Biomolecules

20 pages, 5133 KiB

Open AccessEditor’s ChoiceArticle

Functional, Morphological and Molecular Changes Reveal the Mechanisms Associated with Age-Related Vestibular Loss

by Vasiliki Georgia Paplou, Nick M. A. Schubert, Marcel van Tuinen, Sarath Vijayakumar and Sonja J. Pyott

Biomolecules 2023, 13(9), 1429; https://doi.org/10.3390/biom13091429 - 21 Sep 2023

Cited by 1 | Viewed by 2015

Abstract

Age-related loss of vestibular function and hearing are common disorders that arise from the loss of function of the inner ear and significantly decrease quality of life. The underlying pathophysiological mechanisms are poorly understood and difficult to investigate in humans. Therefore, our study [...] Read more.

Age-related loss of vestibular function and hearing are common disorders that arise from the loss of function of the inner ear and significantly decrease quality of life. The underlying pathophysiological mechanisms are poorly understood and difficult to investigate in humans. Therefore, our study examined young (1.5-month-old) and old (24-month-old) C57BL/6 mice, utilizing physiological, histological, and transcriptomic methods. Vestibular sensory-evoked potentials revealed that older mice had reduced wave I amplitudes and delayed wave I latencies, indicating reduced vestibular function. Immunofluorescence and image analysis revealed that older mice exhibited a significant decline in type I sensory hair cell density, particularly in hair cells connected to dimorphic vestibular afferents. An analysis of gene expression in the isolated vestibule revealed the upregulation of immune-related genes and the downregulation of genes associated with ossification and nervous system development. A comparison with the isolated cochlear sensorineural structures showed similar changes in genes related to immune response, chondrocyte differentiation, and myelin formation. These findings suggest that age-related vestibular hypofunction is linked to diminished peripheral vestibular responses, likely due to the loss of a specific subpopulation of hair cells and calyceal afferents. The upregulation of immune- and inflammation-related genes implies that inflammation contributes to these functional and structural changes. Furthermore, the comparison of gene expression between the vestibule and cochlea indicates both shared and distinct mechanisms contributing to age-related vestibular and hearing impairments. Further research is necessary to understand the mechanistic connection between inflammation and age-related balance and hearing disorders and to translate these findings into clinical treatment strategies. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Vestibular Disorders)

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16 pages, 2464 KiB

Open AccessCommunication

Analysis of Acute and Chronic Methamphetamine Treatment in Mice on Gdnf System Expression Reveals a Potential Mechanism of Schizophrenia Susceptibility

by Laoise Casserly, Daniel R. Garton, Ana Montaño-Rodriguez and Jaan-Olle Andressoo

Biomolecules 2023, 13(9), 1428; https://doi.org/10.3390/biom13091428 - 21 Sep 2023

Cited by 2 | Viewed by 1481

Abstract

The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic [...] Read more.

The increase in presynaptic striatal dopamine is the main dopaminergic abnormality in schizophrenia (SCZ). SCZ is primarily treated by modulating the activity of monoamine systems, with a focus on dopamine and serotonin receptors. Glial cell line-derived neurotrophic factor (GDNF) is a strong dopaminergic factor, that recently was shown to correlate with SCZ in human CSF and in striatal tissue. A 2-3-fold increase in GDNF in the brain was sufficient to induce SCZ-like dopaminergic and behavioural changes in mice. Here, we analysed the effect of acute, chronic, and embryonic methamphetamine, a drug known to enhance the risk of psychosis, on Gdnf and its receptors, Gfra1 and Ret, as well as on monoamine metabolism-related gene expression in the mouse brain. We found that acute methamphetamine application increases Gdnf expression in the striatum and chronic methamphetamine decreases the striatal expression of GDNF receptors Gfra1 and Ret. Both chronic and acute methamphetamine treatment upregulated the expression of genes related to dopamine and serotonin metabolism in the striatum, prefrontal cortex, and substantia nigra. Our results suggest a potential mechanism as to how methamphetamine elicits individual psychosis risk in young adults—variation in initial striatal GDNF induction and subsequent GFRα1 and RET downregulation may determine individual susceptibility to psychosis. Our results may guide future experiments and precision medicine development for methamphetamine-induced psychosis using GDNF/GFRa1/RET antagonists. Full article

(This article belongs to the Special Issue Neurotrophic Factors and Growth Factors - Historical Perspective and New Directions for Medical Use)

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13 pages, 730 KiB

Open AccessArticle

Novel Biomarkers and Imaging Indices for the “Vulnerable Patient” with Carotid Stenosis: A Single-Center Study

by Nikolaos Kadoglou, Konstantinos G. Moulakakis, George Mantas, Aris Spathis, Evangelia Gkougkoudi, Spyridon N. Mylonas, John Kakisis and Christos Liapis

Biomolecules 2023, 13(9), 1427; https://doi.org/10.3390/biom13091427 - 21 Sep 2023

Cited by 5 | Viewed by 1383

Abstract

Background: We investigated the relationship of matrix metalloproteinases (MMPs), cardio-ankle vascular index (CAVI), and Gray-Scale Median (GSM) score with the severity and vulnerability of carotid atherosclerosis and major adverse cardiovascular events (MACE) during follow-up of carotid artery revascularization. Methods: We enrolled 262 patients [...] Read more.

Background: We investigated the relationship of matrix metalloproteinases (MMPs), cardio-ankle vascular index (CAVI), and Gray-Scale Median (GSM) score with the severity and vulnerability of carotid atherosclerosis and major adverse cardiovascular events (MACE) during follow-up of carotid artery revascularization. Methods: We enrolled 262 patients undergoing carotid revascularization therapy (GRT), 109 asymptomatic patients with low-grade carotid stenosis (40–70%) receiving conservative treatment (GCT), and 92 age- and sex-matched control subjects without carotid atherosclerosis (GCO). All participants underwent carotid ultrasound and we assessed at baseline clinical parameters, metabolic profile, CAVI, GSM, and circulating levels of hsCRP, MMP-3,-7,-9, and TIMP-1. Results: Both GRT and GCT presented with elevated CAVI, MMPs, and TIMP-1 levels compared to GCO (p < 0.001). The escalation highly correlated to the presence of symptoms or paralleled the degree of carotid stenosis (p < 0.001). During follow-up (mean duration: 55 months), 51 GRT patients experienced MACE unrelated to the revascularization procedure. Within GRT, diabetes (HR: 2.07; CI: 1.55–2.78, p < 0.001), smoking (HR: 1.67; CI: 1.35–1.95, p < 0.001), high CAVI (HR: 1.22; CI: 1.09–1.43, p = 0.023) and MMP-9 (HR: 1.44; CI: 1.29–2.15, p = 0.005), and low GSM (HR: 1.40; CI: 1.16–2.12, p = 0.002) independently predicted MACE occurrences, despite the optimum medical therapy. Conclusions: Novel imaging and biochemical biomarkers were positively associated with atherosclerosis severity, while CAVI, MMP-9, and low GSM showed a positive, independent relationship with MACE after carotid revascularization, describing “vulnerable patients”. Full article

(This article belongs to the Special Issue Biomarkers for Vascular Disease II)

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14 pages, 3570 KiB

Open AccessArticle

Coupled Electrostatic and Hydrophobic Destabilisation of the Gelsolin-Actin Complex Enables Facile Detection of Ovarian Cancer Biomarker Lysophosphatidic Acid

by Katharina Davoudian, Shayon Bhattacharya, Damien Thompson and Michael Thompson

Biomolecules 2023, 13(9), 1426; https://doi.org/10.3390/biom13091426 - 21 Sep 2023

Cited by 2 | Viewed by 1469

Abstract

Lysophosphatidic acid (LPA) is a promising biomarker candidate to screen for ovarian cancer (OC) and potentially stratify and treat patients according to disease stage. LPA is known to target the actin-binding protein gelsolin which is a key regulator of actin filament assembly. Previous [...] Read more.

Lysophosphatidic acid (LPA) is a promising biomarker candidate to screen for ovarian cancer (OC) and potentially stratify and treat patients according to disease stage. LPA is known to target the actin-binding protein gelsolin which is a key regulator of actin filament assembly. Previous studies have shown that the phosphate headgroup of LPA alone is inadequate to bind to the short chain of amino acids in gelsolin known as the PIP₂-binding domain. Thus, the molecular-level detail of the mechanism of LPA binding is poorly understood. Here, we model LPA binding to the PIP₂-binding domain of gelsolin in the gelsolin-actin complex through extensive ten-microsecond atomistic molecular dynamics (MD) simulations. We predict that LPA binding causes a local conformational rearrangement due to LPA interactions with both gelsolin and actin residues. These conformational changes are a result of the amphipathic nature of LPA, where the anionic phosphate, polar glycerol and ester groups, and lipophilic aliphatic tail mediate LPA binding via charged electrostatic, hydrogen bonding, and van der Waals interactions. The negatively-charged LPA headgroup binds to the PIP₂-binding domain of gelsolin-actin while its hydrophobic tail is inserted into actin, creating a strong LPA-insertion pocket that weakens the gelsolin–actin interface. The computed structure, dynamics, and energetics of the ternary gelsolin–LPA–actin complex confirms that a quantitative OC assay is possible based on LPA-triggered actin release from the gelsolin-actin complex. Full article

(This article belongs to the Section Molecular Biomarkers)

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16 pages, 750 KiB

Open AccessEditor’s ChoiceArticle

Plasma Brain-Derived Neurotrophic Factor Levels in First-Episode and Recurrent Major Depression and before and after Bright Light Therapy in Treatment-Resistant Depression

by Biljana Kosanovic Rajacic, Marina Sagud, Drazen Begic, Matea Nikolac Perkovic, Anja Dvojkovic, Lana Ganoci and Nela Pivac

Biomolecules 2023, 13(9), 1425; https://doi.org/10.3390/biom13091425 - 20 Sep 2023

Cited by 3 | Viewed by 1673

Abstract

Brain-derived neurotrophic factor (BDNF) is implicated in the etiology and treatment response in major depressive disorder (MDD). However, peripheral BDNF concentrations have not been compared across different MDD stages. Bright light therapy (BLT) offers some potential in treatment-resistant depression (TRD), but its effects [...] Read more.

Brain-derived neurotrophic factor (BDNF) is implicated in the etiology and treatment response in major depressive disorder (MDD). However, peripheral BDNF concentrations have not been compared across different MDD stages. Bright light therapy (BLT) offers some potential in treatment-resistant depression (TRD), but its effects on BDNF levels are unknown. This study included a cross-sectional analysis of plasma BDNF concentration in females with TRD, unmedicated MDD patients, and healthy controls (HC), and measurements of longitudinal BLT effects on plasma BDNF levels in TRD patients. The present study included 55 drug-naïve, first-episode patients, 25 drug-free recurrent-episode MDD patients, 71 HC participants, and 54 TRD patients. Patients were rated by Hamilton Depression Rating Scale (HAMD)-17 and the Montgomery–Åsberg Depression Rating Scale (MADRS). Patients with TRD received BLT during 4 weeks. The total HAMD-17 and MADRS scores decreased following BLT. All patient groups had lower plasma BDNF than HC, but BDNF levels did not differ between first- and recurrent-episode BDNF patients and TRD patients before or after BLT. However, responders and remitters to BLT had higher post-treatment plasma BDNF concentrations than patients who did not achieve response or remission. The changes in plasma BDNF levels may be candidates for biomarkers of treatment response to BLT in TRD patients. Full article

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

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35 pages, 10537 KiB

Open AccessArticle

Metabolomics Analysis and Biochemical Profiling of Arsenic-Induced Metabolic Impairment and Disease Susceptibility

by Syed Muhammad Shoaib, Samina Afzal, Ali Feezan, Muhammad Sajid Hamid Akash, Ahmed Nadeem and Tahir Maqbool Mir

Biomolecules 2023, 13(9), 1424; https://doi.org/10.3390/biom13091424 - 20 Sep 2023

Cited by 3 | Viewed by 2301

Abstract

Our study aimed to conduct a comprehensive biochemical profiling and metabolomics analysis to investigate the effects of arsenic-induced metabolic disorders, with a specific focus on disruptions in lipid metabolism, amino acid metabolism, and carbohydrate metabolism. Additionally, we sought to assess the therapeutic potential [...] Read more.

Our study aimed to conduct a comprehensive biochemical profiling and metabolomics analysis to investigate the effects of arsenic-induced metabolic disorders, with a specific focus on disruptions in lipid metabolism, amino acid metabolism, and carbohydrate metabolism. Additionally, we sought to assess the therapeutic potential of resveratrol (RSV) as a remedy for arsenic-induced diabetes, using metformin (MF) as a standard drug for comparison. We measured the total arsenic content in mouse serum by employing inductively coupled plasma mass spectrometry (ICP-MS) after administering a 50-ppm solution of sodium arsenate (50 mg/L) in purified water. Our findings revealed a substantial increase in total arsenic content in the exposed group, with a mean value of 166.80 ± 8.52 ppb (p < 0.05). Furthermore, we investigated the impact of arsenic exposure on various biomarkers using enzyme-linked immunosorbent assay (ELISA) methods. Arsenic exposed mice exhibited significant hyperglycemia (p < 0.001) and elevated levels of homeostatic model assessment of insulin resistance (HOMA-IR), hemoglobin A1c (Hb1Ac), Inflammatory biomarkers as well as liver and kidney function biomarkers (p < 0.05). Additionally, the levels of crucial enzymes linked to carbohydrate metabolism, including α-glucosidase, hexokinase, and glucose-6-phosphatase (G6PS), and oxidative stress biomarkers, such as levels of glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), were significantly reduced in the arsenic-exposed group compared to the control group (p < 0.05). However, the level of MDA was significantly increased. Molecular analysis of gene expression indicated significant upregulation of key enzymes involved in lipid metabolism, such as carnitine palmitoyl-transferase-I (CPT-I), carnitine palmitoyl-transferase-II (CPT-II), lecithin–cholesterol acyltransferase (LCAT), and others. Additionally, alterations in gene expression related to glucose transporter-2 (GLUT-2), glucose-6-phosphatase (G6PC), and glucokinase (GK), associated with carbohydrate metabolism, were observed. Amino acid analysis revealed significant decreases in nine amino acids in arsenic-exposed mice. Metabolomics analysis identified disruptions in lipid metabolomes, amino acids, and arsenic metabolites, highlighting their involvement in essential metabolic pathways. Histopathological observations revealed significant changes in liver architecture, hepatocyte degeneration, and increased Kupffer cells in the livers of arsenic-exposed mice. In conclusion, these findings enhance our comprehension of the impact of environmental toxins on metabolic health and offer potential avenues for remedies against such disruptions. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease 2023)

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13 pages, 3127 KiB

Open AccessArticle

RP-HPLC Separation and ¹H NMR Identification of a Yellow Fluorescent Compound—Riboflavin (Vitamin B₂)—Produced by the Yeast Hyphopichia wangnamkhiaoensis

by Raziel Arturo Jiménez-Nava, Luis Gerardo Zepeda-Vallejo, Fortunata Santoyo-Tepole, Griselda Ma. Chávez-Camarillo and Eliseo Cristiani-Urbina

Biomolecules 2023, 13(9), 1423; https://doi.org/10.3390/biom13091423 - 20 Sep 2023

Cited by 3 | Viewed by 1761

Abstract

The yeast Hyphopichia wangnamkhiaoensis excretes a brilliant yellow fluorescent compound into its growth culture. In this study, we isolated and identified this compound using reverse-phase high-performance liquid chromatography-diode array detector (RP-HPLC-DAD) as well as ¹H NMR and UV–Vis spectroscopy. Two of the [...] Read more.

The yeast Hyphopichia wangnamkhiaoensis excretes a brilliant yellow fluorescent compound into its growth culture. In this study, we isolated and identified this compound using reverse-phase high-performance liquid chromatography-diode array detector (RP-HPLC-DAD) as well as ¹H NMR and UV–Vis spectroscopy. Two of the three RP-HPLC-DAD methods used successfully separated the fluorescent compound and involved (1) a double separation step with isocratic flow elution, first on a C18 column and later on a cyano column, and (2) a separation with a linear gradient elution on a phenyl column. The wavelengths of maximum absorption of the fluorescent compound-containing HPLC fractions (~224, 268, 372, and 446 nm) are in good agreement with those exhibited by flavins. The ¹H NMR spectra revealed methyl (δ 2.30 and 2.40) and aromatic proton (δ 7.79 and 7.77) signals of riboflavin. The ¹H NMR spectra of the samples spiked with riboflavin confirmed that the brilliant yellow fluorescent compound is riboflavin. The maximum excitation and emission wavelengths of the fluorescent compound were 448 and 528 nm, respectively, which are identical to those of riboflavin. Full article

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21 pages, 1624 KiB

Open AccessSystematic Review

An Overview of the Safety Profile and Clinical Impact of CDK4/6 Inhibitors in Breast Cancer—A Systematic Review of Randomized Phase II and III Clinical Trials

by Ioana-Miruna Stanciu, Andreea Ioana Parosanu and Cornelia Nitipir

Biomolecules 2023, 13(9), 1422; https://doi.org/10.3390/biom13091422 - 20 Sep 2023

Cited by 3 | Viewed by 2947

Abstract

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both [...] Read more.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have transformed the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2−) breast cancer over the last decade. These inhibitors are currently established as first- and second-line systemic treatment choices for both endocrine-sensitive and -resistant breast cancer populations alongside endocrine therapy (ET) or monotherapy. Data on targeted therapy continue to mature, and the number of publications has been constantly rising. Although these drugs have been demonstrated to prolong overall survival (as well as progression-free survival (PFS) in breast cancer patients), changing the paradigm of all current knowledge, they also cause important adverse events (AEs). This review provides the latest summary and update on the safety profile of the three CDK4/6 inhibitors, as it appears from all major phase II and III randomized clinical trials regarding palbociclib, ribociclib, and abemaciclib, including the most relevant 15 clinical trials. Full article

(This article belongs to the Special Issue Cell Cycle Proteins and Cancer Therapy)

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17 pages, 6318 KiB

Open AccessEditor’s ChoiceArticle

N-Glycome Profile of the Spike Protein S1: Systemic and Comparative Analysis from Eleven Variants of SARS-CoV-2

by Cristian D. Gutierrez Reyes, Sherifdeen Onigbinde, Akeem Sanni, Andrew I. Bennett, Peilin Jiang, Oluwatosin Daramola, Parisa Ahmadi, Mojibola Fowowe, Mojgan Atashi, Vishal Sandilya, Md Abdul Hakim and Yehia Mechref

Biomolecules 2023, 13(9), 1421; https://doi.org/10.3390/biom13091421 - 20 Sep 2023

Cited by 8 | Viewed by 1909

Abstract

The SARS-CoV-2 virus rapidly spread worldwide, threatening public health. Since it emerged, the scientific community has been engaged in the development of effective therapeutics and vaccines. The subunit S1 in the spike protein of SARS-CoV-2 mediates the viral entry into the host and [...] Read more.

The SARS-CoV-2 virus rapidly spread worldwide, threatening public health. Since it emerged, the scientific community has been engaged in the development of effective therapeutics and vaccines. The subunit S1 in the spike protein of SARS-CoV-2 mediates the viral entry into the host and is therefore one of the major research targets. The S1 protein is extensively glycosylated, and there is compelling evidence that glycans protect the virus’ active site from the human defense system. Therefore, investigation of the S1 protein glycome alterations in the different virus variants will provide a view of the glycan evolution and its relationship with the virus pathogenesis. In this study, we explored the N-glycosylation expression of the S1 protein for eleven SARS-CoV-2 variants: five variants of concern (VOC), including alpha, beta, gamma, delta, and omicron, and six variants of interest (VOI), including epsilon, eta, iota, lambda, kappa, and mu. The results showed significant differences in the N-glycome abundance of all variants. The N-glycome of the VOC showed a large increase in the abundance of sialofucosylated glycans, with the greatest abundance in the omicron variant. In contrast, the results showed a large abundance of fucosylated glycans for most of the VOI. Two glycan compositions, GlcNAc₄,Hex₅,Fuc,NeuAc (4-5-1-1) and GlcNAc₆,Hex₈,Fuc,NeuAc (6-8-1-1), were the most abundant structures across all variants. We believe that our data will contribute to understanding the S1 protein’s structural differences between SARS-CoV-2 mutations. Full article

(This article belongs to the Section Biomacromolecules: Carbohydrates)

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15 pages, 2277 KiB

Open AccessEditor’s ChoiceArticle

Conservation of Glutathione Transferase mRNA and Protein Sequences Similar to Human and Horse Alpha Class GST A3-3 across Dog, Goat, and Opossum Species

by Shawna M. Hubert, Paul B. Samollow, Helena Lindström, Bengt Mannervik and Nancy H. Ing

Biomolecules 2023, 13(9), 1420; https://doi.org/10.3390/biom13091420 - 20 Sep 2023

Cited by 2 | Viewed by 1492

Abstract

The glutathione transferase A3-3 (GST A3-3) homodimeric enzyme is the most efficient enzyme that catalyzes isomerization of the precursors of testosterone, estradiol, and progesterone in the gonads of humans and horses. However, the presence of GST A3-3 orthologs with equally high ketosteroid isomerase [...] Read more.

The glutathione transferase A3-3 (GST A3-3) homodimeric enzyme is the most efficient enzyme that catalyzes isomerization of the precursors of testosterone, estradiol, and progesterone in the gonads of humans and horses. However, the presence of GST A3-3 orthologs with equally high ketosteroid isomerase activity has not been verified in other mammalian species, even though pig and cattle homologs have been cloned and studied. Identifying GSTA3 genes is a challenge because of multiple GSTA gene duplications (e.g., 12 in the human genome); consequently, the GSTA3 gene is not annotated in most genomes. To improve our understanding of GSTA3 gene products and their functions across diverse mammalian species, we cloned homologs of the horse and human GSTA3 mRNAs from the testes of a dog, goat, and gray short-tailed opossum, the genomes of which all currently lack GSTA3 gene annotations. The resultant novel GSTA3 mRNA and inferred protein sequences had a high level of conservation with human GSTA3 mRNA and protein sequences (≥70% and ≥64% identities, respectively). Sequence conservation was also apparent for the 12 residues of the “H-site” in the 222 amino acid GSTA3 protein that is known to interact with the steroid substrates. Modeling predicted that the dog GSTA3-3 may be a more active ketosteroid isomerase than the corresponding goat or opossum enzymes. However, expression of the GSTA3 gene was higher in liver than in other dog tissue. Our results improve understanding of the active sites of mammalian GST A3-3 enzymes, inhibitors of which might be useful for reducing steroidogenesis for medical purposes, such as fertility control or treatment of steroid-dependent diseases. Full article

(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)

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17 pages, 6420 KiB

Open AccessArticle

Redox Metabolism and Vascular Calcification in Chronic Kidney Disease

by Natalia Carrillo-López, Sara Panizo, Beatriz Martín-Carro, Juan Carlos Mayo Barrallo, Pablo Román-García, Raúl García-Castro, Jesús María Fernández-Gómez, Miguel Ángel Hevia-Suárez, Julia Martín-Vírgala, Sara Fernández-Villabrille, Laura Martínez-Arias, Sara Barrio Vázquez, Laura Calleros Basilio, Manuel Naves-Díaz, Jorge Benito Cannata-Andía, Isabel Quirós-González, Cristina Alonso-Montes and José Luis Fernández-Martín

Biomolecules 2023, 13(9), 1419; https://doi.org/10.3390/biom13091419 - 20 Sep 2023

Cited by 1 | Viewed by 1646

Abstract

Vascular calcification (VC) is a common complication in patients with chronic kidney disease which increases their mortality. Although oxidative stress is involved in the onset and progression of this disorder, the specific role of some of the main redox regulators, such as catalase, [...] Read more.

Vascular calcification (VC) is a common complication in patients with chronic kidney disease which increases their mortality. Although oxidative stress is involved in the onset and progression of this disorder, the specific role of some of the main redox regulators, such as catalase, the main scavenger of H₂O₂, remains unclear. In the present study, epigastric arteries of kidney transplant recipients, a rat model of VC, and an in vitro model of VC exhibiting catalase (Cts) overexpression were analysed. Pericalcified areas of human epigastric arteries had increased levels of catalase and cytoplasmic, rather than nuclear runt-related transcription factor 2 (RUNX2). In the rat model, advanced aortic VC concurred with lower levels of the H₂O₂-scavenger glutathione peroxidase 3 compared to controls. In an early model of calcification using vascular smooth muscle cells (VSMCs), Cts VSMCs showed the expected increase in total levels of RUNX2. However, Cts VMSCs also exhibited a lower percentage of the nucleus stained for RUNX2 in response to calcifying media. In this early model of VC, we did not observe a dysregulation of the mitochondrial redox state; instead, an increase in the general redox state was observed in the cytoplasm. These results highlight the complex role of antioxidant enzymes as catalase by regulation of RUNX2 subcellular location delaying the onset of VC. Full article

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

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14 pages, 1198 KiB

Open AccessArticle

Mutated TP53 in Circulating Tumor DNA as a Risk Level Biomarker in Head and Neck Squamous Cell Carcinoma Patients

by Liyona Kampel, Sara Feldstein, Shlomo Tsuriel, Victoria Hannes, Narin N. Carmel Neiderman, Gilad Horowitz, Anton Warshavsky, Leonor Leider-Trejo, Dov Hershkovitz and Nidal Muhanna

Biomolecules 2023, 13(9), 1418; https://doi.org/10.3390/biom13091418 - 20 Sep 2023

Cited by 2 | Viewed by 1492

Abstract

Circulating tumor DNA (ctDNA) has been suggested as a surrogate biomarker for early detection of cancer recurrence. We aimed to explore the utility of ctDNA as a noninvasive prognostic biomarker in newly diagnosed head and neck squamous cell carcinoma (HNSCC) patients. Seventy HNSCC [...] Read more.

Circulating tumor DNA (ctDNA) has been suggested as a surrogate biomarker for early detection of cancer recurrence. We aimed to explore the utility of ctDNA as a noninvasive prognostic biomarker in newly diagnosed head and neck squamous cell carcinoma (HNSCC) patients. Seventy HNSCC specimens were analysed for the detection of TP53 genetic alterations utilizing next-generation sequencing (NGS). TP53 mutations were revealed in 55 (79%). Upon detection of a significant TP53 mutation, circulating cell-free DNA was scrutinized for the presence of the tumor-specific mutation. ctDNA was identified at a minimal allele frequency of 0.08% in 21 out of 30 processed plasma samples. Detectable ctDNA correlated with regional spread (N stage ≥ 1, p = 0.011) and poorer 5-year progression-free survival (20%, 95% CI 10.9 to 28.9, p = 0.034). The high-risk worst pattern of invasion (WPOI grade 4–5) and deep invasion were frequently found in patients whose ctDNA was detected (p = 0.087 and p = 0.072, respectively). Detecting mutated TP53 ctDNA was associated with poor progression-free survival and regional metastases, indicating its potential role as a prognostic biomarker. However, ctDNA detectability in early-stage disease and the mechanisms modulating its release into the bloodstream must be further elucidated. Full article

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

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17 pages, 3099 KiB

Open AccessReview

Review of Non-Eosinophilic Esophagitis-Eosinophilic Gastrointestinal Disease (Non-EoE-EGID) and a Case Series of Twenty-Eight Affected Patients

by Yoshikazu Kinoshita and Tsuyoshi Sanuki

Biomolecules 2023, 13(9), 1417; https://doi.org/10.3390/biom13091417 - 20 Sep 2023

Cited by 3 | Viewed by 2033

Abstract

Eosinophilic gastrointestinal disease (EGID) is divided into eosinophilic esophagitis (EoE) and non-eosinophilic esophagitis eosinophilic gastrointestinal disease (non-EoE-EGID) based on the involved gastrointestinal segments. Reports regarding non-EoE-EGID are limited, in part because of its rarity. The present study was performed to review non-EoE-EGID, including [...] Read more.

Eosinophilic gastrointestinal disease (EGID) is divided into eosinophilic esophagitis (EoE) and non-eosinophilic esophagitis eosinophilic gastrointestinal disease (non-EoE-EGID) based on the involved gastrointestinal segments. Reports regarding non-EoE-EGID are limited, in part because of its rarity. The present study was performed to review non-EoE-EGID, including its pathogenesis, diagnosis, treatment, and prognosis. Additionally, details regarding 28 cases of non-EoE-EGID recently diagnosed at our Japanese tertial medical center are presented and compared with 20 EoE cases diagnosed during the same period at the same medical center. Comparisons of the two groups clarified differences regarding age- and gender-dependent prevalence between the two conditions, and also showed that systemic involvement and disease severity were greater in the non-EoE-EGID patients. Notably, diagnosis of non-EoE-EGID is difficult because of its lack of specific or characteristic symptoms and endoscopic findings. The clinical characteristics of EoE and non-EoE-EGID differ in many ways, while they also share several genetic, clinical, laboratory, and histopathological features. Full article

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

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15 pages, 6689 KiB

Open AccessEditor’s ChoiceArticle

The Effects of an Osteoarthritic Joint Environment on ACL Damage and Degeneration: A Yucatan Miniature Pig Model

by Elias Schwartz, Kenny Chang, Changqi Sun, Fei Zhang, Guoxuan Peng, Brett Owens and Lei Wei

Biomolecules 2023, 13(9), 1416; https://doi.org/10.3390/biom13091416 - 20 Sep 2023

Viewed by 1314

Abstract

Posttraumatic osteoarthritis (PTOA) arises secondary to joint injuries and is characteristically driven by inflammatory mediators. PTOA is often studied in the setting of ACL tears. However, a wide range of other injuries also lead to PTOA pathogenesis. The purpose of this study was [...] Read more.

Posttraumatic osteoarthritis (PTOA) arises secondary to joint injuries and is characteristically driven by inflammatory mediators. PTOA is often studied in the setting of ACL tears. However, a wide range of other injuries also lead to PTOA pathogenesis. The purpose of this study was to characterize the morphological changes in the uninjured ACL in a PTOA inflammatory environment. We retrospectively reviewed 14 ACLs from 13 Yucatan minipigs, 7 of which had undergone our modified intra-articular drilling (mIAD) procedure, which induced PTOA through inflammatory mediators. Seven ACLs were harvested from mIAD minipigs (PTOA) and seven ACLs from control minipigs with no cartilage degeneration (non-PTOA). ACL degeneration was evaluated using histological scoring systems. IL-1β, NF-κB, and TNF-α mRNA expression in the synovium was measured using qRT-PCR. PTOA minipigs demonstrated significant ACL degeneration, marked by a disorganized extracellular matrix, increased vascularity, and changes in cellular shape, density, and alignment. Furthermore, IL-1β, NF-κB, and TNF-α expression was elevated in the synovium of PTOA minipigs. These findings demonstrate the potential for ACL degeneration in a PTOA environment and emphasize the need for anti-inflammatory disease-modifying therapies following joint injury. Full article

(This article belongs to the Special Issue Regulation of Cytokine Signaling in Health and Disease)

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40 pages, 1743 KiB

Open AccessArticle

Chirality Matters: Fine-Tuning of Novel Monoamine Reuptake Inhibitors Selectivity through Manipulation of Stereochemistry

by Predrag Kalaba, Katharina Pacher, Philip John Neill, Vladimir Dragacevic, Martin Zehl, Judith Wackerlig, Michael Kirchhofer, Simone B. Sartori, Hubert Gstach, Shima Kouhnavardi, Anna Fabisikova, Matthias Pillwein, Francisco Monje-Quiroga, Karl Ebner, Alexander Prado-Roller, Nicolas Singewald, Ernst Urban, Thierry Langer, Christian Pifl, Jana Lubec, Johann Jakob Leban and Gert Lubec Show full author list Hide full author list

Biomolecules 2023, 13(9), 1415; https://doi.org/10.3390/biom13091415 - 19 Sep 2023

Cited by 2 | Viewed by 1504

Abstract

The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal structures of human isoforms, make the specific targeting of individual transporters rather challenging. Ligand design itself is also rather limited, as [...] Read more.

The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal structures of human isoforms, make the specific targeting of individual transporters rather challenging. Ligand design itself is also rather limited, as many chemists, fully aware of the synthetic and analytical challenges, tend to modify lead compounds in a way that reduces the number of chiral centers and hence limits the potential chemical space of synthetic ligands. We have previously shown that increasing molecular complexity by introducing additional chiral centers ultimately leads to more selective and potent dopamine reuptake inhibitors. Herein, we significantly extend our structure-activity relationship of dopamine transporter-selective ligands and further demonstrate how stereoisomers of defined absolute configuration may fine-tune and direct the activity towards distinct targets. From the pool of active compounds, using the examples of stereoisomers 7h and 8h, we further showcase how in vitro activity significantly differs in in vivo drug efficacy experiments, calling for proper validation of individual stereoisomers in animal studies. Furthermore, by generating a large library of compounds with defined absolute configurations, we lay the groundwork for computational chemists to further optimize and rationally design specific monoamine transporter reuptake inhibitors. Full article

(This article belongs to the Topic Advances in Diagnostics, Brain Delivery Systems and Therapeutics of Neurodegenerative Disease)

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21 pages, 526 KiB

Open AccessReview

Are Anti-rhGAA Antibodies a Determinant of Treatment Outcome in Adults with Late-Onset Pompe Disease? A Systematic Review

by Imke A. M. Ditters, Harmke A. van Kooten, Nadine A. M. E. van der Beek, Ans T. van der Ploeg, Hidde H. Huidekoper and Johanna M. P. van den Hout

Biomolecules 2023, 13(9), 1414; https://doi.org/10.3390/biom13091414 - 19 Sep 2023

Cited by 2 | Viewed by 1827

Abstract

Background: Pompe disease is a lysosomal storage disease characterised by skeletal and respiratory muscle weakness. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa has been available. ERT significantly improves the prognosis of patients with Pompe disease. The effect of high antibody titres [...] Read more.

Background: Pompe disease is a lysosomal storage disease characterised by skeletal and respiratory muscle weakness. Since 2006, enzyme replacement therapy (ERT) with alglucosidase alfa has been available. ERT significantly improves the prognosis of patients with Pompe disease. The effect of high antibody titres on treatment response in adults with late-onset Pompe disease (LOPD) remains unclear but may contribute to interpatient variation. We therefore conducted a systematic review on this subject. Methods: A systematic search was performed in Embase, Medline Ovid, Web of Science, Psych Info Ovid, Cochrane (Clinical Trials only), and Google Scholar (random top-200). Articles were included if they involved adults with LOPD treated with alglucosidase alfa and mentioned anti-rhGAA antibodies or antibody titres. In addition, articles mentioning dosages different from the standard recommended dosage were included. Results: Our literature search retrieved 2562 publications, and 17 fulfilled our selection criteria, describing 443 cases. Seven publications reported on anti-rhGAA antibody titres on a group level, with the percentage of patients with a high titre as defined in the included articles ranging from 0–33%. Six publications reported on the effect of anti-rhGAA antibody titre on clinical course, and four found no correlation. Two studies reported a negative effect on treatment. The first study found a greater improvement in Medical Research Council (MRC) score in patients with no detectable antibody titre. In the second study, a patient discontinued ERT due to a declining neuromuscular state as a result of high anti-rhGAA antibody titres. Seven publications reported on 17 individual patients with a high antibody titre (range 1:12,800–1:3,906,250). In only two cases were high-sustained neutralising antibodies reported to interfere with treatment efficacy. Conclusions: No clear effect of anti-rhGAA IgG antibodies on treatment response could be established for the majority of LOPD patients with a high antibody titre. In a minority of patients, a clinical decline related to (possible) interference of anti-rhGAA antibodies was described. Full article

(This article belongs to the Special Issue Molecular Basis and Translational Research in Metabolic Myopathies: A Themed Issue in Honor of Professor Corrado Angelini)

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16 pages, 2055 KiB

Open AccessEditor’s ChoiceArticle

Eicosapentaenoic Acid Influences the Lipid Profile of an In Vitro Psoriatic Skin Model Produced with T Cells

by Sophie Morin, Andréa Tremblay, Elizabeth Dumais, Pierre Julien, Nicolas Flamand and Roxane Pouliot

Biomolecules 2023, 13(9), 1413; https://doi.org/10.3390/biom13091413 - 19 Sep 2023

Cited by 2 | Viewed by 1873

Abstract

Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin’s lipid mediators is reported in the disease with a predominance of the inflammatory cascade derived from n-6 polyunsaturated fatty acids (n-6 [...] Read more.

Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin’s lipid mediators is reported in the disease with a predominance of the inflammatory cascade derived from n-6 polyunsaturated fatty acids (n-6 PUFAs). Bioactive lipid mediators derived from arachidonic acid (AA) are involved in the inflammatory functions of T cells in psoriasis, whereas n-3 PUFAs’ derivatives are anti-inflammatory metabolites. Here, we sought to evaluate the influence of a supplementation of the culture media with eicosapentaenoic acid (EPA) on the lipid profile of a psoriatic skin model produced with polarized T cells. Healthy and psoriatic skin substitutes were produced following the auto-assembly technique. Psoriatic skin substitutes produced with or without T cells presented increased epidermal and dermal linolenic acid (LA) and AA levels. N-6 PUFA lipid mediators were strongly measured in psoriatic substitutes, namely, 13-hydroxyoctadecadienoic acid (13-HODE), prostaglandin E₂ (PGE₂) and 12-hydroxyeicosatetraenoic acid (12-HETE). The added EPA elevated the amounts of EPA, n-3 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in the epidermal and dermal phospholipids. The EPA supplementation balanced the production of epidermal lipid mediators, with an increase in prostaglandin E₃ (PGE₃), 12-hydroxyeicosapentaenoic acid (12-HEPE) and N-eicosapentaenoyl-ethanolamine (EPEA) levels. These findings show that EPA modulates the lipid composition of psoriatic skin substitutes by encouraging the return to a cutaneous homeostatic state. Full article

(This article belongs to the Special Issue Lipid Metabolism in Health and Disease 2023)

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14 pages, 5310 KiB

Open AccessArticle

Stability of Blueberry Extracellular Vesicles and Their Gene Regulation Effects in Intestinal Caco-2 Cells

by Yangfan Leng, Liubin Yang, Hangxin Zhu, Dongqin Li, Siyi Pan and Fang Yuan

Biomolecules 2023, 13(9), 1412; https://doi.org/10.3390/biom13091412 - 19 Sep 2023

Cited by 5 | Viewed by 1663

Abstract

Plant extracellular vesicles (P-EVs) are considered promising functional food ingredients due to their various health benefits. In this study, blueberry extracellular vesicles (B-EVs) were collected and purified by size exclusion chromatography (SEC). The chemical compounds in B-EV extracts were analyzed by LC-MS/MS. In [...] Read more.

Plant extracellular vesicles (P-EVs) are considered promising functional food ingredients due to their various health benefits. In this study, blueberry extracellular vesicles (B-EVs) were collected and purified by size exclusion chromatography (SEC). The chemical compounds in B-EV extracts were analyzed by LC-MS/MS. In addition, the stability of B-EVs was evaluated during short- and long-term storage, heating, and in vitro digestion. The results showed that the B-EVs had a desirable particle size (88.2 ± 7.7 nm). Protein and total RNA concentrations were 582 ± 11.2 μg/mL and 15.4 μg/mL, respectively. The optimal storage temperatures for B-EVs were 4 °C and −80 °C for short- and long-term storage, respectively. Fluorescent labeling and qRT-PCR tests showed that B-EVs could be specifically internalized by Caco-2 cells, whereas virtually no cytotoxic or growth-inhibitory effects were observed. B-EVs down-regulated the expression levels of IL-1β and IL-8 and up-regulated the expression levels of NF-κβ and TLR5 in Caco-2 cells. Overall, the results proved that the intact structure of B-EVs could be preserved during food storage and processing conditions. B-EVs had the ability to reach the human intestine through oral delivery. Moreover, they could be absorbed by intestinal cells and affect human intestinal function. Full article

(This article belongs to the Section Molecular Biology)

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14 pages, 2682 KiB

Open AccessArticle

Esketamine Inhibits Cocaine-Seeking Behaviour Subsequent to Various Abstinence Conditions in Rats

by Karolina Wydra, Kacper Witek, Agata Suder and Małgorzata Filip

Biomolecules 2023, 13(9), 1411; https://doi.org/10.3390/biom13091411 - 19 Sep 2023

Cited by 2 | Viewed by 1599

Abstract

Background: Cocaine use disorder (CUD) is a relapsing brain disease caused by a chronic drug intake that involves neural mechanisms and psychological processes, including depression. Preclinical and clinical studies have demonstrated the promise of pharmacological drugs in controlling the reinstatement of cocaine by [...] Read more.

Background: Cocaine use disorder (CUD) is a relapsing brain disease caused by a chronic drug intake that involves neural mechanisms and psychological processes, including depression. Preclinical and clinical studies have demonstrated the promise of pharmacological drugs in controlling the reinstatement of cocaine by targeting the N-methyl-D-aspartate (NMDA) receptor. Recent evidence has revealed that esketamine, a (S) enantiomer of ketamine, shows a high affinity to NMDA receptors and has been used in clinical trials to treat moderate-to-severe depression. Methods: In the present paper, we investigated the effects of esketamine in regulating cocaine-seeking behaviour induced through the use of cocaine (10 mg/kg) or the cocaine-associated conditioned cue after a short (10 days)-lasting period of drug abstinence with extinction training, home cage or enrichment environment conditions in male rats. Furthermore, we investigated the acute effects of esketamine on locomotor activity in drug-naïve animals. Results: Esketamine (2.5–10 mg/kg) administered peripherally attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue after different conditions of abstinence. Conclusions: These results seem to support esketamine as a candidate for the pharmacological management of cocaine-seeking and relapse prevention; however, further preclinical and clinical research is needed to better clarify esketamine’s actions in CUD. Full article

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

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24 pages, 12175 KiB

Open AccessReview

The Role of G Protein-Coupled Estrogen Receptor (GPER) in Vascular Pathology and Physiology

by Fujie Xu, Jipeng Ma, Xiaowu Wang, Xiaoya Wang, Weiyi Fang, Jingwei Sun, Zilin Li and Jincheng Liu

Biomolecules 2023, 13(9), 1410; https://doi.org/10.3390/biom13091410 - 19 Sep 2023

Cited by 7 | Viewed by 3811

Abstract

Objective: Estrogen is indispensable in health and disease and mainly functions through its receptors. The protection of the cardiovascular system by estrogen and its receptors has been recognized for decades. Numerous studies with a focus on estrogen and its receptor system have been [...] Read more.

Objective: Estrogen is indispensable in health and disease and mainly functions through its receptors. The protection of the cardiovascular system by estrogen and its receptors has been recognized for decades. Numerous studies with a focus on estrogen and its receptor system have been conducted to elucidate the underlying mechanism. Although nuclear estrogen receptors, including estrogen receptor-α and estrogen receptor-β, have been shown to be classical receptors that mediate genomic effects, studies now show that GPER mainly mediates rapid signaling events as well as transcriptional regulation via binding to estrogen as a membrane receptor. With the discovery of selective synthetic ligands for GPER and the utilization of GPER knockout mice, significant progress has been made in understanding the function of GPER. In this review, the tissue and cellular localizations, endogenous and exogenous ligands, and signaling pathways of GPER are systematically summarized in diverse physiological and diseased conditions. This article further emphasizes the role of GPER in vascular pathology and physiology, focusing on the latest research progress and evidence of GPER as a promising therapeutic target in hypertension, pulmonary hypertension, and atherosclerosis. Thus, selective regulation of GPER by its agonists and antagonists have the potential to be used in clinical practice for treating such diseases. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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29 pages, 3166 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Calcium Overload Plays a Causal Role in Oxidative Stress in the Failing Heart

by Haikel Dridi, Gaetano Santulli, Laith Bahlouli, Marco C. Miotto, Gunnar Weninger and Andrew R. Marks

Biomolecules 2023, 13(9), 1409; https://doi.org/10.3390/biom13091409 - 19 Sep 2023

Cited by 5 | Viewed by 2825

Abstract

Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca²⁺) handling, [...] Read more.

Heart failure is a serious global health challenge, affecting more than 6.2 million people in the United States and is projected to reach over 8 million by 2030. Independent of etiology, failing hearts share common features, including defective calcium (Ca²⁺) handling, mitochondrial Ca²⁺ overload, and oxidative stress. In cardiomyocytes, Ca²⁺ not only regulates excitation–contraction coupling, but also mitochondrial metabolism and oxidative stress signaling, thereby controlling the function and actual destiny of the cell. Understanding the mechanisms of mitochondrial Ca²⁺ uptake and the molecular pathways involved in the regulation of increased mitochondrial Ca²⁺ influx is an ongoing challenge in order to identify novel therapeutic targets to alleviate the burden of heart failure. In this review, we discuss the mechanisms underlying altered mitochondrial Ca²⁺ handling in heart failure and the potential therapeutic strategies. Full article

(This article belongs to the Special Issue Molecular Basis of Cardiac Fibrotic Remodeling: Prognosis of Fibrosis in the Heart)

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17 pages, 5376 KiB

Open AccessArticle

Multi-Omics Analyses Reveal Mitochondrial Dysfunction Contributing to Temozolomide Resistance in Glioblastoma Cells

by Huaijin Zhang, Yuling Chen, Xiaohui Liu and Haiteng Deng

Biomolecules 2023, 13(9), 1408; https://doi.org/10.3390/biom13091408 - 19 Sep 2023

Cited by 2 | Viewed by 1793

Abstract

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor with poor prognosis. Temozolomide (TMZ) is the standard chemotherapy for glioblastoma treatment, but TMZ resistance significantly compromises its efficacy. In the present study, we generated a TMZ-resistant cell line and identified that [...] Read more.

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor with poor prognosis. Temozolomide (TMZ) is the standard chemotherapy for glioblastoma treatment, but TMZ resistance significantly compromises its efficacy. In the present study, we generated a TMZ-resistant cell line and identified that mitochondrial dysfunction was a novel factor contributing to TMZ resistance though multi-omics analyses and energy metabolism analysis. Furthermore, we found that rotenone treatment induced TMZ resistance to a certain level in glioblastoma cells. Notably, we further demonstrated that elevated Ca²⁺ levels and JNK–STAT3 pathway activation contributed to TMZ resistance and that inhibiting JNK or STAT3 increases susceptibility to TMZ. Taken together, our results indicate that co-administering TMZ with a JNK or STAT3 inhibitor holds promise as a potentially effective treatment for glioblastoma. Full article

(This article belongs to the Section Molecular Medicine)

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11 pages, 2168 KiB

Open AccessReview

Engineering Plastic Eating Enzymes Using Structural Biology

by Amelia Barclay and K. Ravi Acharya

Biomolecules 2023, 13(9), 1407; https://doi.org/10.3390/biom13091407 - 19 Sep 2023

Cited by 3 | Viewed by 4805

Abstract

Plastic pollution has emerged as a significant environmental concern in recent years and has prompted the exploration of innovative biotechnological solutions to mitigate plastic’s negative impact. The discovery of enzymes capable of degrading specific types of plastics holds promise as a potential solution. [...] Read more.

Plastic pollution has emerged as a significant environmental concern in recent years and has prompted the exploration of innovative biotechnological solutions to mitigate plastic’s negative impact. The discovery of enzymes capable of degrading specific types of plastics holds promise as a potential solution. However, challenges with efficiency, industrial scalability, and the diverse range of the plastic waste in question, have hindered their widespread application. Structural biology provides valuable insights into the intricate interactions between enzymes and plastic materials at an atomic level, and a deeper understanding of their underlying mechanisms is essential to harness their potential to address the mounting plastic waste crisis. This review article examines the current biochemical and biophysical methods that may facilitate the development of enzymes capable of degrading polyethylene terephthalate (PET), one of the most extensively used plastics. It also discusses the challenges that must be addressed before substantial advancements can be achieved in using these enzymes as a solution to the plastic pollution problem. Full article

(This article belongs to the Collection Feature Papers in Molecular Structure and Dynamics)

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20 pages, 10534 KiB

Open AccessArticle

SUPPRESSOR OF MAX2 LIKE 6, 7, and 8 Interact with DDB1 BINDING WD REPEAT DOMAIN HYPERSENSITIVE TO ABA DEFICIENT 1 to Regulate the Drought Tolerance and Target SUCROSE NONFERMENTING 1 RELATED PROTEIN KINASE 2.3 to Abscisic Acid Response in Arabidopsis

by Yuke Lian, Chengfei Lian, Lei Wang, Zhimin Li, Guoqiang Yuan, Lijuan Xuan, Huanhuan Gao, Haijun Wu, Tao Yang and Chongying Wang

Biomolecules 2023, 13(9), 1406; https://doi.org/10.3390/biom13091406 - 18 Sep 2023

Cited by 2 | Viewed by 1711

Abstract

SUPPRESSOR OF MAX2-LIKE 6, 7, and 8 (SMXL6,7,8) function as repressors and transcription factors of the strigolactone (SL) signaling pathway, playing an important role in the development and stress tolerance in Arabidopsis thaliana. However, the molecular mechanism by which SMXL6,7,8 negatively regulate [...] Read more.

SUPPRESSOR OF MAX2-LIKE 6, 7, and 8 (SMXL6,7,8) function as repressors and transcription factors of the strigolactone (SL) signaling pathway, playing an important role in the development and stress tolerance in Arabidopsis thaliana. However, the molecular mechanism by which SMXL6,7,8 negatively regulate drought tolerance and ABA response remains largely unexplored. In the present study, the interacting protein and downstream target genes of SMXL6,7,8 were investigated. Our results showed that the substrate receptor for the CUL4-based E3 ligase DDB1-BINDING WD-REPEAT DOMAIN (DWD) HYPERSENSITIVE TO ABA DEFICIENT 1 (ABA1) (DWA1) physically interacted with SMXL6,7,8. The degradation of SMXL6,7,8 proteins were partially dependent on DWA1. Disruption of SMXL6,7,8 resulted in increased drought tolerance and could restore the drought-sensitive phenotype of the dwa1 mutant. In addition, SMXL6,7,8 could directly bind to the promoter of SUCROSE NONFERMENTING 1 (SNF1)-RELATED PROTEIN KINASE 2.3 (SnRK2.3) to repress its transcription. The mutations in SnRK2.2/2.3 significantly suppressed the hypersensitivity of smxl6/7/8 to ABA-mediated inhibition of seed germination. Conclusively, SMXL6,7,8 interact with DWA1 to negatively regulate drought tolerance and target ABA-response genes. These data provide insights into drought tolerance and ABA response in Arabidopsis via the SMXL6,7,8-mediated SL signaling pathway. Full article

(This article belongs to the Special Issue Hormonal Control of Plant Growth and Development)

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22 pages, 3130 KiB

Open AccessPerspective

Peering into the Brain’s Estrogen Receptors: PET Tracers for Visualization of Nuclear and Extranuclear Estrogen Receptors in Brain Disorders

by Shokouh Arjmand, Dirk Bender, Steen Jakobsen, Gregers Wegener and Anne M. Landau

Biomolecules 2023, 13(9), 1405; https://doi.org/10.3390/biom13091405 - 18 Sep 2023

Viewed by 2185

Abstract

Estrogen receptors (ERs) play a multitude of roles in brain function and are implicated in various brain disorders. The use of positron emission tomography (PET) tracers for the visualization of ERs’ intricate landscape has shown promise in oncology but remains limited in the [...] Read more.

Estrogen receptors (ERs) play a multitude of roles in brain function and are implicated in various brain disorders. The use of positron emission tomography (PET) tracers for the visualization of ERs’ intricate landscape has shown promise in oncology but remains limited in the context of brain disorders. Despite recent progress in the identification and development of more selective ligands for various ERs subtypes, further optimization is necessary to enable the reliable and efficient imaging of these receptors. In this perspective, we briefly touch upon the significance of estrogen signaling in the brain and raise the setbacks associated with the development of PET tracers for identification of specific ERs subtypes in the brain. We then propose avenues for developing efficient PET tracers to non-invasively study the dynamics of ERs in the brain, as well as neuropsychiatric diseases associated with their malfunction in a longitudinal manner. This perspective puts several potential candidates on the table and highlights the unmet needs and areas requiring further research to unlock the full potential of PET tracers for ERs imaging, ultimately aiding in deepening our understanding of ERs and forging new avenues for potential therapeutic strategies. Full article

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

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8 pages, 1200 KiB

Open AccessCommunication

Tea Tree Essential Oil Kills Escherichia coli and Staphylococcus epidermidis Persisters

by LeeAnn Nguyen, Brianna DeVico, Maliha Mannan, Matthew Chang, Cristina Rada Santacruz, Christopher Siragusa, Sydney Everhart and Christopher H. Fazen

Biomolecules 2023, 13(9), 1404; https://doi.org/10.3390/biom13091404 - 18 Sep 2023

Cited by 2 | Viewed by 3547

Abstract

Persister cells are a small subpopulation of non-growing bacteria within a population that can survive long exposures to antibiotic treatment. Following antibiotic removal, persister cells can regrow and populate, playing a key role in the chronic reoccurrence of bacterial infections. The development of [...] Read more.

Persister cells are a small subpopulation of non-growing bacteria within a population that can survive long exposures to antibiotic treatment. Following antibiotic removal, persister cells can regrow and populate, playing a key role in the chronic reoccurrence of bacterial infections. The development of new molecules and methods to kill bacterial persisters is critical. Essential oils and other natural products have long been studied for their antimicrobial effects. Here, we studied the effectiveness of tea tree essential oil (TTO), a common component in many commercial care products, against Escherichia coli and Staphylococcus epidermidis persister cells. Using biphasic kill curve assays, we found that concentrations of 0.5% and 1.0% TTO for E. coli and S. epidermidis, respectively, completely eradicated persister cells over a period of 24 h, with the component terpinen-4-ol responsible for most of the killing. Using a colorimetric assay, it was determined that the TTO exhibited its anti-persister effects through a membrane disruption mechanism. Full article

(This article belongs to the Special Issue Recent Advances in Antimicrobial Agents)

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26 pages, 16279 KiB

Open AccessReview

Exploring Pan-Genomes: An Overview of Resources and Tools for Unraveling Structure, Function, and Evolution of Crop Genes and Genomes

by Sushma Naithani, Cecilia H. Deng, Sunil Kumar Sahu and Pankaj Jaiswal

Biomolecules 2023, 13(9), 1403; https://doi.org/10.3390/biom13091403 - 17 Sep 2023

Cited by 6 | Viewed by 5602

Abstract

The availability of multiple sequenced genomes from a single species made it possible to explore intra- and inter-specific genomic comparisons at higher resolution and build clade-specific pan-genomes of several crops. The pan-genomes of crops constructed from various cultivars, accessions, landraces, and wild ancestral [...] Read more.

The availability of multiple sequenced genomes from a single species made it possible to explore intra- and inter-specific genomic comparisons at higher resolution and build clade-specific pan-genomes of several crops. The pan-genomes of crops constructed from various cultivars, accessions, landraces, and wild ancestral species represent a compendium of genes and structural variations and allow researchers to search for the novel genes and alleles that were inadvertently lost in domesticated crops during the historical process of crop domestication or in the process of extensive plant breeding. Fortunately, many valuable genes and alleles associated with desirable traits like disease resistance, abiotic stress tolerance, plant architecture, and nutrition qualities exist in landraces, ancestral species, and crop wild relatives. The novel genes from the wild ancestors and landraces can be introduced back to high-yielding varieties of modern crops by implementing classical plant breeding, genomic selection, and transgenic/gene editing approaches. Thus, pan-genomic represents a great leap in plant research and offers new avenues for targeted breeding to mitigate the impact of global climate change. Here, we summarize the tools used for pan-genome assembly and annotations, web-portals hosting plant pan-genomes, etc. Furthermore, we highlight a few discoveries made in crops using the pan-genomic approach and future potential of this emerging field of study. Full article

(This article belongs to the Special Issue The Genomics Era: From Reference Genomes to Pan-Genomic Graphs)

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30 pages, 3364 KiB

Open AccessEditor’s ChoiceReview

Impact of Polyphenols on Inflammatory and Oxidative Stress Factors in Diabetes Mellitus: Nutritional Antioxidants and Their Application in Improving Antidiabetic Therapy

by Michal Krawczyk, Izabela Burzynska-Pedziwiatr, Lucyna A. Wozniak and Malgorzata Bukowiecka-Matusiak

Biomolecules 2023, 13(9), 1402; https://doi.org/10.3390/biom13091402 - 17 Sep 2023

Cited by 19 | Viewed by 4688

Abstract

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and oxidative stress. Oxidative stress plays a crucial role in the development and progression of diabetes and its complications. Nutritional antioxidants derived from dietary sources have gained significant attention due to their potential [...] Read more.

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and oxidative stress. Oxidative stress plays a crucial role in the development and progression of diabetes and its complications. Nutritional antioxidants derived from dietary sources have gained significant attention due to their potential to improve antidiabetic therapy. This review will delve into the world of polyphenols, investigating their origins in plants, metabolism in the human body, and relevance to the antioxidant mechanism in the context of improving antidiabetic therapy by attenuating oxidative stress, improving insulin sensitivity, and preserving β-cell function. The potential mechanisms of, clinical evidence for, and future perspectives on nutritional antioxidants as adjuvant therapy in diabetes management are discussed. Full article

(This article belongs to the Special Issue Biomarkers of Oxidative and Radical Stress)

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18 pages, 10864 KiB

Open AccessArticle

Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer’s Disease

by Nima Sanadgol, Javad Amini, Cordian Beyer and Adib Zendedel

Biomolecules 2023, 13(9), 1401; https://doi.org/10.3390/biom13091401 - 17 Sep 2023

Cited by 1 | Viewed by 2211

Abstract

The presenilin-1 (PSEN1) gene is crucial in developing Alzheimer’s disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia. Circular RNAs (circRNAs) are non-coding RNA generated through back-splicing, resulting in a covalently closed circular molecule. This study aimed to investigate [...] Read more.

The presenilin-1 (PSEN1) gene is crucial in developing Alzheimer’s disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia. Circular RNAs (circRNAs) are non-coding RNA generated through back-splicing, resulting in a covalently closed circular molecule. This study aimed to investigate PSEN1-gene-derived circular RNAs (circPSEN1s) and their potential functions in AD. Our in silico analysis indicated that circPSEN1s (hsa_circ_0008521 and chr14:73614502-73614802) act as sponge molecules for eight specific microRNAs. Surprisingly, two of these miRNAs (has-mir-4668-5p and has-mir-5584-5p) exclusively interact with circPSEN1s rather than mRNA-PSEN1. Furthermore, the analysis of pathways revealed that these two miRNAs predominantly target mRNAs associated with the PI3K-Akt signaling pathway. With sponging these microRNAs, circPSEN1s were found to protect mRNAs commonly targeted by these miRNAs, including QSER1, BACE2, RNF157, PTMA, and GJD3. Furthermore, the miRNAs sequestered by circPSEN1s have a notable preference for targeting the TGF-β and Hippo signaling pathways. We also demonstrated that circPSEN1s potentially interact with FOXA1, ESR1, HNF1B, BRD4, GATA4, EP300, CBX3, PRDM9, and PPARG proteins. These proteins have a prominent preference for targeting the TGF-β and Notch signaling pathways, where EP300 and FOXA1 have the highest number of protein interactions. Molecular docking analysis also confirms the interaction of these hub proteins and Aβ42 with circPSEN1s. Interestingly, circPSEN1s-targeted molecules (miRNAs and proteins) impacted TGF-β, which served as a shared signaling pathway. Finally, the analysis of microarray data unveiled distinct expression patterns of genes influenced by circPSEN1s (WTIP, TGIF, SMAD4, PPP1CB, and BMPR1A) in the brains of AD patients. In summary, our findings suggested that the interaction of circPSEN1s with microRNAs and proteins could affect the fate of specific mRNAs, interrupt the function of unique proteins, and influence cell signaling pathways, generally TGF-β. Further research is necessary to validate these findings and gain a deeper understanding of the precise mechanisms and significance of circPSEN1s in the context of AD. Full article

(This article belongs to the Special Issue Circular RNAs: Functions, Applications and Prospects)

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Open AccessBrief Report

Comprehensive Organ-Specific Profiling of Douglas Fir (Pseudotsuga menziesii) Proteome

by Caroline Teyssier, Odile Rogier, Stéphane Claverol, Florian Gautier, Marie-Anne Lelu-Walter and Harold Duruflé

Biomolecules 2023, 13(9), 1400; https://doi.org/10.3390/biom13091400 - 16 Sep 2023

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Abstract

The Douglas fir (Pseudotsuga menziesii) is a conifer native to North America that has become increasingly popular in plantations in France due to its many advantages as timber: rapid growth, quality wood, and good adaptation to climate change. Tree genetic improvement [...] Read more.

The Douglas fir (Pseudotsuga menziesii) is a conifer native to North America that has become increasingly popular in plantations in France due to its many advantages as timber: rapid growth, quality wood, and good adaptation to climate change. Tree genetic improvement programs require knowledge of a species’ genetic structure and history and the development of genetic markers. The very slow progress in this field, for Douglas fir as well as the entire genus Pinus, can be explained using the very large size of their genomes, as well as by the presence of numerous highly repeated sequences. Proteomics, therefore, provides a powerful way to access genomic information of otherwise challenging species. Here, we present the first Douglas fir proteomes acquired using nLC-MS/MS from 12 different plant organs or tissues. We identified 3975 different proteins and quantified 3462 of them, then examined the distribution of specific proteins across plant organs/tissues and their implications in various molecular processes. As the first large proteomic study of a resinous tree species with organ-specific profiling, this short note provides an important foundation for future genomic annotations of conifers and other trees. Full article

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

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Biomolecules, Volume 13, Issue 9 (September 2023) – 157 articles

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