Biomolecules

18 pages, 2907 KiB

Open AccessEditor’s ChoiceArticle

Serum N-Glycosylation RPLC-FD-MS Assay to Assess Colorectal Cancer Surgical Interventions

by Alan B. Moran, Georgia Elgood-Hunt, Yuri E. M. van der Burgt, Manfred Wuhrer, Wilma E. Mesker, Rob A. E. M. Tollenaar, Daniel I. R. Spencer and Guinevere S. M. Lageveen-Kammeijer

Biomolecules 2023, 13(6), 896; https://doi.org/10.3390/biom13060896 - 27 May 2023

Cited by 1 | Viewed by 2117

Abstract

A newly developed analytical strategy was applied to profile the total serum N-glycome of 64 colorectal cancer (CRC) patients before and after surgical intervention. In this cohort, it was previously found that serum N-glycome alterations in CRC were associated with patient [...] Read more.

A newly developed analytical strategy was applied to profile the total serum N-glycome of 64 colorectal cancer (CRC) patients before and after surgical intervention. In this cohort, it was previously found that serum N-glycome alterations in CRC were associated with patient survival. Here, fluorescent labeling of serum N-glycans was applied using procainamide and followed by sialic acid derivatization specific for α2,6- and α2,3-linkage types via ethyl esterification and amidation, respectively. This strategy allowed efficient separation of specific positional isomers on reversed-phase liquid chromatography–fluorescence detection–mass spectrometry (RPLC-FD-MS) and complemented the previous glycomics data based on matrix-assisted laser desorption/ionization (MALDI)-MS that did not include such separations. The results from comparing pre-operative CRC to post-operative samples were in agreement with studies that identified a decrease in di-antennary structures with core fucosylation and an increase in sialylated tri- and tetra-antennary N-glycans in CRC patient sera. Pre-operative abundances of N-glycans showed good performance for the classification of adenocarcinoma and led to the revisit of the previous MALDI-MS dataset with regard to histological and clinical data. This strategy has the potential to monitor patient profiles before, during, and after clinical events such as treatment, therapy, or surgery and should also be further explored. Full article

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

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18 pages, 3951 KiB

Open AccessEditor’s ChoiceArticle

Circulating Hsp70 Levels and the Immunophenotype of Peripheral Blood Lymphocytes as Potential Biomarkers for Advanced Lung Cancer and Therapy Failure after Surgery

by Seyer Safi, Luis Messner, Merten Kliebisch, Linn Eggert, Ceyra Ceylangil, Philipp Lennartz, Benedict Jefferies, Henriette Klein, Moritz Schirren, Michael Dommasch, Dominik Lobinger and Gabriele Multhoff

Biomolecules 2023, 13(5), 874; https://doi.org/10.3390/biom13050874 - 22 May 2023

Cited by 2 | Viewed by 1524

Abstract

Lung cancer remains a devastating disease with a poor clinical outcome. A biomarker signature which could distinguish lung cancer from metastatic disease and detect therapeutic failure would significantly improve patient management and allow for individualized, risk-adjusted therapeutic decisions. In this study, circulating Hsp70 [...] Read more.

Lung cancer remains a devastating disease with a poor clinical outcome. A biomarker signature which could distinguish lung cancer from metastatic disease and detect therapeutic failure would significantly improve patient management and allow for individualized, risk-adjusted therapeutic decisions. In this study, circulating Hsp70 levels were measured using ELISA, and the immunophenotype of the peripheral blood lymphocytes were measured using multiparameter flow cytometry, to identify a predictive biomarker signature for lung cancer patients pre- and post-operatively, in patients with lung metastases and in patients with COPD as an inflammatory lung disease. The lowest Hsp70 concentrations were found in the healthy controls followed by the patients with advanced COPD. Hsp70 levels sequentially increased with an advancing tumor stage and metastatic disease. In the early-recurrence patients, Hsp70 levels started to increase within the first three months after surgery, but remained unaltered in the recurrence-free patients. An early recurrence was associated with a significant drop in B cells and an increase in Tregs, whereas the recurrence-free patients had elevated T and NK cell levels. We conclude that circulating Hsp70 concentrations might have the potential to distinguish lung cancer from metastatic disease, and might be able to predict an advanced tumor stage and early recurrence in lung cancer patients. Further studies with larger patient cohorts and longer follow-up periods are needed to validate Hsp70 and immunophenotypic profiles as predictive biomarker signatures. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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15 pages, 612 KiB

Open AccessEditor’s ChoiceReview

Thermal Effect on Heat Shock Protein 70 Family to Prevent Atherosclerotic Cardiovascular Disease

by Masayo Nagai and Hidesuke Kaji

Biomolecules 2023, 13(5), 867; https://doi.org/10.3390/biom13050867 - 20 May 2023

Cited by 3 | Viewed by 1316

Abstract

Heat shock protein 70 (HSP70) is a chaperone protein induced by various stresses on cells and is involved in various disease mechanisms. In recent years, the expression of HSP70 in skeletal muscle has attracted attention for its use as a prevention of atherosclerotic [...] Read more.

Heat shock protein 70 (HSP70) is a chaperone protein induced by various stresses on cells and is involved in various disease mechanisms. In recent years, the expression of HSP70 in skeletal muscle has attracted attention for its use as a prevention of atherosclerotic cardiovascular disease (ASCVD) and as a disease marker. We have previously reported the effect of thermal stimulation targeted to skeletal muscles and skeletal muscle-derived cells. In this article, we reported review articles including our research results. HSP70 contributes to the improvement of insulin resistance as well as chronic inflammation which are underlying pathologies of type 2 diabetes, obesity, and atherosclerosis. Thus, induction of HSP70 expression by external stimulation such as heat and exercise may be useful for ASCVD prevention. It may be possible to induce HSP70 by thermal stimulus in those who have difficulty in exercise because of obesity or locomotive syndrome. It requires further investigation to determine whether monitoring serum HSP70 concentration is useful for ASCVD prevention. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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17 pages, 5746 KiB

Open AccessEditor’s ChoiceArticle

The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling

by Sandip Mukherjee, Molee Chakraborty, Jake Haubner, Glen Ernst, Michael DePasquale, Danielle Carpenter, James C. Barrow and Anutosh Chakraborty

Biomolecules 2023, 13(5), 868; https://doi.org/10.3390/biom13050868 - 20 May 2023

Cited by 4 | Viewed by 1831

Abstract

Obesity and nonalcoholic fatty liver disease (NAFLD) are global health concerns, and thus, drugs for the long-term treatment of these diseases are urgently needed. We previously discovered that the inositol pyrophosphate biosynthetic enzyme IP6K1 is a target in diet-induced obesity (DIO), insulin resistance, [...] Read more.

Obesity and nonalcoholic fatty liver disease (NAFLD) are global health concerns, and thus, drugs for the long-term treatment of these diseases are urgently needed. We previously discovered that the inositol pyrophosphate biosynthetic enzyme IP6K1 is a target in diet-induced obesity (DIO), insulin resistance, and NAFLD. Moreover, high-throughput screening (HTS) assays and structure−activity relationship (SAR) studies identified LI-2242 as a potent IP6K inhibitor compound. Here, we tested the efficacy of LI-2242 in DIO WT C57/BL6J mice. LI-2242 (20 mg/kg/BW daily, i.p.) reduced body weight in DIO mice by specifically reducing the accumulation of body fat. It also improved glycemic parameters and reduced hyperinsulinemia. LI-2242-treated mice displayed reduced the weight of various adipose tissue depots and an increased expression of metabolism- and mitochondrial-energy-oxidation-inducing genes in these tissues. LI-2242 also ameliorated hepatic steatosis by reducing the expression of genes that enhance lipid uptake, lipid stabilization, and lipogenesis. Furthermore, LI-2242 enhances the mitochondrial oxygen consumption rate (OCR) and insulin signaling in adipocytes and hepatocytes in vitro. In conclusion, the pharmacologic inhibition of the inositol pyrophosphate pathway by LI-2242 has therapeutic potential in obesity and NAFLD. Full article

(This article belongs to the Special Issue Inositol Phosphates in Health and Disease)

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19 pages, 3251 KiB

Open AccessEditor’s ChoiceArticle

Enhanced L-β-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine

by Kouji Fukuyama, Eishi Motomura and Motohiro Okada

Biomolecules 2023, 13(5), 862; https://doi.org/10.3390/biom13050862 - 19 May 2023

Cited by 2 | Viewed by 1585

Abstract

Clozapine is an effective antipsychotic for the treatment of antipsychotic-resistant schizophrenia; however, specific types of A/B adverse effects and clozapine-discontinuation syndromes are also well known. To date, both the critical mechanisms of clinical actions (effective for antipsychotic-resistant schizophrenia) and the adverse effects of [...] Read more.

Clozapine is an effective antipsychotic for the treatment of antipsychotic-resistant schizophrenia; however, specific types of A/B adverse effects and clozapine-discontinuation syndromes are also well known. To date, both the critical mechanisms of clinical actions (effective for antipsychotic-resistant schizophrenia) and the adverse effects of clozapine remain to be elucidated. Recently, we demonstrated that clozapine increased the synthesis of L-β-aminoisobutyric acid (L-BAIBA) in the hypothalamus. L-BAIBA is an activator of the adenosine monophosphate-activated protein kinase (AMPK), glycine receptor, GABA_A receptor, and GABA_B receptor (GABA_B-R). These targets of L-BAIBA overlap as potential targets other than the monoamine receptors of clozapine. However, the direct binding of clozapine to these aminoacidic transmitter/modulator receptors remains to be clarified. Therefore, to explore the contribution of increased L-BAIBA on the clinical action of clozapine, this study determined the effects of clozapine and L-BAIBA on tripartite synaptic transmission, including GABA_B-R and the group-III metabotropic glutamate receptor (III-mGluR) using cultured astrocytes, as well as on the thalamocortical hyper-glutamatergic transmission induced by impaired glutamate/NMDA receptors using microdialysis. Clozapine increased astroglial L-BAIBA synthesis in time/concentration-dependent manners. Increased L-BAIBA synthesis was observed until 3 days after clozapine discontinuation. Clozapine did not directly bind III-mGluR or GABA_B-R, whereas L-BAIBA activated these receptors in the astrocytes. Local administration of MK801 into the reticular thalamic nucleus (RTN) increased L-glutamate release in the medial frontal cortex (mPFC) (MK801-evoked L-glutamate release). Local administration of L-BAIBA into the mPFC suppressed MK801-evoked L-glutamate release. These actions of L-BAIBA were inhibited by antagonists of III-mGluR and GABA_B-R, similar to clozapine. These in vitro and in vivo analyses suggest that increased frontal L-BAIBA signaling likely plays an important role in the pharmacological actions of clozapine, such as improving the effectiveness of treating treatment-resistant schizophrenia and several clozapine discontinuation syndromes via the activation of III-mGluR and GABA_B-R in the mPFC. Full article

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

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18 pages, 977 KiB

Open AccessEditor’s ChoiceReview

Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models

by Katarina Maksimovic, Mohieldin Youssef, Justin You, Hoon-Ki Sung and Jeehye Park

Biomolecules 2023, 13(5), 863; https://doi.org/10.3390/biom13050863 - 19 May 2023

Cited by 4 | Viewed by 4027

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS. Full article

(This article belongs to the Special Issue Stress, Aging and Metabolism)

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26 pages, 9848 KiB

Open AccessEditor’s ChoiceReview

Emerging Quantitative Biochemical, Structural, and Biophysical Methods for Studying Ribosome and Protein–RNA Complex Assembly

by Kavan Gor and Olivier Duss

Biomolecules 2023, 13(5), 866; https://doi.org/10.3390/biom13050866 - 19 May 2023

Cited by 3 | Viewed by 2459

Abstract

Ribosome assembly is one of the most fundamental processes of gene expression and has served as a playground for investigating the molecular mechanisms of how protein–RNA complexes (RNPs) assemble. A bacterial ribosome is composed of around 50 ribosomal proteins, several of which are [...] Read more.

Ribosome assembly is one of the most fundamental processes of gene expression and has served as a playground for investigating the molecular mechanisms of how protein–RNA complexes (RNPs) assemble. A bacterial ribosome is composed of around 50 ribosomal proteins, several of which are co-transcriptionally assembled on a ~4500-nucleotide-long pre-rRNA transcript that is further processed and modified during transcription, the entire process taking around 2 min in vivo and being assisted by dozens of assembly factors. How this complex molecular process works so efficiently to produce an active ribosome has been investigated over decades, resulting in the development of a plethora of novel approaches that can also be used to study the assembly of other RNPs in prokaryotes and eukaryotes. Here, we review biochemical, structural, and biophysical methods that have been developed and integrated to provide a detailed and quantitative understanding of the complex and intricate molecular process of bacterial ribosome assembly. We also discuss emerging, cutting-edge approaches that could be used in the future to study how transcription, rRNA processing, cellular factors, and the native cellular environment shape ribosome assembly and RNP assembly at large. Full article

(This article belongs to the Special Issue Ribosomal Proteins in Ribosome Assembly)

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19 pages, 1589 KiB

Open AccessEditor’s ChoiceReview

Altered Purinergic Signaling in Neurodevelopmental Disorders: Focus on P2 Receptors

by Marta Boccazzi, Stefano Raffaele, Thomas Zanettin, Maria P. Abbracchio and Marta Fumagalli

Biomolecules 2023, 13(5), 856; https://doi.org/10.3390/biom13050856 - 18 May 2023

Cited by 3 | Viewed by 1862

Abstract

With the umbrella term ‘neurodevelopmental disorders’ (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary [...] Read more.

With the umbrella term ‘neurodevelopmental disorders’ (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary for the proper development of fetal brain cytoarchitecture and functionality. In recent years, several genetic disorders caused by mutations in key enzymes involved in purine metabolism have been associated with autism-like behavioral outcomes. Further analysis revealed dysregulated purine and pyrimidine levels in the biofluids of subjects with other NDDs. Moreover, the pharmacological blockade of specific purinergic pathways reversed the cognitive and behavioral defects caused by maternal immune activation, a validated and now extensively used rodent model for NDDs. Furthermore, Fragile X and Rett syndrome transgenic animal models as well as models of premature birth, have been successfully utilized to investigate purinergic signaling as a potential pharmacological target for these diseases. In this review, we examine results on the role of the P2 receptor signaling in the etiopathogenesis of NDDs. On this basis, we discuss how this evidence could be exploited to develop more receptor-specific ligands for future therapeutic interventions and novel prognostic markers for the early detection of these conditions. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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41 pages, 4159 KiB

Open AccessEditor’s ChoiceReview

(Patho)Physiology of Glycosylphosphatidylinositol-Anchored Proteins I: Localization at Plasma Membranes and Extracellular Compartments

by Günter A. Müller and Timo D. Müller

Biomolecules 2023, 13(5), 855; https://doi.org/10.3390/biom13050855 - 18 May 2023

Cited by 5 | Viewed by 3023

Abstract

Glycosylphosphatidylinositol (GPI)-anchored proteins (APs) are anchored at the outer leaflet of plasma membranes (PMs) of all eukaryotic organisms studied so far by covalent linkage to a highly conserved glycolipid rather than a transmembrane domain. Since their first description, experimental data have been accumulating [...] Read more.

Glycosylphosphatidylinositol (GPI)-anchored proteins (APs) are anchored at the outer leaflet of plasma membranes (PMs) of all eukaryotic organisms studied so far by covalent linkage to a highly conserved glycolipid rather than a transmembrane domain. Since their first description, experimental data have been accumulating for the capability of GPI-APs to be released from PMs into the surrounding milieu. It became evident that this release results in distinct arrangements of GPI-APs which are compatible with the aqueous milieu upon loss of their GPI anchor by (proteolytic or lipolytic) cleavage or in the course of shielding of the full-length GPI anchor by incorporation into extracellular vesicles, lipoprotein-like particles and (lyso)phospholipid- and cholesterol-harboring micelle-like complexes or by association with GPI-binding proteins or/and other full-length GPI-APs. In mammalian organisms, the (patho)physiological roles of the released GPI-APs in the extracellular environment, such as blood and tissue cells, depend on the molecular mechanisms of their release as well as the cell types and tissues involved, and are controlled by their removal from circulation. This is accomplished by endocytic uptake by liver cells and/or degradation by GPI-specific phospholipase D in order to bypass potential unwanted effects of the released GPI-APs or their transfer from the releasing donor to acceptor cells (which will be reviewed in a forthcoming manuscript). Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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18 pages, 3411 KiB

Open AccessEditor’s ChoiceReview

Ribosomal Protein uS5 and Friends: Protein–Protein Interactions Involved in Ribosome Assembly and Beyond

by Anne-Marie Landry-Voyer, Zabih Mir Hassani, Mariano Avino and François Bachand

Biomolecules 2023, 13(5), 853; https://doi.org/10.3390/biom13050853 - 18 May 2023

Cited by 4 | Viewed by 1965

Abstract

Ribosomal proteins are fundamental components of the ribosomes in all living cells. The ribosomal protein uS5 (Rps2) is a stable component of the small ribosomal subunit within all three domains of life. In addition to its interactions with proximal ribosomal proteins and rRNA [...] Read more.

Ribosomal proteins are fundamental components of the ribosomes in all living cells. The ribosomal protein uS5 (Rps2) is a stable component of the small ribosomal subunit within all three domains of life. In addition to its interactions with proximal ribosomal proteins and rRNA inside the ribosome, uS5 has a surprisingly complex network of evolutionarily conserved non-ribosome-associated proteins. In this review, we focus on a set of four conserved uS5-associated proteins: the protein arginine methyltransferase 3 (PRMT3), the programmed cell death 2 (PDCD2) and its PDCD2-like (PDCD2L) paralog, and the zinc finger protein, ZNF277. We discuss recent work that presents PDCD2 and homologs as a dedicated uS5 chaperone and PDCD2L as a potential adaptor protein for the nuclear export of pre-40S subunits. Although the functional significance of the PRMT3–uS5 and ZNF277–uS5 interactions remain elusive, we reflect on the potential roles of uS5 arginine methylation by PRMT3 and on data indicating that ZNF277 and PRMT3 compete for uS5 binding. Together, these discussions highlight the complex and conserved regulatory network responsible for monitoring the availability and the folding of uS5 for the formation of 40S ribosomal subunits and/or the role of uS5 in potential extra-ribosomal functions. Full article

(This article belongs to the Special Issue Ribosomal Proteins in Ribosome Assembly)

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26 pages, 1574 KiB

Open AccessEditor’s ChoiceReview

Microvascular Contributions to Alzheimer Disease Pathogenesis: Is Alzheimer Disease Primarily an Endotheliopathy?

by Rawan Tarawneh

Biomolecules 2023, 13(5), 830; https://doi.org/10.3390/biom13050830 - 13 May 2023

Cited by 1 | Viewed by 4336

Abstract

Alzheimer disease (AD) models are based on the notion that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset, and culminates in neurodegeneration; however, emerging evidence from animal and clinical studies suggests that [...] Read more.

Alzheimer disease (AD) models are based on the notion that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset, and culminates in neurodegeneration; however, emerging evidence from animal and clinical studies suggests that reduced blood flow due to capillary loss and endothelial dysfunction are early and primary events in AD pathogenesis, which may precede amyloid and tau aggregation, and contribute to neuronal and synaptic injury via direct and indirect mechanisms. Recent data from clinical studies suggests that endothelial dysfunction is closely associated with cognitive outcomes in AD and that therapeutic strategies which promote endothelial repair in early AD may offer a potential opportunity to prevent or slow disease progression. This review examines evidence from clinical, imaging, neuropathological, and animal studies supporting vascular contributions to the onset and progression of AD pathology. Together, these observations support the notion that the onset of AD may be primarily influenced by vascular, rather than neurodegenerative, mechanisms and emphasize the importance of further investigations into the vascular hypothesis of AD. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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26 pages, 816 KiB

Open AccessEditor’s ChoiceReview

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System

by Kenneth Maiese

Biomolecules 2023, 13(5), 816; https://doi.org/10.3390/biom13050816 - 11 May 2023

Cited by 10 | Viewed by 3531

Abstract

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral [...] Read more.

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer’s disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked. Full article

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12 pages, 1454 KiB

Open AccessEditor’s ChoiceArticle

Role of the MDR Efflux Pump AcrAB in Epithelial Cell Invasion by Shigella flexneri

by Marco Coluccia, Aude Béranger, Rita Trirocco, Giulia Fanelli, Francesco Zanzi, Bianca Colonna, Milena Grossi, Gianni Prosseda and Martina Pasqua

Biomolecules 2023, 13(5), 823; https://doi.org/10.3390/biom13050823 - 11 May 2023

Cited by 3 | Viewed by 1708

Abstract

The tripartite complex AcrAB-TolC is the major RND pump in Escherichia coli and other Enterobacteriaceae, including Shigella, the etiological agent of bacillary dysentery. In addition to conferring resistance to many classes of antibiotics, AcrAB plays a role in the pathogenesis and virulence [...] Read more.

The tripartite complex AcrAB-TolC is the major RND pump in Escherichia coli and other Enterobacteriaceae, including Shigella, the etiological agent of bacillary dysentery. In addition to conferring resistance to many classes of antibiotics, AcrAB plays a role in the pathogenesis and virulence of several bacterial pathogens. Here, we report data demonstrating that AcrAB specifically contributes to Shigella flexneri invasion of epithelial cells. We found that deletion of both acrA and acrB genes causes reduced survival of S. flexneri M90T strain within Caco-2 epithelial cells and prevents cell-to-cell spread of the bacteria. Infections with single deletion mutant strains indicate that both AcrA and AcrB favor the viability of the intracellular bacteria. Finally, we were able to further confirm the requirement of the AcrB transporter activity for intraepithelial survival by using a specific EP inhibitor. Overall, the data from the present study expand the role of the AcrAB pump to an important human pathogen, such as Shigella, and add insights into the mechanism governing the Shigella infection process. Full article

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

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19 pages, 4128 KiB

Open AccessEditor’s ChoiceArticle

Evolution of the Immunoglobulin Isotypes—Variations of Biophysical Properties among Animal Classes

by Nancy D. Pomarici, Roberta Cacciato, Janik Kokot, Monica L. Fernández-Quintero and Klaus R. Liedl

Biomolecules 2023, 13(5), 801; https://doi.org/10.3390/biom13050801 - 08 May 2023

Cited by 1 | Viewed by 1985

Abstract

The adaptive immune system arose around 500 million years ago in jawed fish, and, since then, it has mediated the immune defense against pathogens in all vertebrates. Antibodies play a central role in the immune reaction, recognizing and attacking external invaders. During the [...] Read more.

The adaptive immune system arose around 500 million years ago in jawed fish, and, since then, it has mediated the immune defense against pathogens in all vertebrates. Antibodies play a central role in the immune reaction, recognizing and attacking external invaders. During the evolutionary process, several immunoglobulin isotypes emerged, each having a characteristic structural organization and dedicated function. In this work, we investigate the evolution of the immunoglobulin isotypes, in order to highlight the relevant features that were preserved over time and the parts that, instead, mutated. The residues that are coupled in the evolution process are often involved in intra- or interdomain interactions, meaning that they are fundamental to maintaining the immunoglobulin fold and to ensuring interactions with other domains. The explosive growth of available sequences allows us to point out the evolutionary conserved residues and compare the biophysical properties among different animal classes and isotypes. Our study offers a general overview of the evolution of immunoglobulin isotypes and advances the knowledge of their characteristic biophysical properties, as a first step in guiding protein design from evolution. Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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29 pages, 2633 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Strategies for Spinocerebellar Ataxia Type 1

by Laurie M. C. Kerkhof, Bart P. C. van de Warrenburg, Willeke M. C. van Roon-Mom and Ronald A. M. Buijsen

Biomolecules 2023, 13(5), 788; https://doi.org/10.3390/biom13050788 - 02 May 2023

Viewed by 4169

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the ATXN1 gene and is characterized mostly by a profound loss [...] Read more.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the ATXN1 gene and is characterized mostly by a profound loss of cerebellar Purkinje cells, leading to disturbances in coordination, balance, and gait. At present, no curative treatment is available for SCA1. However, increasing knowledge on the cellular and molecular mechanisms of SCA1 has led the way towards several therapeutic strategies that can potentially slow disease progression. SCA1 therapeutics can be classified as genetic, pharmacological, and cell replacement therapies. These different therapeutic strategies target either the (mutant) ATXN1 RNA or the ataxin-1 protein, pathways that play an important role in downstream SCA1 disease mechanisms or which help restore cells that are lost due to SCA1 pathology. In this review, we will provide a summary of the different therapeutic strategies that are currently being investigated for SCA1. Full article

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

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19 pages, 435 KiB

Open AccessEditor’s ChoiceReview

Mechanisms Controlling the Expression and Secretion of BDNF

by Juan Carlos Arévalo and Rubén Deogracias

Biomolecules 2023, 13(5), 789; https://doi.org/10.3390/biom13050789 - 02 May 2023

Cited by 9 | Viewed by 3830

Abstract

Brain-derived nerve factor (BDNF), through TrkB receptor activation, is an important modulator for many different physiological and pathological functions in the nervous system. Among them, BDNF plays a crucial role in the development and correct maintenance of brain circuits and synaptic plasticity as [...] Read more.

Brain-derived nerve factor (BDNF), through TrkB receptor activation, is an important modulator for many different physiological and pathological functions in the nervous system. Among them, BDNF plays a crucial role in the development and correct maintenance of brain circuits and synaptic plasticity as well as in neurodegenerative diseases. The proper functioning of the central nervous system depends on the available BDNF concentrations, which are tightly regulated at transcriptional and translational levels but also by its regulated secretion. In this review we summarize the new advances regarding the molecular players involved in BDNF release. In addition, we will address how changes of their levels or function in these proteins have a great impact in those functions modulated by BDNF under physiological and pathological conditions. Full article

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

20 pages, 1556 KiB

Open AccessEditor’s ChoiceReview

Role of Angiotensin II in Cardiovascular Diseases: Introducing Bisartans as a Novel Therapy for Coronavirus 2019

by Jordan Swiderski, Laura Kate Gadanec, Vasso Apostolopoulos, Graham J. Moore, Konstantinos Kelaidonis, John M. Matsoukas and Anthony Zulli

Biomolecules 2023, 13(5), 787; https://doi.org/10.3390/biom13050787 - 02 May 2023

Cited by 3 | Viewed by 4068

Abstract

Cardiovascular diseases (CVDs) are the main contributors to global morbidity and mortality. Major pathogenic phenotypes of CVDs include the development of endothelial dysfunction, oxidative stress, and hyper-inflammatory responses. These phenotypes have been found to overlap with the pathophysiological complications of coronavirus disease 2019 [...] Read more.

Cardiovascular diseases (CVDs) are the main contributors to global morbidity and mortality. Major pathogenic phenotypes of CVDs include the development of endothelial dysfunction, oxidative stress, and hyper-inflammatory responses. These phenotypes have been found to overlap with the pathophysiological complications of coronavirus disease 2019 (COVID-19). CVDs have been identified as major risk factors for severe and fatal COVID-19 states. The renin–angiotensin system (RAS) is an important regulatory system in cardiovascular homeostasis. However, its dysregulation is observed in CVDs, where upregulation of angiotensin type 1 receptor (AT₁R) signaling via angiotensin II (AngII) leads to the AngII-dependent pathogenic development of CVDs. Additionally, the interaction between the spike protein of severe acute respiratory syndrome coronavirus 2 with angiotensin-converting enzyme 2 leads to the downregulation of the latter, resulting in the dysregulation of the RAS. This dysregulation favors AngII/AT₁R toxic signaling pathways, providing a mechanical link between cardiovascular pathology and COVID-19. Therefore, inhibiting AngII/AT₁R signaling through angiotensin receptor blockers (ARBs) has been indicated as a promising therapeutic approach to the treatment of COVID-19. Herein, we review the role of AngII in CVDs and its upregulation in COVID-19. We also provide a future direction for the potential implication of a novel class of ARBs called bisartans, which are speculated to contain multifunctional targeting towards COVID-19. Full article

(This article belongs to the Special Issue The Role of Angiotensin in Cardiovascular Disease)

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23 pages, 6079 KiB

Open AccessEditor’s ChoiceReview

Relaxin-like Gonad-Stimulating Peptides in Asteroidea

by Masatoshi Mita

Biomolecules 2023, 13(5), 781; https://doi.org/10.3390/biom13050781 - 30 Apr 2023

Cited by 5 | Viewed by 3714

Abstract

Starfish relaxin-like gonad-stimulating peptide (RGP) is the first identified peptide hormone with gonadotropin-like activity in invertebrates. RGP is a heterodimeric peptide, comprising A and B chains with disulfide cross-linkages. Although RGP had been named a gonad-stimulating substance (GSS), the purified peptide is a [...] Read more.

Starfish relaxin-like gonad-stimulating peptide (RGP) is the first identified peptide hormone with gonadotropin-like activity in invertebrates. RGP is a heterodimeric peptide, comprising A and B chains with disulfide cross-linkages. Although RGP had been named a gonad-stimulating substance (GSS), the purified peptide is a member of relaxin-type peptide family. Thus, GSS was renamed as RGP. The cDNA of RGP encodes not only the A and B chains, but also signal and C-peptides. After the rgp gene is translated as a precursor, mature RGP is produced by eliminating the signal and C-peptides. Hitherto, twenty-four RGP orthologs have been identified or predicted from starfish in the orders Valvatida, Forcipulatida, Paxillosida, Spinulosida, and Velatida. The molecular evolution of the RGP family is in good accordance with the phylogenetic taxonomy in Asteroidea. Recently, another relaxin-like peptide with gonadotropin-like activity, RLP2, was found in starfish. RGP is mainly present in the radial nerve cords and circumoral nerve rings, but also in the arm tips, the gonoducts, and the coelomocytes. RGP acts on ovarian follicle cells and testicular interstitial cells to induce the production of 1-methyladenine (1-MeAde), a starfish maturation-inducing hormone. RGP-induced 1-MeAde production is accompanied by an increase in intracellular cyclic AMP levels. This suggests that the receptor for RGP (RGPR) is a G protein-coupled receptor (GPCR). Two types of GPCRs, RGPR1 and RGPR2, have been postulated as candidates. Furthermore, 1-MeAde produced by RGP not only induces oocyte maturation, but also induces gamete shedding, possibly by stimulating the secretion of acetylcholine in the ovaries and testes. Thus, RGP plays an important role in starfish reproduction, but its secretion mechanism is still unknown. It has also been revealed that RGP is found in the peripheral adhesive papillae of the brachiolaria arms. However, gonads are not developed in the larvae before metamorphosis. It may be possible to discover new physiological functions of RGP other than gonadotropin-like activity. Full article

(This article belongs to the Special Issue Gametogenesis and Gamete Interaction)

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21 pages, 3287 KiB

Open AccessEditor’s ChoiceArticle

Mice Mutated in the Third Fibronectin Domain of L1 Show Enhanced Hippocampal Neuronal Cell Death, Astrogliosis and Alterations in Behavior

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

Biomolecules 2023, 13(5), 776; https://doi.org/10.3390/biom13050776 - 29 Apr 2023

Cited by 2 | Viewed by 1579

Abstract

Adhesion molecules play major roles in cell proliferation, migration, survival, neurite outgrowth and synapse formation during nervous system development and in adulthood. The neural cell adhesion molecule L1 contributes to these functions during development and in synapse formation and synaptic plasticity after trauma [...] Read more.

Adhesion molecules play major roles in cell proliferation, migration, survival, neurite outgrowth and synapse formation during nervous system development and in adulthood. The neural cell adhesion molecule L1 contributes to these functions during development and in synapse formation and synaptic plasticity after trauma in adulthood. Mutations of L1 in humans result in L1 syndrome, which is associated with mild-to-severe brain malformations and mental disabilities. Furthermore, mutations in the extracellular domain were shown to cause a severe phenotype more often than mutations in the intracellular domain. To explore the outcome of a mutation in the extracellular domain, we generated mice with disruption of the dibasic sequences RK and KR that localize to position ₈₅₈RKHSKR₈₆₃ in the third fibronectin type III domain of murine L1. These mice exhibit alterations in exploratory behavior and enhanced marble burying activity. Mutant mice display higher numbers of caspase 3-positive neurons, a reduced number of principle neurons in the hippocampus, and an enhanced number of glial cells. Experiments suggest that disruption of the dibasic sequence in L1 results in subtle impairments in brain structure and functions leading to obsessive-like behavior in males and reduced anxiety in females. Full article

(This article belongs to the Special Issue More than Just Adhesion: Recognition Molecules, a Theme Issue Honoring Professor Melitta Schachner)

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17 pages, 6737 KiB

Open AccessEditor’s ChoiceArticle

Unexpected Distribution of Chitin and Chitin Synthase across Soft-Bodied Cnidarians

by Lauren E. Vandepas, Michael G. Tassia, Kenneth M. Halanych and Chris T. Amemiya

Biomolecules 2023, 13(5), 777; https://doi.org/10.3390/biom13050777 - 29 Apr 2023

Cited by 2 | Viewed by 2015

Abstract

Cnidarians are commonly recognized as sea jellies, corals, or complex colonies such as the Portuguese man-of-war. While some cnidarians possess rigid internal calcareous skeletons (e.g., corals), many are soft-bodied. Intriguingly, genes coding for the chitin-biosynthetic enzyme, chitin synthase (CHS), were recently identified [...] Read more.

Cnidarians are commonly recognized as sea jellies, corals, or complex colonies such as the Portuguese man-of-war. While some cnidarians possess rigid internal calcareous skeletons (e.g., corals), many are soft-bodied. Intriguingly, genes coding for the chitin-biosynthetic enzyme, chitin synthase (CHS), were recently identified in the model anemone Nematostella vectensis, a species lacking hard structures. Here we report the prevalence and diversity of CHS across Cnidaria and show that cnidarian chitin synthase genes display diverse protein domain organizations. We found that CHS is expressed in cnidarian species and/or developmental stages with no reported chitinous or rigid morphological structures. Chitin affinity histochemistry indicates that chitin is present in soft tissues of some scyphozoan and hydrozoan medusae. To further elucidate the biology of chitin in cnidarian soft tissues, we focused on CHS expression in N. vectensis. Spatial expression data show that three CHS orthologs are differentially expressed in Nematostella embryos and larvae during development, suggesting that chitin has an integral role in the biology of this species. Understanding how a non-bilaterian lineage such as Cnidaria employs chitin may provide new insight into hitherto unknown functions of polysaccharides in animals, as well as their role in the evolution of biological novelty. Full article

(This article belongs to the Collection Feature Papers in Biochemistry)

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13 pages, 1831 KiB

Open AccessEditor’s ChoiceArticle

Glucose Transporter Glut1-Dependent Metabolic Reprogramming Regulates Lipopolysaccharide-Induced Inflammation in RAW264.7 Macrophages

by Alex Cornwell, Hubert Ziółkowski and Alireza Badiei

Biomolecules 2023, 13(5), 770; https://doi.org/10.3390/biom13050770 - 29 Apr 2023

Cited by 2 | Viewed by 2252

Abstract

This study investigated the critical role of Glut1-mediated glucose metabolism in the inflammatory response of macrophages, which are energy-intensive cells within the innate immune system. Inflammation leads to increased Glut1 expression, ensuring sufficient glucose uptake to support macrophage functions. We demonstrated that using [...] Read more.

This study investigated the critical role of Glut1-mediated glucose metabolism in the inflammatory response of macrophages, which are energy-intensive cells within the innate immune system. Inflammation leads to increased Glut1 expression, ensuring sufficient glucose uptake to support macrophage functions. We demonstrated that using siRNA to knock down Glut1 reduces the expression of various pro-inflammatory cytokines and markers, such as IL-6, iNOS, MHC II/CD40, reactive oxygen species, and the hydrogen sulfide (H₂S)-producing enzyme cystathionine γ-lyase (CSE). Glut1 activates a pro-inflammatory profile through a nuclear factor (NF)-κB, while silencing Glut1 can prevent lipopolysaccharide (LPS)-induced IκB degradation, blocking NF-κB activation. Glut1’s role in autophagy, an essential process for macrophage functions such as antigen presentation, phagocytosis, and cytokine secretion, was also measured. The findings show that LPS stimulation decreases autophagosome formation, but Glut1 knockdown reverses this effect, increasing autophagy beyond control levels. The study highlights Glut1’s importance in macrophage immune responses and its regulation of apoptosis during LPS stimulation. Knocking down Glut1 negatively impacts cell viability and mitochondrial intrinsic pathway signaling. These findings collectively suggest that targeting macrophage glucose metabolism through Glut1 could potentially serve as a target for controlling inflammation. Full article

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14 pages, 2601 KiB

Open AccessEditor’s ChoiceReview

Cardiac Imaging Biomarkers in Chronic Kidney Disease

by Silvia C. Valbuena-López, Giovanni Camastra, Luca Cacciotti, Eike Nagel, Valentina O. Puntmann and Luca Arcari

Biomolecules 2023, 13(5), 773; https://doi.org/10.3390/biom13050773 - 29 Apr 2023

Cited by 2 | Viewed by 2182

Abstract

Uremic cardiomyopathy (UC), the peculiar cardiac remodeling secondary to the systemic effects of renal dysfunction, is characterized by left ventricular (LV) diffuse fibrosis with hypertrophy (LVH) and stiffness and the development of heart failure and increased rates of cardiovascular mortality. Several imaging modalities [...] Read more.

Uremic cardiomyopathy (UC), the peculiar cardiac remodeling secondary to the systemic effects of renal dysfunction, is characterized by left ventricular (LV) diffuse fibrosis with hypertrophy (LVH) and stiffness and the development of heart failure and increased rates of cardiovascular mortality. Several imaging modalities can be used to obtain a non-invasive assessment of UC by different imaging biomarkers, which is the focus of the present review. Echocardiography has been largely employed in recent decades, especially for the determination of LVH by 2-dimensional imaging and diastolic dysfunction by pulsed-wave and tissue Doppler, where it retains a robust prognostic value; more recent techniques include parametric assessment of cardiac deformation by speckle tracking echocardiography and the use of 3D-imaging. Cardiac magnetic resonance (CMR) imaging allows a more accurate assessment of cardiac dimensions, including the right heart, and deformation by feature-tracking imaging; however, the most evident added value of CMR remains tissue characterization. T1 mapping demonstrated diffuse fibrosis in CKD patients, increasing with the worsening of renal disease and evident even in early stages of the disease, with few, but emerging, prognostic data. Some studies using T2 mapping highlighted the presence of subtle, diffuse myocardial edema. Finally, computed tomography, though rarely used to specifically assess UC, might provide incidental findings carrying prognostic relevance, including information on cardiac and vascular calcification. In summary, non-invasive cardiovascular imaging provides a wealth of imaging biomarkers for the characterization and risk-stratification of UC; integrating results from different imaging techniques can aid a better understanding of the physiopathology of UC and improve the clinical management of patients with CKD. Full article

(This article belongs to the Special Issue Novel Biomarkers of Kidney Diseases)

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17 pages, 5074 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Physico-Chemical Changes Induced by Gamma Irradiation on Some Structural Protein Extracts

by Maria Stanca, Carmen Gaidau, Traian Zaharescu, George-Alin Balan, Iulia Matei, Aurica Precupas, Anca Ruxandra Leonties and Gabriela Ionita

Biomolecules 2023, 13(5), 774; https://doi.org/10.3390/biom13050774 - 29 Apr 2023

Cited by 4 | Viewed by 1436

Abstract

In this study, the effect of gamma irradiation (10 kGy) on proteins extracted from animal hide, scales, and wool was evidenced by calorimetric (μDSC) and spectroscopic (IR, circular dichroism, and EPR) methods. Keratin was obtained from sheep wool, collagen and bovine gelatin from [...] Read more.

In this study, the effect of gamma irradiation (10 kGy) on proteins extracted from animal hide, scales, and wool was evidenced by calorimetric (μDSC) and spectroscopic (IR, circular dichroism, and EPR) methods. Keratin was obtained from sheep wool, collagen and bovine gelatin from bovine hide, and fish gelatin from fish scales. The μDSC experiments evidenced that gamma irradiation influences the thermal stability of these proteins differently. The thermal stability of keratin decreases, while a resistance to thermal denaturation was noticed for collagen and gelatins after gamma irradiation. The analysis of the IR spectra demonstrated that gamma irradiation determines changes in the vibrational modes of the amide groups that are associated with protein denaturation, most meaningfully in the case of keratin. As evidenced by circular dichroism for all proteins considered, exposure to gamma radiation produces changes in the secondary structure that are more significant than those produced by UV irradiation. Riboflavin has different effects on the secondary structure of the investigated proteins, a stabilizing effect for keratin and fish gelatin and a destabilizing effect for bovine gelatin, observed in both irradiated and non-irradiated samples. The EPR spectroscopy evidences the presence, in the gamma-irradiated samples, of free radicals centered on oxygen, and the increase in their EPR signals over time due to the presence of riboflavin. Full article

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

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8 pages, 2403 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Cornea: No Difference in the Wound Healing Response to Injury Related to Whether, or Not, There’s a Bowman’s Layer

by Steven E. Wilson

Biomolecules 2023, 13(5), 771; https://doi.org/10.3390/biom13050771 - 29 Apr 2023

Cited by 3 | Viewed by 2328

Abstract

Bowman’s layer is an acellular layer in the anterior stroma found in the corneas of humans, most other primates, chickens, and some other species. Many other species, however, including the rabbit, dog, wolf, cat, tiger, and lion, do not have a Bowman’s layer. [...] Read more.

Bowman’s layer is an acellular layer in the anterior stroma found in the corneas of humans, most other primates, chickens, and some other species. Many other species, however, including the rabbit, dog, wolf, cat, tiger, and lion, do not have a Bowman’s layer. Millions of humans who have had photorefractive keratectomy over the past thirty plus years have had Bowman’s layer removed by excimer laser ablation over their central cornea without apparent sequelae. A prior study showed that Bowman’s layer does not contribute significantly to mechanical stability within the cornea. Bowman’s layer does not have a barrier function, as many cytokines and growth factors, as well as other molecules, such as EBM component perlecan, pass bidirectionally through Bowman’s layer in normal corneal functions, and during the response to epithelial scrape injury. We hypothesized that Bowman’s layer represents a visible indicator of ongoing cytokine and growth factor-mediated interactions that occur between corneal epithelial cells (and corneal endothelial cells) and stromal keratocytes that maintain the normal corneal tissue organization via negative chemotactic and apoptotic effects of modulators produced by the epithelium on stromal keratocytes. Interleukin-1 alpha, produced constitutively by corneal epithelial cells and endothelial cells, is thought to be one of these cytokines. Bowman’s layer is destroyed in corneas with advanced Fuchs’ dystrophy or pseudophakic bullous keratopathy when the epithelium becomes edematous and dysfunctional, and fibrovascular tissue commonly develops beneath and/or within the epithelium in these corneas. Bowman’s-like layers have been noted to develop surrounding epithelial plugs within the stromal incisions years after radial keratotomy. Although there are species-related differences in corneal wound healing, and even between strains within a species, these differences are not related to the presence or absence of Bowman’s layer. Full article

(This article belongs to the Special Issue Ocular Damage and Wound Healing: From Mechanisms Exploration to Treatment)

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18 pages, 1065 KiB

Open AccessEditor’s ChoiceReview

Update on Diabetic Kidney Disease (DKD): Focus on Non-Albuminuric DKD and Cardiovascular Risk

by Sabrina Scilletta, Maurizio Di Marco, Nicoletta Miano, Agnese Filippello, Stefania Di Mauro, Alessandra Scamporrino, Marco Musmeci, Giuseppe Coppolino, Francesco Di Giacomo Barbagallo, Giosiana Bosco, Roberto Scicali, Salvatore Piro, Francesco Purrello and Antonino Di Pino

Biomolecules 2023, 13(5), 752; https://doi.org/10.3390/biom13050752 - 26 Apr 2023

Cited by 7 | Viewed by 5155

Abstract

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD [...] Read more.

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m², absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD. Full article

(This article belongs to the Special Issue Biomarkers in Renal Diseases)

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34 pages, 6792 KiB

Open AccessFeature PaperEditor’s ChoiceReview

A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders

by Katherine O. Kopp, Margaret E. Greer, Elliot J. Glotfelty, Shih-Chang Hsueh, David Tweedie, Dong Seok Kim, Marcella Reale, Neil Vargesson and Nigel H. Greig

Biomolecules 2023, 13(5), 747; https://doi.org/10.3390/biom13050747 - 26 Apr 2023

Cited by 4 | Viewed by 3616

Abstract

The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, [...] Read more.

The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, in large part, are mediated by IMiD binding to the human protein cereblon that forms a critical component of the E3 ubiquitin ligase complex. This complex ubiquitinates and thereby regulates the levels of multiple endogenous proteins. However, IMiD-cereblon binding modifies cereblon’s normal targeted protein degradation towards a new set of neosubstrates that underlies the favorable pharmacological action of classical IMiDs, but also their adverse actions—in particular, their teratogenicity. The ability of classical IMiDs to reduce the synthesis of key proinflammatory cytokines, especially TNF-α levels, makes them potentially valuable to reposition as drugs to mitigate inflammatory-associated conditions and, particularly, neurological disorders driven by an excessive neuroinflammatory element, as occurs in traumatic brain injury, Alzheimer’s and Parkinson’s diseases, and ischemic stroke. The teratogenic and anticancer actions of classical IMiDs are substantial liabilities for effective drugs in these disorders and can theoretically be dialed out of the drug class. We review a select series of novel IMiDs designed to avoid binding with human cereblon and/or evade degradation of downstream neosubstrates considered to underpin the adverse actions of thalidomide-like drugs. These novel non-classical IMiDs hold potential as new medications for erythema nodosum leprosum (ENL), a painful inflammatory skin condition associated with Hansen’s disease for which thalidomide remains widely used, and, in particular, as a new treatment strategy for neurodegenerative disorders in which neuroinflammation is a key component. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 3389 KiB

Open AccessEditor’s ChoiceArticle

Liposomal DQ in Combination with Copper Inhibits ARID1A Mutant Ovarian Cancer Growth

by Xuejia Kang, Qi Wang, Siqi Wu, Chuanyu Wang, Manjusha Annaji, Chung-Hui Huang, Jianzhong Shen, Pengyu Chen and R. Jayachandra Babu

Biomolecules 2023, 13(5), 744; https://doi.org/10.3390/biom13050744 - 25 Apr 2023

Viewed by 1684

Abstract

Therapeutic strategies for ARID1A-mutant ovarian cancers are limited. Higher basal reactive oxygen species (ROS) and lower basal glutathione (GSH) empower the aggressive proliferation ability and strong metastatic property of OCCCs, indicated by the increased marker of epithelial-mesenchymal transition (EMT) and serving the immunosuppressive [...] Read more.

Therapeutic strategies for ARID1A-mutant ovarian cancers are limited. Higher basal reactive oxygen species (ROS) and lower basal glutathione (GSH) empower the aggressive proliferation ability and strong metastatic property of OCCCs, indicated by the increased marker of epithelial-mesenchymal transition (EMT) and serving the immunosuppressive microenvironment. However, the aberrant redox homeostasis also empowers the sensitivity of DQ-Lipo/Cu in a mutant cell line. DQ, a carbamodithioic acid derivative, generates dithiocarbamate (DDC) in response to ROS, and the chelation of Cu and DDC further generates ROS and provides a ROS cascade. Besides, quinone methide (QM) released by DQ targets the vulnerability of GSH; this effect, plus the increase of ROS, destroys the redox homeostasis and causes cancer cell death. Also importantly, the formed Cu(DDC)₂ is a potent cytotoxic anti-cancer drug that successfully induces immunogenic cell death (ICD). The synergistic effect of EMT regulation and ICD will contribute to managing cancer metastasis and possible drug resistance. In summary, our DQ-Lipo/Cu shows promising inhibitory effects in cancer proliferation, EMT markers, and “heat” the immune response. Full article

(This article belongs to the Section Molecular Medicine)

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17 pages, 2389 KiB

Open AccessEditor’s ChoiceArticle

Plasmalogens: Free Radical Reactivity and Identification of Trans Isomers Relevant to Biological Membranes

by Carla Ferreri, Alessandra Ferocino, Gessica Batani, Chryssostomos Chatgilialoglu, Vanda Randi, Maria Vittoria Riontino, Fabrizio Vetica and Anna Sansone

Biomolecules 2023, 13(5), 730; https://doi.org/10.3390/biom13050730 - 24 Apr 2023

Cited by 4 | Viewed by 2241

Abstract

Plasmalogens are membrane phospholipids with two fatty acid hydrocarbon chains linked to L-glycerol, one containing a characteristic cis-vinyl ether function and the other one being a polyunsaturated fatty acid (PUFA) residue linked through an acyl function. All double bonds in these structures display [...] Read more.

Plasmalogens are membrane phospholipids with two fatty acid hydrocarbon chains linked to L-glycerol, one containing a characteristic cis-vinyl ether function and the other one being a polyunsaturated fatty acid (PUFA) residue linked through an acyl function. All double bonds in these structures display the cis geometrical configuration due to desaturase enzymatic activity and they are known to be involved in the peroxidation process, whereas the reactivity through cis-trans double bond isomerization has not yet been identified. Using 1-(1Z-octadecenyl)-2-arachidonoyl-sn-glycero-3-phosphocholine (C18 plasm-20:4 PC) as a representative molecule, we showed that the cis-trans isomerization can occur at both plasmalogen unsaturated moieties, and the product has characteristic analytical signatures useful for omics applications. Using plasmalogen-containing liposomes and red blood cell (RBC) ghosts under biomimetic Fenton-like conditions, in the presence or absence of thiols, peroxidation, and isomerization processes were found to occur with different reaction outcomes due to the particular liposome compositions. These results allow gaining a full scenario of plasmalogen reactivity under free radical conditions. Moreover, clarification of the plasmalogen reactivity under acidic and alkaline conditions was carried out, identifying the best protocol for RBC membrane fatty acid analysis due to their plasmalogen content of 15–20%. These results are important for lipidomic applications and for achieving a full scenario of radical stress in living organisms. Full article

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

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29 pages, 4603 KiB

Open AccessEditor’s ChoiceArticle

Structural and Biochemical Characterization of Mycobacterium tuberculosis Zinc SufU-SufS Complex

by Ingie Elchennawi, Philippe Carpentier, Christelle Caux, Marine Ponge and Sandrine Ollagnier de Choudens

Biomolecules 2023, 13(5), 732; https://doi.org/10.3390/biom13050732 - 24 Apr 2023

Viewed by 3185

Abstract

Iron-sulfur (Fe-S) clusters are inorganic prosthetic groups in proteins composed exclusively of iron and inorganic sulfide. These cofactors are required in a wide range of critical cellular pathways. Iron-sulfur clusters do not form spontaneously in vivo; several proteins are required to mobilize sulfur [...] Read more.

Iron-sulfur (Fe-S) clusters are inorganic prosthetic groups in proteins composed exclusively of iron and inorganic sulfide. These cofactors are required in a wide range of critical cellular pathways. Iron-sulfur clusters do not form spontaneously in vivo; several proteins are required to mobilize sulfur and iron, assemble and traffic-nascent clusters. Bacteria have developed several Fe-S assembly systems, such as the ISC, NIF, and SUF systems. Interestingly, in Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), the SUF machinery is the primary Fe-S biogenesis system. This operon is essential for the viability of Mtb under normal growth conditions, and the genes it contains are known to be vulnerable, revealing the Mtb SUF system as an interesting target in the fight against tuberculosis. In the present study, two proteins of the Mtb SUF system were characterized for the first time: Rv1464(sufS) and Rv1465(sufU). The results presented reveal how these two proteins work together and thus provide insights into Fe-S biogenesis/metabolism by this pathogen. Combining biochemistry and structural approaches, we showed that Rv1464 is a type II cysteine-desulfurase enzyme and that Rv1465 is a zinc-dependent protein interacting with Rv1464. Endowed with a sulfurtransferase activity, Rv1465 significantly enhances the cysteine-desulfurase activity of Rv1464 by transferring the sulfur atom from persulfide on Rv1464 to its conserved Cys40 residue. The zinc ion is important for the sulfur transfer reaction between SufS and SufU, and His354 in SufS plays an essential role in this reaction. Finally, we showed that Mtb SufS-SufU is more resistant to oxidative stress than E. coli SufS-SufE and that the presence of zinc in SufU is likely responsible for this improved resistance. This study on Rv1464 and Rv1465 will help guide the design of future anti-tuberculosis agents. Full article

(This article belongs to the Special Issue Biomolecule-Metal Ion Interaction)

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16 pages, 3638 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Peptidoglycan Synthesis and Regulation in Bacteria

by Anne Galinier, Clémentine Delan-Forino, Elodie Foulquier, Hakima Lakhal and Frédérique Pompeo

Biomolecules 2023, 13(5), 720; https://doi.org/10.3390/biom13050720 - 22 Apr 2023

Cited by 4 | Viewed by 2812

Abstract

Bacteria must synthesize their cell wall and membrane during their cell cycle, with peptidoglycan being the primary component of the cell wall in most bacteria. Peptidoglycan is a three-dimensional polymer that enables bacteria to resist cytoplasmic osmotic pressure, maintain their cell shape and [...] Read more.

Bacteria must synthesize their cell wall and membrane during their cell cycle, with peptidoglycan being the primary component of the cell wall in most bacteria. Peptidoglycan is a three-dimensional polymer that enables bacteria to resist cytoplasmic osmotic pressure, maintain their cell shape and protect themselves from environmental threats. Numerous antibiotics that are currently used target enzymes involved in the synthesis of the cell wall, particularly peptidoglycan synthases. In this review, we highlight recent progress in our understanding of peptidoglycan synthesis, remodeling, repair, and regulation in two model bacteria: the Gram-negative Escherichia coli and the Gram-positive Bacillus subtilis. By summarizing the latest findings in this field, we hope to provide a comprehensive overview of peptidoglycan biology, which is critical for our understanding of bacterial adaptation and antibiotic resistance. Full article

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

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25 pages, 9999 KiB

Open AccessEditor’s ChoiceReview

Bio-Based Valorization of Lignin-Derived Phenolic Compounds: A Review

by Ludmila Martínková, Michal Grulich, Miroslav Pátek, Barbora Křístková and Margit Winkler

Biomolecules 2023, 13(5), 717; https://doi.org/10.3390/biom13050717 - 22 Apr 2023

Cited by 8 | Viewed by 2698

Abstract

Lignins are the most abundant biopolymers that consist of aromatic units. Lignins are obtained by fractionation of lignocellulose in the form of “technical lignins”. The depolymerization (conversion) of lignin and the treatment of depolymerized lignin are challenging processes due to the complexity and [...] Read more.

Lignins are the most abundant biopolymers that consist of aromatic units. Lignins are obtained by fractionation of lignocellulose in the form of “technical lignins”. The depolymerization (conversion) of lignin and the treatment of depolymerized lignin are challenging processes due to the complexity and resistance of lignins. Progress toward mild work-up of lignins has been discussed in numerous reviews. The next step in the valorization of lignin is the conversion of lignin-based monomers, which are limited in number, into a wider range of bulk and fine chemicals. These reactions may need chemicals, catalysts, solvents, or energy from fossil resources. This is counterintuitive to green, sustainable chemistry. Therefore, in this review, we focus on biocatalyzed reactions of lignin monomers, e.g., vanillin, vanillic acid, syringaldehyde, guaiacols, (iso)eugenol, ferulic acid, p-coumaric acid, and alkylphenols. For each monomer, its production from lignin or lignocellulose is summarized, and, mainly, its biotransformations that provide useful chemicals are discussed. The technological maturity of these processes is characterized based on, e.g., scale, volumetric productivities, or isolated yields. The biocatalyzed reactions are compared with their chemically catalyzed counterparts if the latter are available. Full article

(This article belongs to the Special Issue Recent Advances in the Enzymatic Synthesis of Phenolic Compounds Derivatives)

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14 pages, 977 KiB

Open AccessEditor’s ChoiceReview

An Integrated View of Stressors as Causative Agents in OA Pathogenesis

by Joseph S. Floramo, Vladimir Molchanov, Huadie Liu, Ye Liu, Sonya E. L. Craig and Tao Yang

Biomolecules 2023, 13(5), 721; https://doi.org/10.3390/biom13050721 - 22 Apr 2023

Cited by 1 | Viewed by 3195

Abstract

Cells in the body are exposed to dynamic external and internal environments, many of which cause cell damage. The cell’s response to this damage, broadly called the stress response, is meant to promote survival and repair or remove damage. However, not all damage [...] Read more.

Cells in the body are exposed to dynamic external and internal environments, many of which cause cell damage. The cell’s response to this damage, broadly called the stress response, is meant to promote survival and repair or remove damage. However, not all damage can be repaired, and sometimes, even worse, the stress response can overtax the system itself, further aggravating homeostasis and leading to its loss. Aging phenotypes are considered a manifestation of accumulated cellular damage and defective repair. This is particularly apparent in the primary cell type of the articular joint, the articular chondrocytes. Articular chondrocytes are constantly facing the challenge of stressors, including mechanical overloading, oxidation, DNA damage, proteostatic stress, and metabolic imbalance. The consequence of the accumulation of stress on articular chondrocytes is aberrant mitogenesis and differentiation, defective extracellular matrix production and turnover, cellular senescence, and cell death. The most severe form of stress-induced chondrocyte dysfunction in the joints is osteoarthritis (OA). Here, we summarize studies on the cellular effects of stressors on articular chondrocytes and demonstrate that the molecular effectors of the stress pathways connect to amplify articular joint dysfunction and OA development. Full article

(This article belongs to the Special Issue Recent Advances in Skeletal Development and Diseases)

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15 pages, 1638 KiB

Open AccessEditor’s ChoiceArticle

Adenosine A_2A Receptors Shut Down Adenosine A₁ Receptor-Mediated Presynaptic Inhibition to Promote Implementation of Hippocampal Long-Term Potentiation

by Cátia R. Lopes, Francisco Q. Gonçalves, Simão Olaio, Angelo R. Tomé, Rodrigo A. Cunha and João Pedro Lopes

Biomolecules 2023, 13(4), 715; https://doi.org/10.3390/biom13040715 - 21 Apr 2023

Cited by 5 | Viewed by 1499

Abstract

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A₁ and A_2A receptors (A₁R, A_2AR), respectively. Supramaximal activation of A₁R can block hippocampal synaptic transmission, and the tonic engagement of [...] Read more.

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A₁ and A_2A receptors (A₁R, A_2AR), respectively. Supramaximal activation of A₁R can block hippocampal synaptic transmission, and the tonic engagement of A₁R-mediated inhibition is increased with increased frequency of nerve stimulation. This is compatible with an activity-dependent increase in extracellular adenosine in hippocampal excitatory synapses, which can reach levels sufficient to block synaptic transmission. We now report that A_2AR activation decreases A₁R-medated inhibition of synaptic transmission, with particular relevance during high-frequency-induced long-term potentiation (LTP). Thus, whereas the A₁R antagonist DPCPX (50 nM) was devoid of effects on LTP magnitude, the addition of an A_2AR antagonist SCH58261 (50 nM) allowed a facilitatory effect of DPCPX on LTP to be revealed. Additionally, the activation of A_2AR with CGS21680 (30 nM) decreased the potency of the A₁R agonist CPA (6–60 nM) to inhibit hippocampal synaptic transmission in a manner prevented by SCH58261. These observations show that A_2AR play a key role in dampening A₁R during high-frequency induction of hippocampal LTP. This provides a new framework for understanding how the powerful adenosine A₁R-mediated inhibition of excitatory transmission can be controlled to allow the implementation of hippocampal LTP. Full article

(This article belongs to the Special Issue Pharmacology of Purinergic Receptors—Honorary Special Issue Dedicated to Prof. Pier Andrea Borea)

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20 pages, 847 KiB

Open AccessEditor’s ChoiceReview

Vitamin D and Autoimmune Rheumatic Diseases

by Lambros Athanassiou, Ifigenia Kostoglou-Athanassiou, Michael Koutsilieris and Yehuda Shoenfeld

Biomolecules 2023, 13(4), 709; https://doi.org/10.3390/biom13040709 - 21 Apr 2023

Cited by 12 | Viewed by 5909

Abstract

Vitamin D is a steroid hormone with potent immune-modulating properties. It has been shown to stimulate innate immunity and induce immune tolerance. Extensive research efforts have shown that vitamin D deficiency may be related to the development of autoimmune diseases. Vitamin D deficiency [...] Read more.

Vitamin D is a steroid hormone with potent immune-modulating properties. It has been shown to stimulate innate immunity and induce immune tolerance. Extensive research efforts have shown that vitamin D deficiency may be related to the development of autoimmune diseases. Vitamin D deficiency has been observed in patients with rheumatoid arthritis (RA) and has been shown to be inversely related to disease activity. Moreover, vitamin D deficiency may be implicated in the pathogenesis of the disease. Vitamin D deficiency has also been observed in patients with systemic lupus erythematosus (SLE). It has been found to be inversely related to disease activity and renal involvement. In addition, vitamin D receptor polymorphisms have been studied in SLE. Vitamin D levels have been studied in patients with Sjogren’s syndrome, and vitamin D deficiency may be related to neuropathy and the development of lymphoma in the context of Sjogren’s syndrome. Vitamin D deficiency has been observed in ankylosing spondylitis, psoriatic arthritis (PsA), and idiopathic inflammatory myopathies. Vitamin D deficiency has also been observed in systemic sclerosis. Vitamin D deficiency may be implicated in the pathogenesis of autoimmunity, and it may be administered to prevent autoimmune disease and reduce pain in the context of autoimmune rheumatic disorders. Full article

(This article belongs to the Section Molecular Medicine)

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21 pages, 4159 KiB

Open AccessEditor’s ChoiceArticle

A Soluble Platelet-Derived Growth Factor Receptor-β Originates via Pre-mRNA Splicing in the Healthy Brain and Is Upregulated during Hypoxia and Aging

by Laura Beth Payne, Hanaa Abdelazim, Maruf Hoque, Audra Barnes, Zuzana Mironovova, Caroline E. Willi, Jordan Darden, Clifton Houk, Meghan W. Sedovy, Scott R. Johnstone and John C. Chappell

Biomolecules 2023, 13(4), 711; https://doi.org/10.3390/biom13040711 - 21 Apr 2023

Cited by 1 | Viewed by 2403

Abstract

The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRβ) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity [...] Read more.

The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRβ) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity and viability, which fuels cognitive and memory deficits. Receptor tyrosine kinases such as PDGF-BB and vascular endothelial growth factor-A (VEGF-A) are often modulated by soluble isoforms of cognate receptors that establish signaling activity within a physiological range. Soluble PDGFRβ (sPDGFRβ) isoforms have been reported to form by enzymatic cleavage from cerebrovascular mural cells, and pericytes in particular, largely under pathological conditions. However, pre-mRNA alternative splicing has not been widely explored as a possible mechanism for generating sPDGFRβ variants, and specifically during tissue homeostasis. Here, we found sPDGFRβ protein in the murine brain and other tissues under normal, physiological conditions. Utilizing brain samples for follow-on analysis, we identified mRNA sequences corresponding to sPDGFRβ isoforms, which facilitated construction of predicted protein structures and related amino acid sequences. Human cell lines yielded comparable sequences and protein model predictions. Retention of ligand binding capacity was confirmed for sPDGFRβ by co-immunoprecipitation. Visualizing fluorescently labeled sPDGFRβ transcripts revealed a spatial distribution corresponding to murine brain pericytes alongside cerebrovascular endothelium. Soluble PDGFRβ protein was detected throughout the brain parenchyma in distinct regions, such as along the lateral ventricles, with signals also found more broadly adjacent to cerebral microvessels consistent with pericyte labeling. To better understand how sPDGFRβ variants might be regulated, we found elevated transcript and protein levels in the murine brain with age, and acute hypoxia increased sPDGFRβ variant transcripts in a cell-based model of intact vessels. Our findings indicate that soluble isoforms of PDGFRβ likely arise from pre-mRNA alternative splicing, in addition to enzymatic cleavage mechanisms, and these variants exist under normal physiological conditions. Follow-on studies will be needed to establish potential roles for sPDGFRβ in regulating PDGF-BB signaling to maintain pericyte quiescence, BBB integrity, and cerebral perfusion—critical processes underlying neuronal health and function, and in turn, memory and cognition. Full article

(This article belongs to the Special Issue The Role of Vascular Dysfunction in Neuronal Degeneration and Cognitive Impairment)

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20 pages, 3079 KiB

Open AccessEditor’s ChoiceReview

Protective Effect of Olive Oil Microconstituents in Atherosclerosis: Emphasis on PAF Implicated Atherosclerosis Theory

by Smaragdi Antonopoulou and Constantinos A. Demopoulos

Biomolecules 2023, 13(4), 700; https://doi.org/10.3390/biom13040700 - 20 Apr 2023

Cited by 11 | Viewed by 1687

Abstract

Atherosclerosis is a progressive vascular multifactorial process. The mechanisms underlining the initiating event of atheromatous plaque formation are inflammation and oxidation. Among the modifiable risk factors for cardiovascular diseases, diet and especially the Mediterranean diet (MedDiet), has been widely recognized as one of [...] Read more.

Atherosclerosis is a progressive vascular multifactorial process. The mechanisms underlining the initiating event of atheromatous plaque formation are inflammation and oxidation. Among the modifiable risk factors for cardiovascular diseases, diet and especially the Mediterranean diet (MedDiet), has been widely recognized as one of the healthiest dietary patterns. Olive oil (OO), the main source of the fatty components of the MedDiet is superior to the other “Mono-unsaturated fatty acids containing oils” due to the existence of specific microconstituents. In this review, the effects of OO microconstituents in atherosclerosis, based on data from in vitro and in vivo studies with special attention on their inhibitory activity against PAF (Platelet-Activating Factor) actions, are presented and critically discussed. In conclusion, we propose that the anti-atherogenic effect of OO is attributed to the synergistic action of its microconstituents, mainly polar lipids that act as PAF inhibitors, specific polyphenols and α-tocopherol that also exert anti-PAF activity. This beneficial effect, also mediated through anti-PAF action, can occur from microconstituents extracted from olive pomace, a toxic by-product of the OO production process that constitutes a significant ecological problem. Daily intake of moderate amounts of OO consumed in the context of a balanced diet is significant for healthy adults. Full article

(This article belongs to the Section Cellular Biochemistry)

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33 pages, 7619 KiB

Open AccessEditor’s ChoiceReview

Multiomics Analysis Reveals Novel Genetic Determinants for Lens Differentiation, Structure, and Transparency

by Joshua Disatham, Lisa Brennan, Ales Cvekl and Marc Kantorow

Biomolecules 2023, 13(4), 693; https://doi.org/10.3390/biom13040693 - 19 Apr 2023

Cited by 4 | Viewed by 2189

Abstract

Recent advances in next-generation sequencing and data analysis have provided new gateways for identification of novel genome-wide genetic determinants governing tissue development and disease. These advances have revolutionized our understanding of cellular differentiation, homeostasis, and specialized function in multiple tissues. Bioinformatic and functional [...] Read more.

Recent advances in next-generation sequencing and data analysis have provided new gateways for identification of novel genome-wide genetic determinants governing tissue development and disease. These advances have revolutionized our understanding of cellular differentiation, homeostasis, and specialized function in multiple tissues. Bioinformatic and functional analysis of these genetic determinants and the pathways they regulate have provided a novel basis for the design of functional experiments to answer a wide range of long-sought biological questions. A well-characterized model for the application of these emerging technologies is the development and differentiation of the ocular lens and how individual pathways regulate lens morphogenesis, gene expression, transparency, and refraction. Recent applications of next-generation sequencing analysis on well-characterized chicken and mouse lens differentiation models using a variety of omics techniques including RNA-seq, ATAC-seq, whole-genome bisulfite sequencing (WGBS), chip-seq, and CUT&RUN have revealed a wide range of essential biological pathways and chromatin features governing lens structure and function. Multiomics integration of these data has established new gene functions and cellular processes essential for lens formation, homeostasis, and transparency including the identification of novel transcription control pathways, autophagy remodeling pathways, and signal transduction pathways, among others. This review summarizes recent omics technologies applied to the lens, methods for integrating multiomics data, and how these recent technologies have advanced our understanding ocular biology and function. The approach and analysis are relevant to identifying the features and functional requirements of more complex tissues and disease states. 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, 2180 KiB

Open AccessEditor’s ChoiceReview

Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities

by Prashanta Silwal, Allison M. Nguyen-Thai, Haneef Ahamed Mohammad, Yanshan Wang, Paul D. Robbins, Joon Y. Lee and Nam V. Vo

Biomolecules 2023, 13(4), 686; https://doi.org/10.3390/biom13040686 - 18 Apr 2023

Cited by 17 | Viewed by 3190

Abstract

Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors [...] Read more.

Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors that hamper normal tissue homeostasis. Chronic accumulation of senescent cells is thought to be associated with intervertebral disc degeneration (IDD) in an aging population. This IDD is one of the largest age-dependent chronic disorders, often associated with neurological dysfunctions such as, low back pain, radiculopathy, and myelopathy. Senescent cells (SnCs) increase in number in the aged, degenerated discs, and have a causative role in driving age-related IDD. This review summarizes current evidence supporting the role of CS on onset and progression of age-related IDD. The discussion includes molecular pathways involved in CS such as p53-p21^CIP1, p16^INK4a, NF-κB, and MAPK, and the potential therapeutic value of targeting these pathways. We propose several mechanisms of CS in IDD including mechanical stress, oxidative stress, genotoxic stress, nutritional deprivation, and inflammatory stress. There are still large knowledge gaps in disc CS research, an understanding of which will provide opportunities to develop therapeutic interventions to treat age-related IDD. Full article

(This article belongs to the Special Issue Cell Senescence in Musculoskeletal Pathology and Associated Pain)

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17 pages, 1129 KiB

Open AccessEditor’s ChoiceReview

The Multifaceted Role of Glutathione S-Transferases in Health and Disease

by Aslam M. A. Mazari, Leilei Zhang, Zhi-Wei Ye, Jie Zhang, Kenneth D. Tew and Danyelle M. Townsend

Biomolecules 2023, 13(4), 688; https://doi.org/10.3390/biom13040688 - 18 Apr 2023

Cited by 23 | Viewed by 5073

Abstract

In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable structural similarity with some overlapping functionalities. As a primary function, GSTs play a putative role in Phase II metabolism by [...] Read more.

In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable structural similarity with some overlapping functionalities. As a primary function, GSTs play a putative role in Phase II metabolism by protecting living cells against a wide variety of toxic molecules by conjugating them with the tripeptide glutathione. This conjugation reaction is extended to forming redox sensitive post-translational modifications on proteins: S-glutathionylation. Apart from these catalytic functions, specific GSTs are involved in the regulation of stress-induced signaling pathways that govern cell proliferation and apoptosis. Recently, studies on the effects of GST genetic polymorphisms on COVID-19 disease development revealed that the individuals with higher numbers of risk-associated genotypes showed higher risk of COVID-19 prevalence and severity. Furthermore, overexpression of GSTs in many tumors is frequently associated with drug resistance phenotypes. These functional properties make these proteins promising targets for therapeutics, and a number of GST inhibitors have progressed in clinical trials for the treatment of cancer and other diseases. Full article

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

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19 pages, 3900 KiB

Open AccessEditor’s ChoiceReview

Circular RNA Expression Profiling by Microarray—A Technical and Practical Perspective

by Yanggu Shi and Jindong Shang

Biomolecules 2023, 13(4), 679; https://doi.org/10.3390/biom13040679 - 17 Apr 2023

Cited by 2 | Viewed by 1590

Abstract

Circular RNAs, as covalently circularized RNA loops, have many unique biochemical properties. Many circRNA biological functions and clinical indications are being continually discovered. Increasingly, circRNAs are being used as a new class of biomarkers, which are potentially superior to linear RNAs due to [...] Read more.

Circular RNAs, as covalently circularized RNA loops, have many unique biochemical properties. Many circRNA biological functions and clinical indications are being continually discovered. Increasingly, circRNAs are being used as a new class of biomarkers, which are potentially superior to linear RNAs due to the unusual cell/tissue/disease specificities and the exonuclease-resistant stabilized circular form in the biofluids. Profiling circRNA expression has been a common step in circRNA research to provide much needed insight into circRNA biology and to facilitate rapid advances in the circRNA field. We will review circRNA microarrays as a practical and effective circRNA profiling technology for regularly equipped biological or clinical research labs, share valuable experiences, and highlight the significant findings from the profiling studies. Full article

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

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15 pages, 2396 KiB

Open AccessEditor’s ChoiceReview

Phytochemical Interactions with Calmodulin and Critical Calmodulin Binding Proteins Involved in Amyloidogenesis in Alzheimer’s Disease

by Danton H. O'Day

Biomolecules 2023, 13(4), 678; https://doi.org/10.3390/biom13040678 - 15 Apr 2023

Cited by 1 | Viewed by 1810

Abstract

An increasing number of plant-based herbal treatments, dietary supplements, medical foods and nutraceuticals and their component phytochemicals are used as alternative treatments to prevent or slow the onset and progression of Alzheimer’s disease. Their appeal stems from the fact that no current pharmaceutical [...] Read more.

An increasing number of plant-based herbal treatments, dietary supplements, medical foods and nutraceuticals and their component phytochemicals are used as alternative treatments to prevent or slow the onset and progression of Alzheimer’s disease. Their appeal stems from the fact that no current pharmaceutical or medical treatment can accomplish this. While a handful of pharmaceuticals are approved to treat Alzheimer’s, none has been shown to prevent, significantly slow or stop the disease. As a result, many see the appeal of alternative plant-based treatments as an option. Here, we show that many phytochemicals proposed or used as Alzheimer’s treatments share a common theme: they work via a calmodulin-mediated mode of action. Some phytochemicals bind to and inhibit calmodulin directly while others bind to and regulate calmodulin-binding proteins, including Aβ monomers and BACE1. Phytochemical binding to Aβ monomers can prevent the formation of Aβ oligomers. A limited number of phytochemicals are also known to stimulate calmodulin gene expression. The significance of these interactions to amyloidogenesis in Alzheimer’s disease is reviewed. Full article

(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)

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14 pages, 1040 KiB

Open AccessEditor’s ChoiceReview

The Emerging Role of IL-9 in the Anticancer Effects of Anti-PD-1 Therapy

by Daria Vinokurova and Lionel Apetoh

Biomolecules 2023, 13(4), 670; https://doi.org/10.3390/biom13040670 - 12 Apr 2023

Cited by 2 | Viewed by 1851

Abstract

PD-1 blockade rescues failing anticancer immune responses, resulting in durable remissions in some cancer patients. Cytokines such as IFNγ and IL-2 contribute to the anti-tumor effect of PD-1 blockade. IL-9 was identified over the last decade as a cytokine demonstrating a potent ability [...] Read more.

PD-1 blockade rescues failing anticancer immune responses, resulting in durable remissions in some cancer patients. Cytokines such as IFNγ and IL-2 contribute to the anti-tumor effect of PD-1 blockade. IL-9 was identified over the last decade as a cytokine demonstrating a potent ability to harness the anticancer functions of innate and adaptive immune cells in mice. Recent translational investigations suggest that the anticancer activity of IL-9 also extends to some human cancers. Increased T cell-derived IL-9 was proposed to predict the response to anti-PD-1 therapy. Preclinical investigations accordingly revealed that IL-9 could synergize with anti-PD-1 therapy in eliciting anticancer responses. Here, we review the findings suggesting an important contribution of IL-9 in the efficacy of anti-PD-1 therapy and discuss their clinical relevance. We will also discuss the role of host factors like the microbiota and TGFβ in the tumor microenvironment (TME) in the regulation of IL-9 secretion and anti-PD-1 treatment efficacy. Full article

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12 pages, 927 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Roles of sPLA₂s in Skin Homeostasis and Disease

by Kei Yamamoto, Haruka Hakoi, Saki Nomura and Makoto Murakami

Biomolecules 2023, 13(4), 668; https://doi.org/10.3390/biom13040668 - 12 Apr 2023

Cited by 1 | Viewed by 1605

Abstract

Among the phospholipase A₂ (PLA₂) family, the secreted PLA₂ (sPLA₂) family in mammals contains 11 members that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using knockout and/or transgenic mice for a nearly full [...] Read more.

Among the phospholipase A₂ (PLA₂) family, the secreted PLA₂ (sPLA₂) family in mammals contains 11 members that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using knockout and/or transgenic mice for a nearly full set of sPLA₂s, in combination with comprehensive lipidomics, have revealed the diverse pathophysiological roles of sPLA₂s in various biological events. Individual sPLA₂s exert specific functions within tissue microenvironments, likely through the hydrolysis of extracellular phospholipids. Lipids are an essential biological component for skin homeostasis, and disturbance of lipid metabolism by deletion or overexpression of lipid-metabolizing enzymes or lipid-sensing receptors often leads to skin abnormalities that are easily visible on the outside. Over the past decades, our studies using knockout and transgenic mice for various sPLA₂s have uncovered several new aspects of these enzymes as modulators of skin homeostasis and disease. This article summarizes the roles of several sPLA₂s in skin pathophysiology, providing additional insight into the research fields of sPLA₂s, lipids, and skin biology. Full article

(This article belongs to the Collection Bioactive Lipids in Inflammation, Diabetes and Cancer)

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15 pages, 1785 KiB

Open AccessEditor’s ChoiceReview

The Hop2-Mnd1 Complex and Its Regulation of Homologous Recombination

by Hideo Tsubouchi

Biomolecules 2023, 13(4), 662; https://doi.org/10.3390/biom13040662 - 10 Apr 2023

Cited by 2 | Viewed by 2730

Abstract

Homologous recombination (HR) is essential for meiosis in most sexually reproducing organisms, where it is induced upon entry into meiotic prophase. Meiotic HR is conducted by the collaborative effort of proteins responsible for DNA double-strand break repair and those produced specifically during meiosis. [...] Read more.

Homologous recombination (HR) is essential for meiosis in most sexually reproducing organisms, where it is induced upon entry into meiotic prophase. Meiotic HR is conducted by the collaborative effort of proteins responsible for DNA double-strand break repair and those produced specifically during meiosis. The Hop2-Mnd1 complex was originally identified as a meiosis-specific factor that is indispensable for successful meiosis in budding yeast. Later, it was found that Hop2-Mnd1 is conserved from yeasts to humans, playing essential roles in meiosis. Accumulating evidence suggests that Hop2-Mnd1 promotes RecA-like recombinases towards homology search/strand exchange. This review summarizes studies on the mechanism of the Hop2-Mnd1 complex in promoting HR and beyond. Full article

(This article belongs to the Special Issue Yeast Models for Gene Regulation)

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24 pages, 4390 KiB

Open AccessEditor’s ChoiceReview

Myocardial Inflammation as a Manifestation of Genetic Cardiomyopathies: From Bedside to the Bench

by Giovanni Peretto, Elena Sommariva, Chiara Di Resta, Martina Rabino, Andrea Villatore, Davide Lazzeroni, Simone Sala, Giulio Pompilio and Leslie T. Cooper

Biomolecules 2023, 13(4), 646; https://doi.org/10.3390/biom13040646 - 04 Apr 2023

Cited by 11 | Viewed by 2815

Abstract

Over recent years, preclinical and clinical evidence has implicated myocardial inflammation (M-Infl) in the pathophysiology and phenotypes of traditionally genetic cardiomyopathies. M-Infl resembling myocarditis on imaging and histology occurs frequently as a clinical manifestation of classically genetic cardiac diseases, including dilated and arrhythmogenic [...] Read more.

Over recent years, preclinical and clinical evidence has implicated myocardial inflammation (M-Infl) in the pathophysiology and phenotypes of traditionally genetic cardiomyopathies. M-Infl resembling myocarditis on imaging and histology occurs frequently as a clinical manifestation of classically genetic cardiac diseases, including dilated and arrhythmogenic cardiomyopathy. The emerging role of M-Infl in disease pathophysiology is leading to the identification of druggable targets for molecular treatment of the inflammatory process and a new paradigm in the field of cardiomyopathies. Cardiomyopathies constitute a leading cause of heart failure and arrhythmic sudden death in the young population. The aim of this review is to present, from bedside to bench, the current state of the art about the genetic basis of M-Infl in nonischemic cardiomyopathies of the dilated and arrhythmogenic spectrum in order to prompt future research towards the identification of novel mechanisms and treatment targets, with the ultimate goal of lowering disease morbidity and mortality. Full article

(This article belongs to the Special Issue Advance in Genomics of Rare Genetic Diseases)

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21 pages, 5694 KiB

Open AccessEditor’s ChoiceArticle

Tyrosinase Magnetic Cross-Linked Enzyme Aggregates: Biocatalytic Study in Deep Eutectic Solvent Aqueous Solutions

by Myrto G. Bellou, Michaela Patila, Renia Fotiadou, Konstantinos Spyrou, Feng Yan, Petra Rudolf, Dimitrios P. Gournis and Haralambos Stamatis

Biomolecules 2023, 13(4), 643; https://doi.org/10.3390/biom13040643 - 03 Apr 2023

Cited by 1 | Viewed by 9399

Abstract

In the field of biocatalysis, the implementation of sustainable processes such as enzyme immobilization or employment of environmentally friendly solvents, like Deep Eutectic Solvents (DESs) are of paramount importance. In this work, tyrosinase was extracted from fresh mushrooms and used in a carrier-free [...] Read more.

In the field of biocatalysis, the implementation of sustainable processes such as enzyme immobilization or employment of environmentally friendly solvents, like Deep Eutectic Solvents (DESs) are of paramount importance. In this work, tyrosinase was extracted from fresh mushrooms and used in a carrier-free immobilization towards the preparation of both non-magnetic and magnetic cross-linked enzyme aggregates (CLEAs). The prepared biocatalyst was characterized and the biocatalytic and structural traits of free tyrosinase and tyrosinase magnetic CLEAs (mCLEAs) were evaluated in numerous DES aqueous solutions. The results showed that the nature and the concentration of the DESs used as co-solvents significantly affected the catalytic activity and stability of tyrosinase, while the immobilization enhanced the activity of the enzyme in comparison with the non-immobilized enzyme up to 3.6-fold. The biocatalyst retained the 100% of its initial activity after storage at −20 °C for 1 year and the 90% of its activity after 5 repeated cycles. Tyrosinase mCLEAs were further applied in the homogeneous modification of chitosan with caffeic acid in the presence of DES. The biocatalyst demonstrated great ability in the functionalization of chitosan with caffeic acid in the presence of 10% v/v DES [Bet:Gly (1:3)], enhancing the antioxidant activity of the films. Full article

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18 pages, 1251 KiB

Open AccessEditor’s ChoiceReview

Microtubule Regulation in Plants: From Morphological Development to Stress Adaptation

by An-Shan Hsiao and Ji-Ying Huang

Biomolecules 2023, 13(4), 627; https://doi.org/10.3390/biom13040627 - 30 Mar 2023

Cited by 4 | Viewed by 4564

Abstract

Microtubules (MTs) are essential elements of the eukaryotic cytoskeleton and are critical for various cell functions. During cell division, plant MTs form highly ordered structures, and cortical MTs guide the cell wall cellulose patterns and thus control cell size and shape. Both are [...] Read more.

Microtubules (MTs) are essential elements of the eukaryotic cytoskeleton and are critical for various cell functions. During cell division, plant MTs form highly ordered structures, and cortical MTs guide the cell wall cellulose patterns and thus control cell size and shape. Both are important for morphological development and for adjusting plant growth and plasticity under environmental challenges for stress adaptation. Various MT regulators control the dynamics and organization of MTs in diverse cellular processes and response to developmental and environmental cues. This article summarizes the recent progress in plant MT studies from morphological development to stress responses, discusses the latest techniques applied, and encourages more research into plant MT regulation. Full article

(This article belongs to the Special Issue Molecular Functions of Microtubules)

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10 pages, 2839 KiB

Open AccessEditor’s ChoiceArticle

CRISPR/Cas9 Mediated Fluorescent Tagging of Caenorhabditis elegans SPE-38 Reveals a Complete Localization Pattern in Live Spermatozoa

by Yamei Zuo, Xue Mei and Andrew Singson

Biomolecules 2023, 13(4), 623; https://doi.org/10.3390/biom13040623 - 30 Mar 2023

Cited by 1 | Viewed by 1568

Abstract

The Caenorhabditis elegans spe-38 gene encodes a four-pass transmembrane molecule that is required in sperm for fertilization. In previous work, the localization of the SPE-38 protein was examined using polyclonal antibodies on spermatids and mature amoeboid spermatozoa. SPE-38 is localized to unfused membranous organelles [...] Read more.

The Caenorhabditis elegans spe-38 gene encodes a four-pass transmembrane molecule that is required in sperm for fertilization. In previous work, the localization of the SPE-38 protein was examined using polyclonal antibodies on spermatids and mature amoeboid spermatozoa. SPE-38 is localized to unfused membranous organelles (MOs) in nonmotile spermatids. Different fixation conditions revealed that SPE-38 either localized to fused MOs and the cell body plasma membrane or the pseudopod plasma membrane of mature sperm. To address this localization paradox in mature sperm, CRISPR/Cas9 genome editing was used to tag endogenous SPE-38 with fluorescent wrmScarlet-I. Homozygous male and hermaphrodite worms encoding SPE-38::wrmScarlet-I were fertile indicating the fluorescent tag does not interfere with SPE-38 function during sperm activation or fertilization. We found that SPE-38::wrmScarlet-I localized to MOs in spermatids consistent with previous antibody localization. In mature and motile spermatozoa we found SPE-38::wrmScarlet-I in fused MOs, the cell body plasma membrane, and the pseudopod plasma membrane. We conclude that the localization pattern observed with SPE-38::wrmScarlet-I represents the complete distribution of SPE-38 in mature spermatozoa and this localization pattern is consistent with a hypothesized role of SPE-38 directly in sperm-egg binding and/or fusion. Full article

(This article belongs to the Special Issue Gametogenesis and Gamete Interaction)

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14 pages, 1901 KiB

Open AccessEditor’s ChoiceArticle

Blood–Brain Barrier Integrity Is Perturbed in a Mecp2-Null Mouse Model of Rett Syndrome

by Giuseppe Pepe, Salvatore Fioriniello, Federico Marracino, Luca Capocci, Vittorio Maglione, Maurizio D’Esposito, Alba Di Pardo and Floriana Della Ragione

Biomolecules 2023, 13(4), 606; https://doi.org/10.3390/biom13040606 - 28 Mar 2023

Cited by 4 | Viewed by 2522

Abstract

Rett syndrome (RTT, online MIM 312750) is a devastating neurodevelopmental disorder characterized by motor and cognitive disabilities. It is mainly caused by pathogenetic variants in the X-linked MECP2 gene, encoding an epigenetic factor crucial for brain functioning. Despite intensive studies, the RTT pathogenetic [...] Read more.

Rett syndrome (RTT, online MIM 312750) is a devastating neurodevelopmental disorder characterized by motor and cognitive disabilities. It is mainly caused by pathogenetic variants in the X-linked MECP2 gene, encoding an epigenetic factor crucial for brain functioning. Despite intensive studies, the RTT pathogenetic mechanism remains to be fully elucidated. Impaired vascular function has been previously reported in RTT mouse models; however, whether an altered brain vascular homeostasis and the subsequent blood–brain barrier (BBB) breakdown occur in RTT and contribute to the disease-related cognitive impairment is still unknown. Interestingly, in symptomatic Mecp2-null (Mecp2^-/y, Mecp2^tm1.1Bird) mice, we found enhanced BBB permeability associated with an aberrant expression of the tight junction proteins Ocln and Cldn-5 in different brain areas, in terms of both transcript and protein levels. Additionally, Mecp2-null mice showed an altered expression of different genes encoding factors with a role in the BBB structure and function, such as Cldn3, Cldn12, Mpdz, Jam2, and Aqp4. With this study, we provide the first evidence of impaired BBB integrity in RTT and highlight a potential new molecular hallmark of the disease that might open new perspectives for the setting-up of novel therapeutic strategies. Full article

(This article belongs to the Special Issue Neurodevelopmental Disorders: Linking Genetics and Epigenetics to Disease-Related Pathways)

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15 pages, 2600 KiB

Open AccessEditor’s ChoiceArticle

Triphenyltin(IV) Carboxylates with Exceptionally High Cytotoxicity against Different Breast Cancer Cell Lines

by Ivana Predarska, Mohamad Saoud, Ibrahim Morgan, Peter Lönnecke, Goran N. Kaluđerović and Evamarie Hey-Hawkins

Biomolecules 2023, 13(4), 595; https://doi.org/10.3390/biom13040595 - 26 Mar 2023

Cited by 5 | Viewed by 1725

Abstract

Organotin(IV) carboxylates are a class of compounds explored as alternatives to platinum-containing chemotherapeutics due to propitious in vitro and in vivo results, and distinct mechanisms of action. In this study, triphenyltin(IV) derivatives of non-steroidal anti-inflammatory drugs (indomethacin (HIND) and flurbiprofen (HFBP)) are synthesized [...] Read more.

Organotin(IV) carboxylates are a class of compounds explored as alternatives to platinum-containing chemotherapeutics due to propitious in vitro and in vivo results, and distinct mechanisms of action. In this study, triphenyltin(IV) derivatives of non-steroidal anti-inflammatory drugs (indomethacin (HIND) and flurbiprofen (HFBP)) are synthesized and characterized, namely [Ph₃Sn(IND)] and [Ph₃Sn(FBP)]. The crystal structure of [Ph₃Sn(IND)] reveals penta-coordination of the central tin atom with almost perfect trigonal bipyramidal geometry with phenyl groups in the equatorial positions and two axially located oxygen atoms belonging to two distinct carboxylato (IND) ligands leading to formation of a coordination polymer with bridging carboxylato ligands. Employing MTT and CV probes, the antiproliferative effects of both organotin(IV) complexes, indomethacin, and flurbiprofen were evaluated on different breast carcinoma cells (BT-474, MDA-MB-468, MCF-7 and HCC1937). [Ph₃Sn(IND)] and [Ph₃Sn(FBP)], unlike the inactive ligand precursors, were found extremely active towards all examined cell lines, demonstrating IC₅₀ concentrations in the range of 0.076–0.200 µM. Flow cytometry was employed to examine the mode of action showing that neither apoptotic nor autophagic mechanisms were triggered within the first 48 h of treatment. However, both tin(IV) complexes inhibited cell proliferation potentially related to the dramatic reduction in NO production, resulting from downregulation of nitric oxide synthase (iNOS) enzyme expression. Full article

(This article belongs to the Special Issue Recent Advances in Anti-tumor Metal Complexes and Drug Delivery Systems)

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