is a non-selective cation channel that is expressed in cardiomyocytes, but there is a lack of knowledge of its (patho)physiological role in vivo. Here, we examine the role of TRPC5 on cardiac function under basal conditions and during cardiac hypertrophy. Cardiovascular parameters were assessed in wild-type (WT) and global TRPC5 knockout (KO) mice. Despite no difference in blood pressure or activity, heart rate was significantly reduced in TRPC5 KO mice. Echocardiography imaging revealed an increase in stroke volume, but cardiac contractility was unaffected. The reduced heart rate persisted in isolated TRPC5 KO hearts, suggesting changes in basal cardiac pacing. Heart rate was further investigated by evaluating the reflex change following drug-induced pressure changes. The reflex bradycardic response following phenylephrine was greater in TRPC5 KO mice but the tachycardic response to SNP was unchanged, indicating an enhancement in the parasympathetic control of the heart rate. Moreover, the reduction in heart rate to carbachol was greater in isolated TRPC5 KO hearts. To evaluate the role of TRPC5 in cardiac pathology, mice were subjected to abdominal aortic banding (AAB). An exaggerated cardiac hypertrophy response to AAB was observed in TRPC5 KO mice, with an increased expression of hypertrophy markers, fibrosis, reactive oxygen species, and angiogenesis. This study provides novel evidence for a direct effect of TRPC5 on cardiac function. We propose that (1) TRPC5 is required for maintaining heart rate by regulating basal cardiac pacing and in response to pressure lowering, and (2) TRPC5 protects against pathological cardiac hypertrophy. Full article

(This article belongs to the Special Issue TRP Channels in Cardiovascular and Inflammatory Disease)

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