Biomolecules

13 pages, 951 KiB

Open AccessEditor’s ChoiceReview

The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases

by Knut Hestad, Jan Alexander, Helge Rootwelt and Jan O. Aaseth

Biomolecules 2022, 12(7), 998; https://doi.org/10.3390/biom12070998 - 18 Jul 2022

Cited by 88 | Viewed by 9144

Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan [...] Read more.

Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands. Full article

(This article belongs to the Special Issue Biochemistry in Medicine—Honorary Special Issue Commemorating Research and Work of Professors Jan O. Aaseth and Jan Alexander)

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15 pages, 1892 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Comparison of Tau and Amyloid-β Targeted Immunotherapy Nanoparticles for Alzheimer’s Disease

by Yara Mashal, Hosam Abdelhady and Arun K. Iyer

Biomolecules 2022, 12(7), 1001; https://doi.org/10.3390/biom12071001 - 18 Jul 2022

Cited by 14 | Viewed by 4292

Abstract

Alzheimer’s disease (AD) is a rapidly growing global concern associated with the accumulation of amyloid-β plaques and intracellular neurofibrillary tangles in the brain combined with a high acetylcholinesterase activity. AD diagnosis is usually made too late, when patients have an extensive neuronal death, [...] Read more.

Alzheimer’s disease (AD) is a rapidly growing global concern associated with the accumulation of amyloid-β plaques and intracellular neurofibrillary tangles in the brain combined with a high acetylcholinesterase activity. AD diagnosis is usually made too late, when patients have an extensive neuronal death, and brain damage is irreversible. Several therapeutic targets have been defined mainly related to two hypotheses of AD: the tau hypothesis and the amyloid-β hypothesis. Here, we intend to investigate and to compare different therapeutic approaches for AD, mainly based on nanoparticles (NPs) targeted at the brain and at the pathological hallmarks of the disease. We analyzed preclinical trials that have successfully improved drug bioavailability in the brain by using targeted nanocarriers towards either tau, amyloid-β, or both. We then compared these trials to find out which protein is more efficient in therapeutic targeting. We found that the search for a cure was mostly based on the amyloid-β hypothesis, with Aβ dysplasia emerging as the most confirmed and convincing therapeutic target. Targeted NPs have proven useful to enhance both the bioavailability and the performance of therapies against AD in animal models. A better understanding of AD mechanisms will help the successful application of targeted NPs for combined therapies. Full article

(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)

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22 pages, 5889 KiB

Open AccessEditor’s ChoiceArticle

Development of a Multi-Enzymatic Approach for the Modification of Biopolymers with Ferulic Acid

by Archontoula Giannakopoulou, Georgia Tsapara, Anastassios N. Troganis, Panagiota Koralli, Christos L. Chochos, Angeliki C. Polydera, Petros Katapodis, Nektaria-Marianthi Barkoula and Haralambos Stamatis

Biomolecules 2022, 12(7), 992; https://doi.org/10.3390/biom12070992 - 17 Jul 2022

Cited by 4 | Viewed by 3952

Abstract

A series of polymers, including chitosan (CS), carboxymethylcellulose (CMC) and a chitosan–gelatin (CS–GEL) hybrid polymer, were functionalized with ferulic acid (FA) derived from the enzymatic treatment of arabinoxylan through the synergistic action of two enzymes, namely, xylanase and feruloyl esterase. Subsequently, the ferulic [...] Read more.

A series of polymers, including chitosan (CS), carboxymethylcellulose (CMC) and a chitosan–gelatin (CS–GEL) hybrid polymer, were functionalized with ferulic acid (FA) derived from the enzymatic treatment of arabinoxylan through the synergistic action of two enzymes, namely, xylanase and feruloyl esterase. Subsequently, the ferulic acid served as the substrate for laccase from Agaricus bisporus (AbL) in order to enzymatically functionalize the above-mentioned polymers. The successful grafting of the oxidized ferulic acid products onto the different polymers was confirmed through ultraviolet–visible (UV–Vis) spectroscopy, attenuated total reflectance (ATR) spectroscopy, scanning electron microscopy (SEM) and nuclear magnetic resonance (NMR) spectroscopy. Additionally, an enhancement of the antioxidant properties of the functionalized polymers was observed according to the DDPH and ABTS protocols. Finally, the modified polymers exhibited strong antimicrobial activity against bacterial populations of Escherichia coli BL21DE3 strain, suggesting their potential application in pharmaceutical, cosmeceutical and food industries. Full article

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

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21 pages, 2847 KiB

Open AccessEditor’s ChoiceArticle

Analysis of Alternative mRNA Splicing in Vemurafenib-Resistant Melanoma Cells

by Honey Bokharaie, Walter Kolch and Aleksandar Krstic

Biomolecules 2022, 12(7), 993; https://doi.org/10.3390/biom12070993 - 17 Jul 2022

Cited by 9 | Viewed by 4606

Abstract

Alternative mRNA splicing is common in cancers. In BRAF V600E-mutated malignant melanoma, a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively dimerizes and conveys drug resistance. Here, we have analysed AS [...] Read more.

Alternative mRNA splicing is common in cancers. In BRAF V600E-mutated malignant melanoma, a frequent mechanism of acquired resistance to BRAF inhibitors involves alternative splicing (AS) of BRAF. The resulting shortened BRAF protein constitutively dimerizes and conveys drug resistance. Here, we have analysed AS in SK-MEL-239 melanoma cells and a BRAF inhibitor (vemurafenib)-resistant derivative that expresses an AS, shortened BRAF V600E transcript. Transcriptome analysis showed differential expression of spliceosome components between the two cell lines. As there is no consensus approach to analysing AS events, we used and compared four common AS softwares based on different principles, DEXSeq, rMATS, ASpli, and LeafCutter. Two of them correctly identified the BRAF V600E AS in the vemurafenib-resistant cells. Only 12 AS events were identified by all four softwares. Testing the AS predictions experimentally showed that these overlapping predictions are highly accurate. Interestingly, they identified AS caused alterations in the expression of melanin synthesis and cell migration genes in the vemurafenib-resistant cells. This analysis shows that combining different AS analysis approaches produces reliable results and meaningful, biologically testable hypotheses. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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24 pages, 5103 KiB

Open AccessEditor’s ChoiceArticle

Cloning and Characterization of Drosophila melanogaster Juvenile Hormone Epoxide Hydrolases (JHEH) and Their Promoters

by Dov Borovsky, Hilde Breyssens, Esther Buytaert, Tom Peeters, Carole Laroye, Karolien Stoffels and Pierre Rougé

Biomolecules 2022, 12(7), 991; https://doi.org/10.3390/biom12070991 - 16 Jul 2022

Cited by 6 | Viewed by 3226

Abstract

Juvenile hormone epoxide hydrolase (JHEH) plays an important role in the metabolism of JH III in insects. To study the control of JHEH in female Drosophila melanogaster, JHEH 1, 2 and 3 cDNAs were cloned and sequenced. Northern blot analyses showed that [...] Read more.

Juvenile hormone epoxide hydrolase (JHEH) plays an important role in the metabolism of JH III in insects. To study the control of JHEH in female Drosophila melanogaster, JHEH 1, 2 and 3 cDNAs were cloned and sequenced. Northern blot analyses showed that the three transcripts are expressed in the head thorax, the gut, the ovaries and the fat body of females. Molecular modeling shows that the enzyme is a homodimer that binds juvenile hormone III acid (JH IIIA) at the catalytic groove better than JH III. Analyses of the three JHEH promoters and expressing short promoter sequences behind a reporter gene (lacZ) in D. melanogaster cell culture identified a JHEH 3 promoter sequence (626 bp) that is 10- and 25-fold more active than the most active promoter sequences of JHEH 2 and JHEH 1, respectively. A transcription factor (TF) Sp1 that is involved in the activation of JHEH 3 promoter sequence was identified. Knocking down Sp1 using dsRNA inhibited the transcriptional activity of this promoter in transfected D. melanogaster cells and JH III and 20HE downregulated the JHEH 3 promoter. On the other hand, JH IIIA and farnesoic acid did not affect the promoter, indicating that JH IIIA is JHEH’s preferred substrate. A transgenic D. melanogaster expressing a highly activated JHEH 3 promoter behind a lacZ reporter gene showed promoter transcriptional activity in many D. melanogaster tissues. Full article

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

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20 pages, 1173 KiB

Open AccessEditor’s ChoiceReview

Epigenetic Reprogramming of the Inflammatory Response in Obesity and Type 2 Diabetes

by Federica Zatterale, Gregory Alexander Raciti, Immacolata Prevenzano, Alessia Leone, Michele Campitelli, Veronica De Rosa, Francesco Beguinot and Luca Parrillo

Biomolecules 2022, 12(7), 982; https://doi.org/10.3390/biom12070982 - 14 Jul 2022

Cited by 18 | Viewed by 4212

Abstract

For the past several decades, the prevalence of obesity and type 2 diabetes (T2D) has continued to rise on a global level. The risk contributing to this pandemic implicates both genetic and environmental factors, which are functionally integrated by epigenetic mechanisms. While these [...] Read more.

For the past several decades, the prevalence of obesity and type 2 diabetes (T2D) has continued to rise on a global level. The risk contributing to this pandemic implicates both genetic and environmental factors, which are functionally integrated by epigenetic mechanisms. While these conditions are accompanied by major abnormalities in fuel metabolism, evidence indicates that altered immune cell functions also play an important role in shaping of obesity and T2D phenotypes. Interestingly, these events have been shown to be determined by epigenetic mechanisms. Consistently, recent epigenome-wide association studies have demonstrated that immune cells from obese and T2D individuals feature specific epigenetic profiles when compared to those from healthy subjects. In this work, we have reviewed recent literature reporting epigenetic changes affecting the immune cell phenotype and function in obesity and T2D. We will further discuss therapeutic strategies targeting epigenetic marks for treating obesity and T2D-associated inflammation. Full article

(This article belongs to the Special Issue Advances in Immunogenetic Markers of Human Multifactorial Diseases)

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14 pages, 538 KiB

Open AccessEditor’s ChoiceReview

Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

by Mariangela Succoio, Rosa Sacchettini, Alessandro Rossi, Giancarlo Parenti and Margherita Ruoppolo

Biomolecules 2022, 12(7), 968; https://doi.org/10.3390/biom12070968 - 11 Jul 2022

Cited by 39 | Viewed by 24159

Abstract

Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of [...] Read more.

Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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22 pages, 3630 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Understanding How Heart Metabolic Derangement Shows Differential Stage Specificity for Heart Failure with Preserved and Reduced Ejection Fraction

by Federico Ferro, Renza Spelat, Camilla Valente and Paolo Contessotto

Biomolecules 2022, 12(7), 969; https://doi.org/10.3390/biom12070969 - 11 Jul 2022

Cited by 11 | Viewed by 4088

Abstract

Heart failure (HF) is a clinical condition defined by structural and functional abnormalities in the heart that gradually result in reduced cardiac output (HFrEF) and/or increased cardiac pressures at rest and under stress (HFpEF). The presence of asymptomatic individuals hampers HF identification, resulting [...] Read more.

Heart failure (HF) is a clinical condition defined by structural and functional abnormalities in the heart that gradually result in reduced cardiac output (HFrEF) and/or increased cardiac pressures at rest and under stress (HFpEF). The presence of asymptomatic individuals hampers HF identification, resulting in delays in recognizing patients until heart dysfunction is manifested, thus increasing the chance of poor prognosis. Given the recent advances in metabolomics, in this review we dissect the main alterations occurring in the metabolic pathways behind the decrease in cardiac function caused by HF. Indeed, relevant preclinical and clinical research has been conducted on the metabolite connections and differences between HFpEF and HFrEF. Despite these promising results, it is crucial to note that, in addition to identifying single markers and reliable threshold levels within the healthy population, the introduction of composite panels would strongly help in the identification of those individuals with an increased HF risk. That said, additional research in the field is required to overcome the current drawbacks and shed light on the pathophysiological changes that lead to HF. Finally, greater collaborative data sharing, as well as standardization of procedures and approaches, would enhance this research field to fulfil its potential. Full article

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

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21 pages, 1201 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Exosomes in Alpha-Synucleinopathies: Propagators of Pathology or Potential Candidates for Nanotherapeutics?

by Panagiota Mavroeidi, Maria Vetsi, Dimitra Dionysopoulou and Maria Xilouri

Biomolecules 2022, 12(7), 957; https://doi.org/10.3390/biom12070957 - 8 Jul 2022

Cited by 17 | Viewed by 4123

Abstract

The pathological accumulation of alpha-synuclein governs the pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed alpha-synucleinopathies. Alpha-synuclein can be released in the extracellular space, partly via exosomes, and this extracellular protein pool may [...] Read more.

The pathological accumulation of alpha-synuclein governs the pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed alpha-synucleinopathies. Alpha-synuclein can be released in the extracellular space, partly via exosomes, and this extracellular protein pool may contribute to disease progression by facilitating the spread of pathological alpha-synuclein or activating immune cells. The content of exosomes depends on their origin and includes specific proteins, lipids, functional mRNAs and various non-coding RNAs. Given their ability to mediate intercellular communication via the transport of multilevel information, exosomes are considered to be transporters of toxic agents. Beyond neurons, glial cells also release exosomes, which may contain inflammatory molecules and this glia-to-neuron or neuron-to-glia transmission of exosomal alpha-synuclein may contribute to the propagation of pathology and neuroinflammation throughout the brain. In addition, as their content varies as per their originating and recipient cells, these vesicles can be utilized as a diagnostic biomarker for early disease detection, whereas targeted exosomes may be used as scaffolds to deliver therapeutic agents into the brain. This review summarizes the current knowledge regarding the role of exosomes in the progression of alpha-synuclein-related pathology and their potential use as biomarkers and nanotherapeutics in alpha-synucleinopathies. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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23 pages, 2695 KiB

Open AccessEditor’s ChoiceArticle

Cell Confluence Modulates TRPV4 Channel Activity in Response to Hypoxia

by Solène Barbeau, Alexandre Joushomme, Yann Chappe, Guillaume Cardouat, Isabelle Baudrimont, Véronique Freund-Michel, Christelle Guibert, Roger Marthan, Patrick Berger, Pierre Vacher, Yann Percherancier, Jean-François Quignard and Thomas Ducret

Biomolecules 2022, 12(7), 954; https://doi.org/10.3390/biom12070954 - 7 Jul 2022

Cited by 4 | Viewed by 3223

Abstract

Transient receptor potential vanilloid 4 (TRPV4) is a polymodal Ca²⁺-permeable channel involved in various hypoxia-sensitive pathophysiological phenomena. Different tools are available to study channel activity, requiring cells to be cultured at specific optimal densities. In the present study, we examined if [...] Read more.

Transient receptor potential vanilloid 4 (TRPV4) is a polymodal Ca²⁺-permeable channel involved in various hypoxia-sensitive pathophysiological phenomena. Different tools are available to study channel activity, requiring cells to be cultured at specific optimal densities. In the present study, we examined if cell density may influence the effect of hypoxia on TRPV4 activity. Transiently TRPV4-transfected HEK293T cells were seeded at low or high densities corresponding to non-confluent or confluent cells, respectively, on the day of experiments, and cultured under in vitro normoxia or hypoxia. TRPV4-mediated cytosolic Ca²⁺ responses, single-channel currents, and Ca²⁺ influx through the channel were measured using Ca²⁺ imaging/microspectrofluorimetric assay, patch-clamp, and Bioluminescence Resonance Energy Transfer (BRET), respectively. TRPV4 plasma membrane translocation was studied using confocal microscopy, biotinylation of cell surface proteins, and BRET. Our results show that hypoxia exposure has a differential effect on TRPV4 activation depending on cell confluence. At low confluence levels, TRPV4 response is increased in hypoxia, whereas at high confluence levels, TRPV4 response is strongly inhibited, due to channel internalization. Thus, cell density appears to be a crucial parameter for TRPV4 channel activity. Full article

(This article belongs to the Special Issue Physiological Cell Culture)

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16 pages, 7465 KiB

Open AccessEditor’s ChoiceArticle

Acute Effects of Focused Ultrasound-Induced Blood-Brain Barrier Opening on Anti-Pyroglu3 Abeta Antibody Delivery and Immune Responses

by Praveen Bathini, Tao Sun, Mathias Schenk, Stephan Schilling, Nathan J. McDannold and Cynthia A. Lemere

Biomolecules 2022, 12(7), 951; https://doi.org/10.3390/biom12070951 - 6 Jul 2022

Cited by 12 | Viewed by 4234

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound [...] Read more.

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid plaques and hyperphosphorylated tau in the brain. Currently, therapeutic agents targeting amyloid appear promising for AD, however, delivery to the CNS is limited due to the blood-brain-barrier (BBB). Focused ultrasound (FUS) is a method to induce a temporary opening of the BBB to enhance the delivery of therapeutic agents to the CNS. In this study, we evaluated the acute effects of FUS and whether the use of FUS-induced BBB opening enhances the delivery of 07/2a mAb, an anti-pyroglutamate-3 Aβ antibody, in aged 24 mo-old APP/PS1dE9 transgenic mice. FUS was performed either unilaterally or bilaterally with mAb infusion and the short-term effect was analyzed 4 h and 72 h post-treatment. Quantitative analysis by ELISA showed a 5–6-fold increase in 07/2a mAb levels in the brain at both time points and an increased brain-to-blood ratio of the antibody. Immunohistochemistry demonstrated an increase in IgG2a mAb detection particularly in the cortex, enhanced immunoreactivity of resident Iba1+ and phagocytic CD68+ microglial cells, and a transient increase in the infiltration of Ly6G+ immune cells. Cerebral microbleeds were not altered in the unilaterally or bilaterally sonicated hemispheres. Overall, this study shows the potential of FUS therapy for the enhanced delivery of CNS therapeutics. Full article

(This article belongs to the Special Issue Common Mechanisms in Alzheimer’s Disease and Other Neurodegenerative Disorders)

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16 pages, 2123 KiB

Open AccessEditor’s ChoiceArticle

A Novel Analytical Approach to Assessing Sorption of Trace Organic Compounds into Micro- and Nanoplastic Particles

by Julia Reichel, Johanna Graßmann, Oliver Knoop, Thomas Letzel and Jörg E. Drewes

Biomolecules 2022, 12(7), 953; https://doi.org/10.3390/biom12070953 - 6 Jul 2022

Cited by 2 | Viewed by 3031

Abstract

Assessing the sorption of trace organic compounds (TOrCs) into micro- and nanoplastic particles has traditionally been performed using an aqueous phase analysis or solvent extractions from the particle. Using thermal extraction/desorption–gas chromatography/mass spectrometry (TD-Pyr-GC/MS) offers a possibility to analyze the TOrCs directly from [...] Read more.

Assessing the sorption of trace organic compounds (TOrCs) into micro- and nanoplastic particles has traditionally been performed using an aqueous phase analysis or solvent extractions from the particle. Using thermal extraction/desorption–gas chromatography/mass spectrometry (TD-Pyr-GC/MS) offers a possibility to analyze the TOrCs directly from the particle without a long sample preparation. In this study, a combination of two analytical methods is demonstrated. First, the aqueous phase is quantified for TOrC concentrations using Gerstel Twister^® and TD-GC/MS. Subsequently, the TOrCs on the particles are analyzed. Different polymer types and sizes (polymethyl methacrylate (PMMA), 48 µm; polyethylene (PE), 48 µm; polystyrene (PS), 41 µm; and PS, 78 nm) were analyzed for three selected TOrCs (phenanthrene, triclosan, and α-cypermethrin). The results revealed that, over a period of 48 h, the highest and fastest sorption occurred for PS 78 nm particles. This was confirmed with a theoretical calculation of the particle surface area. It was also shown for the first time that direct quantification of TOrCs from PS 78 nm nanoparticles is possible. Furthermore, in a mixed solute solution, the three selected TOrCs were sorbed onto the particles simultaneously. Full article

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

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13 pages, 636 KiB

Open AccessEditor’s ChoiceReview

Metal-Based Compounds in Antiviral Therapy

by Chiara Abate, Federica Carnamucio, Ottavia Giuffrè and Claudia Foti

Biomolecules 2022, 12(7), 933; https://doi.org/10.3390/biom12070933 - 3 Jul 2022

Cited by 35 | Viewed by 4181

Abstract

In recent years, the study of metal complexes and metal-based nanomaterials has aroused particular interest, leading to the promotion of new effective systems for the abatement of various viral diseases. Starting from the analysis of chemical properties, this review focuses on the employment [...] Read more.

In recent years, the study of metal complexes and metal-based nanomaterials has aroused particular interest, leading to the promotion of new effective systems for the abatement of various viral diseases. Starting from the analysis of chemical properties, this review focuses on the employment of metal-based nanoparticles as antiviral drugs and how this interaction leads to a substantial enhancement in antiviral activity. The use of metal-based antiviral drugs has also spread for the formulation of antiviral vaccines, thanks especially to the remarkable adjuvant activities of some of the metal complexes. In particular, the small size and inert nature of Au- and Ag-based nanoparticles have been exploited for the design of systems for antiviral drug delivery, leading to the development of specific and safe therapies that lead to a decrease in side effects. Full article

(This article belongs to the Special Issue State-of-the-Art Highlighting Antiviral Therapy and Viral Diseases Diagnosis in Italy 2020–2021)

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13 pages, 1818 KiB

Open AccessEditor’s ChoiceArticle

NMR Reveals Specific Tracts within the Intrinsically Disordered Regions of the SARS-CoV-2 Nucleocapsid Protein Involved in RNA Encountering

by Letizia Pontoriero, Marco Schiavina, Sophie M. Korn, Andreas Schlundt, Roberta Pierattelli and Isabella C. Felli

Biomolecules 2022, 12(7), 929; https://doi.org/10.3390/biom12070929 - 2 Jul 2022

Cited by 21 | Viewed by 3405

Abstract

The SARS-CoV-2 nucleocapsid (N) protein is crucial for the highly organized packaging and transcription of the genomic RNA. Studying atomic details of the role of its intrinsically disordered regions (IDRs) in RNA recognition is challenging due to the absence of structure and to [...] Read more.

The SARS-CoV-2 nucleocapsid (N) protein is crucial for the highly organized packaging and transcription of the genomic RNA. Studying atomic details of the role of its intrinsically disordered regions (IDRs) in RNA recognition is challenging due to the absence of structure and to the repetitive nature of their primary sequence. IDRs are known to act in concert with the folded domains of N and here we use NMR spectroscopy to identify the priming events of N interacting with a regulatory SARS-CoV-2 RNA element. ¹³C-detected NMR experiments, acquired simultaneously to ¹H detected ones, provide information on the two IDRs flanking the N-terminal RNA binding domain (NTD) within the N-terminal region of the protein (NTR, 1–248). We identify specific tracts of the IDRs that most rapidly sense and engage with RNA, and thus provide an atom-resolved picture of the interplay between the folded and disordered regions of N during RNA interaction. Full article

(This article belongs to the Special Issue Physics of Protein Folding, Misfolding, and Intrinsic Disorder: A Themed Issue in Honour of Professor Vladimir Uversky on the Occasion of His 60th Birthday)

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21 pages, 1356 KiB

Open AccessEditor’s ChoiceReview

Emerging Link between Tsc1 and FNIP Co-Chaperones of Hsp90 and Cancer

by Sarah J. Backe, Rebecca A. Sager, Katherine A. Meluni, Mark R. Woodford, Dimitra Bourboulia and Mehdi Mollapour

Biomolecules 2022, 12(7), 928; https://doi.org/10.3390/biom12070928 - 1 Jul 2022

Cited by 6 | Viewed by 4006

Abstract

Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and [...] Read more.

Heat shock protein-90 (Hsp90) is an ATP-dependent molecular chaperone that is tightly regulated by a group of proteins termed co-chaperones. This chaperone system is essential for the stabilization and activation of many key signaling proteins. Recent identification of the co-chaperones FNIP1, FNIP2, and Tsc1 has broadened the spectrum of Hsp90 regulators. These new co-chaperones mediate the stability of critical tumor suppressors FLCN and Tsc2 as well as the various classes of Hsp90 kinase and non-kinase clients. Many early observations of the roles of FNIP1, FNIP2, and Tsc1 suggested functions independent of FLCN and Tsc2 but have not been fully delineated. Given the broad cellular impact of Hsp90-dependent signaling, it is possible to explain the cellular activities of these new co-chaperones by their influence on Hsp90 function. Here, we review the literature on FNIP1, FNIP2, and Tsc1 as co-chaperones and discuss the potential downstream impact of this regulation on normal cellular function and in human diseases. Full article

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

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20 pages, 6070 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Monoterpenes as Sirtuin-1 Activators: Therapeutic Potential in Aging and Related Diseases

by Cátia Sousa and Alexandrina Ferreira Mendes

Biomolecules 2022, 12(7), 921; https://doi.org/10.3390/biom12070921 - 30 Jun 2022

Cited by 9 | Viewed by 4502

Abstract

Sirtuin 1 (SIRT) is a class III, NAD⁺-dependent histone deacetylase that also modulates the activity of numerous non-histone proteins through deacylation. SIRT1 plays critical roles in regulating and integrating cellular energy metabolism, response to stress, and circadian rhythm by modulating epigenetic [...] Read more.

Sirtuin 1 (SIRT) is a class III, NAD⁺-dependent histone deacetylase that also modulates the activity of numerous non-histone proteins through deacylation. SIRT1 plays critical roles in regulating and integrating cellular energy metabolism, response to stress, and circadian rhythm by modulating epigenetic and transcriptional regulation, mitochondrial homeostasis, proteostasis, telomere maintenance, inflammation, and the response to hypoxia. SIRT1 expression and activity decrease with aging, and enhancing its activity extends life span in various organisms, including mammals, and improves many age-related diseases, including cancer, metabolic, cardiovascular, neurodegenerative, respiratory, musculoskeletal, and renal diseases, but the opposite, that is, aggravation of various diseases, such as some cancers and neurodegenerative diseases, has also been reported. Accordingly, many natural and synthetic SIRT1 activators and inhibitors have been developed. Known SIRT1 activators of natural origin are mainly polyphenols. Nonetheless, various classes of non-polyphenolic monoterpenoids have been identified as inducers of SIRT1 expression and/or activity. This narrative review discusses current information on the evidence that supports the role of those compounds as SIRT1 activators and their potential both as tools for research and as pharmaceuticals for therapeutic application in age-related diseases. Full article

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

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22 pages, 4840 KiB

Open AccessEditor’s ChoiceArticle

Data Size and Quality Matter: Generating Physically-Realistic Distance Maps of Protein Tertiary Structures

by Fardina Fathmiul Alam and Amarda Shehu

Biomolecules 2022, 12(7), 908; https://doi.org/10.3390/biom12070908 - 29 Jun 2022

Cited by 7 | Viewed by 3955

Abstract

With the debut of AlphaFold2, we now can get a highly-accurate view of a reasonable equilibrium tertiary structure of a protein molecule. Yet, a single-structure view is insufficient and does not account for the high structural plasticity of protein molecules. Obtaining a multi-structure [...] Read more.

With the debut of AlphaFold2, we now can get a highly-accurate view of a reasonable equilibrium tertiary structure of a protein molecule. Yet, a single-structure view is insufficient and does not account for the high structural plasticity of protein molecules. Obtaining a multi-structure view of a protein molecule continues to be an outstanding challenge in computational structural biology. In tandem with methods formulated under the umbrella of stochastic optimization, we are now seeing rapid advances in the capabilities of methods based on deep learning. In recent work, we advance the capability of these models to learn from experimentally-available tertiary structures of protein molecules of varying lengths. In this work, we elucidate the important role of the composition of the training dataset on the neural network’s ability to learn key local and distal patterns in tertiary structures. To make such patterns visible to the network, we utilize a contact map-based representation of protein tertiary structure. We show interesting relationships between data size, quality, and composition on the ability of latent variable models to learn key patterns of tertiary structure. In addition, we present a disentangled latent variable model which improves upon the state-of-the-art variable autoencoder-based model in key, physically-realistic structural patterns. We believe this work opens up further avenues of research on deep learning-based models for computing multi-structure views of protein molecules. Full article

(This article belongs to the Special Issue Protein Modeling and Simulation: Selected articles from the Computational Structural Bioinformatics Workshop 2021)

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29 pages, 1408 KiB

Open AccessEditor’s ChoiceReview

Keeping Cell Death Alive: An Introduction into the French Cell Death Research Network

by Gabriel Ichim, Benjamin Gibert, Sahil Adriouch, Catherine Brenner, Nathalie Davoust, Solange Desagher, David Devos, Svetlana Dokudovskaya, Laurence Dubrez, Jérôme Estaquier, Germain Gillet, Isabelle Guénal, Philippe P. Juin, Guido Kroemer, Patrick Legembre, Romain Levayer, Stéphen Manon, Patrick Mehlen, Olivier Meurette, Olivier Micheau, Bernard Mignotte, Florence Nguyen-Khac, Nikolay Popgeorgiev, Jean-Luc Poyet, Muriel Priault, Jean-Ehrland Ricci, Franck B. Riquet, Santos A. Susin, Magali Suzanne, Pierre Vacher, Ludivine Walter and Bertrand Mollereau Show full author list Hide full author list

Biomolecules 2022, 12(7), 901; https://doi.org/10.3390/biom12070901 - 28 Jun 2022

Cited by 3 | Viewed by 4674

Abstract

Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated [...] Read more.

Since the Nobel Prize award more than twenty years ago for discovering the core apoptotic pathway in C. elegans, apoptosis and various other forms of regulated cell death have been thoroughly characterized by researchers around the world. Although many aspects of regulated cell death still remain to be elucidated in specific cell subtypes and disease conditions, many predicted that research into cell death was inexorably reaching a plateau. However, this was not the case since the last decade saw a multitude of cell death modalities being described, while harnessing their therapeutic potential reached clinical use in certain cases. In line with keeping research into cell death alive, francophone researchers from several institutions in France and Belgium established the French Cell Death Research Network (FCDRN). The research conducted by FCDRN is at the leading edge of emerging topics such as non-apoptotic functions of apoptotic effectors, paracrine effects of cell death, novel canonical and non-canonical mechanisms to induce apoptosis in cell death-resistant cancer cells or regulated forms of necrosis and the associated immunogenic response. Collectively, these various lines of research all emerged from the study of apoptosis and in the next few years will increase the mechanistic knowledge into regulated cell death and how to harness it for therapy. Full article

(This article belongs to the Special Issue State-of-the-Art Cell Death in France 2020-2021)

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23 pages, 1612 KiB

Open AccessEditor’s ChoiceReview

Getting Closer to Decrypting the Phase Transitions of Bacterial Biomolecules

by Katarzyna Sołtys, Aneta Tarczewska, Dominika Bystranowska and Nikola Sozańska

Biomolecules 2022, 12(7), 907; https://doi.org/10.3390/biom12070907 - 28 Jun 2022

Cited by 10 | Viewed by 5349

Abstract

Liquid–liquid phase separation (LLPS) of biomolecules has emerged as a new paradigm in cell biology, and the process is one proposed mechanism for the formation of membraneless organelles (MLOs). Bacterial cells have only recently drawn strong interest in terms of studies on both [...] Read more.

Liquid–liquid phase separation (LLPS) of biomolecules has emerged as a new paradigm in cell biology, and the process is one proposed mechanism for the formation of membraneless organelles (MLOs). Bacterial cells have only recently drawn strong interest in terms of studies on both liquid-to-liquid and liquid-to-solid phase transitions. It seems that these processes drive the formation of prokaryotic cellular condensates that resemble eukaryotic MLOs. In this review, we present an overview of the key microbial biomolecules that undergo LLPS, as well as the formation and organization of biomacromolecular condensates within the intracellular space. We also discuss the current challenges in investigating bacterial biomacromolecular condensates. Additionally, we highlight a summary of recent knowledge about the participation of bacterial biomolecules in a phase transition and provide some new in silico analyses that can be helpful for further investigations. Full article

(This article belongs to the Special Issue Molecular Phase Transitions in Physiology and Pathology: Freezing and Precipitation in Biology)

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17 pages, 2276 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Multifaceted Role of Aquaporin-9 in Health and Its Potential as a Clinical Biomarker

by Inês V. da Silva, Sabino Garra, Giuseppe Calamita and Graça Soveral

Biomolecules 2022, 12(7), 897; https://doi.org/10.3390/biom12070897 - 27 Jun 2022

Cited by 40 | Viewed by 4555

Abstract

Aquaporins (AQPs) are transmembrane channels essential for water, energy, and redox homeostasis, with proven involvement in a variety of pathophysiological conditions such as edema, glaucoma, nephrogenic diabetes insipidus, oxidative stress, sepsis, cancer, and metabolic dysfunctions. The 13 AQPs present in humans are widely [...] Read more.

Aquaporins (AQPs) are transmembrane channels essential for water, energy, and redox homeostasis, with proven involvement in a variety of pathophysiological conditions such as edema, glaucoma, nephrogenic diabetes insipidus, oxidative stress, sepsis, cancer, and metabolic dysfunctions. The 13 AQPs present in humans are widely distributed in all body districts, drawing cell lineage-specific expression patterns closely related to cell native functions. Compelling evidence indicates that AQPs are proteins with great potential as biomarkers and targets for therapeutic intervention. Aquaporin-9 (AQP9) is the most expressed in the liver, with implications in general metabolic and redox balance due to its aquaglyceroporin and peroxiporin activities, facilitating glycerol and hydrogen peroxide (H₂O₂) diffusion across membranes. AQP9 is also expressed in other tissues, and their altered expression is described in several human diseases, such as liver injury, inflammation, cancer, infertility, and immune disorders. The present review compiles the current knowledge of AQP9 implication in diseases and highlights its potential as a new biomarker for diagnosis and prognosis in clinical medicine. Full article

(This article belongs to the Special Issue 10th Anniversary of Biomolecules—Advances in Biomarkers, Therapeutics and Prevention)

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15 pages, 3586 KiB

Open AccessEditor’s ChoiceArticle

Characterization of Endothelium-Dependent Relaxation in the Saphenous Artery and Its Caudal Branches in Young and Old Adult Sprague Dawley Rats

by Andrea N. Wang, Graham M. Fraser and John J. McGuire

Biomolecules 2022, 12(7), 889; https://doi.org/10.3390/biom12070889 - 25 Jun 2022

Cited by 3 | Viewed by 3998

Abstract

Ageing is associated with reduced endothelium-derived nitric oxide (NO) production in the femoral artery of Sprague Dawley (SD) rats. In the current study, we examined endothelium-dependent relaxation (EDR) in the saphenous artery and its caudal branches. We used acetylcholine and the Proteinase-Activated receptor-2 [...] Read more.

Ageing is associated with reduced endothelium-derived nitric oxide (NO) production in the femoral artery of Sprague Dawley (SD) rats. In the current study, we examined endothelium-dependent relaxation (EDR) in the saphenous artery and its caudal branches. We used acetylcholine and the Proteinase-Activated receptor-2 (PAR2)-specific agonist (2fLIGRLO) with nitroarginine methylester (L-NAME) to assess EDR in two groups of male SD rats (age in weeks: young, 10–12; old, 27–29). Acetylcholine and 2fLIGRLO were potent NO-dependent relaxant agents in all arteries. For all arteries, EDR by acetylcholine decreased significantly in old compared to young SD rats. Interestingly, PAR2-induced EDR of proximal saphenous artery segments and caudal branches decreased significantly in old compared to young, but did not differ for the in-between middle and distal ends of the saphenous artery. L-NAME treatment increased subsequent contractions of proximal and middle segments of saphenous arteries by phenylephrine and U46619 in young, but not in old, SD rats. We conclude the SD saphenous artery and caudal branches exhibit regional characteristics that differ in response to specific EDR agonists, endothelial NO synthase inhibitor, and changes to endothelium function with increased age, which are, in part, attributed to decreased sensitivity of vascular smooth muscle to the gaseous transmitter NO. Full article

(This article belongs to the Special Issue Gaseous Transmitters and Cardiovascular System)

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13 pages, 1806 KiB

Open AccessEditor’s ChoiceReview

The Mitochondrial HSP90 Paralog TRAP1: Structural Dynamics, Interactome, Role in Metabolic Regulation, and Inhibitors

by Abhinav Joshi, Takeshi Ito, Didier Picard and Len Neckers

Biomolecules 2022, 12(7), 880; https://doi.org/10.3390/biom12070880 - 24 Jun 2022

Cited by 22 | Viewed by 4999

Abstract

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in [...] Read more.

The HSP90 paralog TRAP1 was discovered more than 20 years ago; yet, a detailed understanding of the function of this mitochondrial molecular chaperone remains elusive. The dispensable nature of TRAP1 in vitro and in vivo further complicates an understanding of its role in mitochondrial biology. TRAP1 is more homologous to the bacterial HSP90, HtpG, than to eukaryotic HSP90. Lacking co-chaperones, the unique structural features of TRAP1 likely regulate its temperature-sensitive ATPase activity and shed light on the alternative mechanisms driving the chaperone’s nucleotide-dependent cycle in a defined environment whose physiological temperature approaches 50 °C. TRAP1 appears to be an important bioregulator of mitochondrial respiration, mediating the balance between oxidative phosphorylation and glycolysis, while at the same time promoting mitochondrial homeostasis and displaying cytoprotective activity. Inactivation/loss of TRAP1 has been observed in several neurodegenerative diseases while TRAP1 expression is reported to be elevated in multiple cancers and, as with HSP90, evidence of addiction to TRAP1 has been observed. In this review, we summarize what is currently known about this unique HSP90 paralog and why a better understanding of TRAP1 structure, function, and regulation is likely to enhance our understanding of the mechanistic basis of mitochondrial homeostasis. Full article

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

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33 pages, 4624 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

A Novel and Selective Dopamine Transporter Inhibitor, (S)-MK-26, Promotes Hippocampal Synaptic Plasticity and Restores Effort-Related Motivational Dysfunctions

by Shima Kouhnavardi, Alev Ecevitoglu, Vladimir Dragačević, Fabrizio Sanna, Edgar Arias-Sandoval, Predrag Kalaba, Michael Kirchhofer, Jana Lubec, Marco Niello, Marion Holy, Martin Zehl, Matthias Pillwein, Judith Wackerlig, Rita Murau, Andrea Mohrmann, Kathryn R. Beard, Harald H. Sitte, Ernst Urban, Claudia Sagheddu, Marco Pistis, Roberto Plasenzotti, John D. Salamone, Thierry Langer, Gert Lubec and Francisco J. Monje Show full author list Hide full author list

Biomolecules 2022, 12(7), 881; https://doi.org/10.3390/biom12070881 - 24 Jun 2022

Cited by 18 | Viewed by 5877

Abstract

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all [...] Read more.

Dopamine (DA), the most abundant human brain catecholaminergic neurotransmitter, modulates key behavioral and neurological processes in young and senescent brains, including motricity, sleep, attention, emotion, learning and memory, and social and reward-seeking behaviors. The DA transporter (DAT) regulates transsynaptic DA levels, influencing all these processes. Compounds targeting DAT (e.g., cocaine and amphetamines) were historically used to shape mood and cognition, but these substances typically lead to severe negative side effects (tolerance, abuse, addiction, and dependence). DA/DAT signaling dysfunctions are associated with neuropsychiatric and progressive brain disorders, including Parkinson’s and Alzheimer diseases, drug addiction and dementia, resulting in devastating personal and familial concerns and high socioeconomic costs worldwide. The development of low-side-effect, new/selective medicaments with reduced abuse-liability and which ameliorate DA/DAT-related dysfunctions is therefore crucial in the fields of medicine and healthcare. Using the rat as experimental animal model, the present work describes the synthesis and pharmacological profile of (S)-MK-26, a new modafinil analogue with markedly improved potency and selectivity for DAT over parent drug. Ex vivo electrophysiology revealed significantly augmented hippocampal long-term synaptic potentiation upon acute, intraperitoneally delivered (S)-MK-26 treatment, whereas in vivo experiments in the hole-board test showed only lesser effects on reference memory performance in aged rats. However, in effort-related FR5/chow and PROG/chow feeding choice experiments, (S)-MK-26 treatment reversed the depression-like behavior induced by the dopamine-depleting drug tetrabenazine (TBZ) and increased the selection of high-effort alternatives. Moreover, in in vivo microdialysis experiments, (S)-MK-26 significantly increased extracellular DA levels in the prefrontal cortex and in nucleus accumbens core and shell. These studies highlight (S)-MK-26 as a potent enhancer of transsynaptic DA and promoter of synaptic plasticity, with predominant beneficial effects on effort-related behaviors, thus proposing therapeutic potentials for (S)-MK-26 in the treatment of low-effort exertion and motivational dysfunctions characteristic of depression and aging-related disorders. Full article

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20 pages, 2949 KiB

Open AccessEditor’s ChoiceArticle

Development of a Biotechnology Platform for the Fast-Growing Cyanobacterium Synechococcus sp. PCC 11901

by Lauren A. Mills, José Ángel Moreno-Cabezuelo, Artur Włodarczyk, Angelo J. Victoria, Rebeca Mejías, Anja Nenninger, Simon Moxon, Paolo Bombelli, Tiago T. Selão, Alistair J. McCormick and David J. Lea-Smith

Biomolecules 2022, 12(7), 872; https://doi.org/10.3390/biom12070872 - 23 Jun 2022

Cited by 17 | Viewed by 6838

Abstract

Synechococcus sp. PCC 11901 reportedly demonstrates the highest, most sustained growth of any known cyanobacterium under optimized conditions. Due to its recent discovery, our knowledge of its biology, including the factors underlying sustained, fast growth, is limited. Furthermore, tools specific for genetic manipulation [...] Read more.

Synechococcus sp. PCC 11901 reportedly demonstrates the highest, most sustained growth of any known cyanobacterium under optimized conditions. Due to its recent discovery, our knowledge of its biology, including the factors underlying sustained, fast growth, is limited. Furthermore, tools specific for genetic manipulation of PCC 11901 are not established. Here, we demonstrate that PCC 11901 shows faster growth than other model cyanobacteria, including the fast-growing species Synechococcuselongatus UTEX 2973, under optimal growth conditions for UTEX 2973. Comparative genomics between PCC 11901 and Synechocystis sp. PCC 6803 reveal conservation of most metabolic pathways but PCC 11901 has a simplified electron transport chain and reduced light harvesting complex. This may underlie its superior light use, reduced photoinhibition, and higher photosynthetic and respiratory rates. To aid biotechnology applications, we developed a vitamin B₁₂ auxotrophic mutant but were unable to generate unmarked knockouts using two negative selectable markers, suggesting that recombinase- or CRISPR-based approaches may be required for repeated genetic manipulation. Overall, this study establishes PCC 11901 as one of the most promising species currently available for cyanobacterial biotechnology and provides a useful set of bioinformatics tools and strains for advancing this field, in addition to insights into the factors underlying its fast growth phenotype. Full article

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19 pages, 865 KiB

Open AccessEditor’s ChoiceReview

Polyphenol and Tannin Nutraceuticals and Their Metabolites: How the Human Gut Microbiota Influences Their Properties

by Marco Fabbrini, Federica D’Amico, Monica Barone, Gabriele Conti, Mariachiara Mengoli, Patrizia Brigidi and Silvia Turroni

Biomolecules 2022, 12(7), 875; https://doi.org/10.3390/biom12070875 - 23 Jun 2022

Cited by 37 | Viewed by 5491

Abstract

Nutraceuticals have been receiving increasing attention in the last few years due to their potential role as adjuvants against non-communicable chronic diseases (cardiovascular disease, diabetes, cancer, etc.). However, a limited number of studies have been performed to evaluate the bioavailability of such compounds, [...] Read more.

Nutraceuticals have been receiving increasing attention in the last few years due to their potential role as adjuvants against non-communicable chronic diseases (cardiovascular disease, diabetes, cancer, etc.). However, a limited number of studies have been performed to evaluate the bioavailability of such compounds, and it is generally reported that a substantial elevation of their plasma concentration can only be achieved when they are consumed at pharmacological levels. Even so, positive effects have been reported associated with an average dietary consumption of several nutraceutical classes, meaning that the primary compound might not be solely responsible for all the biological effects. The in vivo activities of such biomolecules might be carried out by metabolites derived from gut microbiota fermentative transformation. This review discusses the structure and properties of phenolic nutraceuticals (i.e., polyphenols and tannins) and the putative role of the human gut microbiota in influencing the beneficial effects of such compounds. Full article

(This article belongs to the Special Issue Bioactive Natural Compounds against Animal and Human Pathogens)

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14 pages, 2185 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Early Signs of Molecular Defects in iPSC-Derived Neural Stems Cells from Patients with Familial Parkinson’s Disease

by Elissavet Akrioti, Timokratis Karamitros, Panagiotis Gkaravelas, Georgia Kouroupi, Rebecca Matsas and Era Taoufik

Biomolecules 2022, 12(7), 876; https://doi.org/10.3390/biom12070876 - 23 Jun 2022

Cited by 7 | Viewed by 4777

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, classically associated with extensive loss of dopaminergic neurons of the substantia nigra pars compacta. The hallmark of the disease is the accumulation of pathogenic conformations of the presynaptic protein, α-synuclein (αSyn), and the [...] Read more.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, classically associated with extensive loss of dopaminergic neurons of the substantia nigra pars compacta. The hallmark of the disease is the accumulation of pathogenic conformations of the presynaptic protein, α-synuclein (αSyn), and the formation of intraneuronal protein aggregate inclusions. Neurodegeneration of dopamine neurons leads to a prominent dopaminergic deficiency in the basal ganglia, responsible for motor disturbances. However, it is now recognized that the disease involves more widespread neuronal dysfunction, leading to early and late non-motor symptoms. The development of in vitro systems based on the differentiation of human-induced pluripotent stem cells provides us the unique opportunity to monitor alterations at the cellular and molecular level throughout the differentiation procedure and identify perturbations that occur early, even at the neuronal precursor stage. Here we aim to identify whether p.A53T-αSyn induced disturbances at the molecular level are already present in neural precursors. Towards this, we present data from transcriptomics analysis of control and p.A53T-αSyn NPCs showing altered expression in transcripts involved in axon guidance, adhesion, synaptogenesis, ion transport, and metabolism. The comparative analysis with the transcriptomics profile of p.A53T-αSyn neurons shows both distinct and overlapping pathways leading to neurodegeneration while meta-analysis with transcriptomics data from both neurodegenerative and neurodevelopmental disorders reveals that p.A53T-pathology has a significant overlap with the latter category. This is the first study showing that molecular dysregulation initiates early at the p.A53T-αSyn NPC level, suggesting that synucleinopathies may have a neurodevelopmental component. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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15 pages, 1411 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Life and Death Decisions—The Many Faces of Autophagy in Cell Survival and Cell Death

by Ge Yu and Daniel J. Klionsky

Biomolecules 2022, 12(7), 866; https://doi.org/10.3390/biom12070866 - 21 Jun 2022

Cited by 28 | Viewed by 3955

Abstract

Autophagy is a process conserved from yeast to humans. Since the discovery of autophagy, its physiological role in cell survival and cell death has been intensively investigated. The inherent ability of the autophagy machinery to sequester, deliver, and degrade cytoplasmic components enables autophagy [...] Read more.

Autophagy is a process conserved from yeast to humans. Since the discovery of autophagy, its physiological role in cell survival and cell death has been intensively investigated. The inherent ability of the autophagy machinery to sequester, deliver, and degrade cytoplasmic components enables autophagy to participate in cell survival and cell death in multiple ways. The primary role of autophagy is to send cytoplasmic components to the vacuole or lysosomes for degradation. By fine-tuning autophagy, the cell regulates the removal and recycling of cytoplasmic components in response to various stress or signals. Recent research has shown the implications of the autophagy machinery in other pathways independent of lysosomal degradation, expanding the pro-survival role of autophagy. Autophagy also facilitates certain forms of regulated cell death. In addition, there is complex crosstalk between autophagy and regulated cell death pathways, with a number of genes shared between them, further suggesting a deeper connection between autophagy and cell death. Finally, the mitochondrion presents an example where the cell utilizes autophagy to strike a balance between cell survival and cell death. In this review, we consider the current knowledge on the physiological role of autophagy as well as its regulation and discuss the multiple functions of autophagy in cell survival and cell death. Full article

(This article belongs to the Special Issue The Many Faces of Autophagy: Balancing Survival and Cell Death)

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16 pages, 4049 KiB

Open AccessEditor’s ChoiceArticle

Midazolam as a Probe for Heterotropic Drug-Drug Interactions Mediated by CYP3A4

by Ilia G. Denisov, Yelena V. Grinkova, Mark A. McLean, Tyler Camp and Stephen G. Sligar

Biomolecules 2022, 12(6), 853; https://doi.org/10.3390/biom12060853 - 20 Jun 2022

Cited by 14 | Viewed by 3945

Abstract

Human cytochrome P450 CYP3A4 is involved in the processing of more than 35% of current pharmaceuticals and therefore is responsible for multiple drug-drug interactions (DDI). In order to develop a method for the detection and prediction of the possible involvement of new drug [...] Read more.

Human cytochrome P450 CYP3A4 is involved in the processing of more than 35% of current pharmaceuticals and therefore is responsible for multiple drug-drug interactions (DDI). In order to develop a method for the detection and prediction of the possible involvement of new drug candidates in CYP3A4-mediated DDI, we evaluated the application of midazolam (MDZ) as a probe substrate. MDZ is hydroxylated by CYP3A4 in two positions: 1-hydroxy MDZ formed at lower substrate concentrations, and up to 35% of 4-hydroxy MDZ at high concentrations. The ratio of the formation rates of these two products (the site of metabolism ratio, SOM) was used as a measure of allosteric heterotropic interactions caused by effector molecules using CYP3A4 incorporated in lipid nanodiscs. The extent of the changes in the SOM in the presence of effectors is determined by chemical structure and is concentration-dependent. MD simulations of CYP3A4 in the lipid bilayer suggest that experimental results can be explained by the movement of the F-F’ loop and concomitant changes in the shape and volume of the substrate-binding pocket. As a result of PGS binding at the allosteric site, several residues directly contacting MDZ move away from the substrate molecule, enabling the repositioning of the latter for minor product formation. Full article

(This article belongs to the Special Issue New Insights into Cytochrome P450s)

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14 pages, 2356 KiB

Open AccessEditor’s ChoiceArticle

Growth-Suppressive and Apoptosis-Inducing Effects of Tetrandrine in SW872 Human Malignant Liposarcoma Cells via Activation of Caspase-9, Down-Regulation of XIAP and STAT-3, and ER Stress

by Mohammed Samsuzzaman and Byeong-Churl Jang

Biomolecules 2022, 12(6), 843; https://doi.org/10.3390/biom12060843 - 17 Jun 2022

Cited by 6 | Viewed by 2666

Abstract

Liposarcoma is a rare and heterogeneous soft tissue malignant tumor and has a significant impact on mortality with a poor prognosis. To date, there is no effective treatment for liposarcoma, whereas surgical resection is only the gold treatment with numerous adverse effects. Here [...] Read more.

Liposarcoma is a rare and heterogeneous soft tissue malignant tumor and has a significant impact on mortality with a poor prognosis. To date, there is no effective treatment for liposarcoma, whereas surgical resection is only the gold treatment with numerous adverse effects. Here we investigated whether tetrandrine inhibits the growth of SW872 human malignant liposarcoma cells. Of note, tetrandrine at 10 μM vastly inhibited growth and induced apoptosis, as evidenced by increased nuclear DNA fragmentation and sub-G1 population of SW872 cells. Mechanistically, treatment with tetrandrine led to activation of caspase-9/3 in SW872 cells, and z-VAD-fmk, a pan-caspase inhibitor, attenuated the tetrandrine-induced apoptosis and growth suppression in SW872 cells. In addition, tetrandrine treatment resulted in down-regulation of XIAP andSTAT-3 in SW872 cells, and importantly knockdown of STAT-3 caused a significant reduction of the cell survival. Tetrandrine also had abilities to up-regulate not only the expression of GRP78 and ATF-4 but also the phosphorylation of eIF-2α in SW872 cells. In summary, these results demonstrated that tetrandrine has strong growth-suppressive and apoptosis-inducing effects on SW872 cells, which are mediated through control of the intrinsic caspase pathway, down-regulation of XIAP and STAT-3, and triggering ER stress. Full article

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

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11 pages, 812 KiB

Open AccessEditor’s ChoiceReview

CPLANE Complex and Ciliopathies

by Jesús Eduardo Martín-Salazar and Diana Valverde

Biomolecules 2022, 12(6), 847; https://doi.org/10.3390/biom12060847 - 17 Jun 2022

Cited by 13 | Viewed by 3337

Abstract

Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some [...] Read more.

Primary cilia are non-motile organelles associated with the cell cycle, which can be found in most vertebrate cell types. Cilia formation occurs through a process called ciliogenesis, which involves several mechanisms including planar cell polarity (PCP) and the Hedgehog (Hh) signaling pathway. Some gene complexes, such as BBSome or CPLANE (ciliogenesis and planar polarity effector), have been linked to ciliogenesis. CPLANE complex is composed of INTU, FUZ and WDPCP, which bind to JBTS17 and RSG1 for cilia formation. Defects in these genes have been linked to a malfunction of intraflagellar transport and defects in the planar cell polarity, as well as defective activation of the Hedgehog signalling pathway. These faults lead to defective cilium formation, resulting in ciliopathies, including orofacial–digital syndrome (OFDS) and Bardet–Biedl syndrome (BBS). Considering the close relationship, between the CPLANE complex and cilium formation, it can be expected that defects in the genes that encode subunits of the CPLANE complex may be related to other ciliopathies. Full article

(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)

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24 pages, 4142 KiB

Open AccessEditor’s ChoiceArticle

Non-Equilibrium Protein Folding and Activation by ATP-Driven Chaperones

by Huafeng Xu

Biomolecules 2022, 12(6), 832; https://doi.org/10.3390/biom12060832 - 15 Jun 2022

Cited by 5 | Viewed by 4475

Abstract

Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying [...] Read more.

Recent experimental studies suggest that ATP-driven molecular chaperones can stabilize protein substrates in their native structures out of thermal equilibrium. The mechanism of such non-equilibrium protein folding is an open question. Based on available structural and biochemical evidence, I propose here a unifying principle that underlies the conversion of chemical energy from ATP hydrolysis to the conformational free energy associated with protein folding and activation. I demonstrate that non-equilibrium folding requires the chaperones to break at least one of four symmetry conditions. The Hsp70 and Hsp90 chaperones each break a different subset of these symmetries and thus they use different mechanisms for non-equilibrium protein folding. I derive an upper bound on the non-equilibrium elevation of the native concentration, which implies that non-equilibrium folding only occurs in slow-folding proteins that adopt an unstable intermediate conformation in binding to ATP-driven chaperones. Contrary to the long-held view of Anfinsen’s hypothesis that proteins fold to their conformational free energy minima, my results predict that some proteins may fold into thermodynamically unstable native structures with the assistance of ATP-driven chaperones, and that the native structures of some chaperone-dependent proteins may be shaped by their chaperone-mediated folding pathways. Full article

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

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16 pages, 3725 KiB

Open AccessEditor’s ChoiceArticle

Selective Upregulation of SIRT1 Expression in Retinal Ganglion Cells by AAV-Mediated Gene Delivery Increases Neuronal Cell Survival and Alleviates Axon Demyelination Associated with Optic Neuritis

by Ahmara G. Ross, Brahim Chaqour, Devin S. McDougald, Kimberly E. Dine, Thu T. Duong, Ryan E. Shindler, Jipeng Yue, Tehui Liu and Kenneth S. Shindler

Biomolecules 2022, 12(6), 830; https://doi.org/10.3390/biom12060830 - 14 Jun 2022

Cited by 20 | Viewed by 4349

Abstract

Optic neuritis (ON), the most common ocular manifestation of multiple sclerosis, is an autoimmune inflammatory demyelinating disease also characterized by degeneration of retinal ganglion cells (RGCs) and their axons, which commonly leads to visual impairment despite attempted treatments. Although ON disease etiology is [...] Read more.

Optic neuritis (ON), the most common ocular manifestation of multiple sclerosis, is an autoimmune inflammatory demyelinating disease also characterized by degeneration of retinal ganglion cells (RGCs) and their axons, which commonly leads to visual impairment despite attempted treatments. Although ON disease etiology is not known, changes in the redox system and exacerbated optic nerve inflammation play a major role in the pathogenesis of the disease. Silent information regulator 1 (sirtuin-1/SIRT1) is a ubiquitously expressed NAD⁺-dependent deacetylase, which functions to reduce/prevent both oxidative stress and inflammation in various tissues. Non-specific upregulation of SIRT1 by pharmacologic and genetic approaches attenuates RGC loss in experimental ON. Herein, we hypothesized that targeted expression of SIRT1 selectively in RGCs using an adeno-associated virus (AAV) vector as a delivery vehicle is an effective approach to reducing neurodegeneration and preserving vision in ON. We tested this hypothesis through intravitreal injection of AAV7m8.SNCG.SIRT1, an AAV2-derived vector optimized for highly efficient SIRT1 transgene transfer and protein expression into RGCs in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis that recapitulates optic neuritis RGC loss and axon demyelination. Our data show that EAE mice injected with a control vehicle exhibit progressive alteration of visual function reflected by decreasing optokinetic response (OKR) scores, whereas comparatively, AAV7m8.SNCG.SIRT1-injected EAE mice maintain higher OKR scores, suggesting that SIRT1 reduces the visual deficit imparted by EAE. Consistent with this, RGC survival determined by immunolabeling is increased and axon demyelination is decreased in the AAV7m8.SNCG.SIRT1 RGC-injected group of EAE mice compared to the mouse EAE counterpart injected with a vehicle or with control vector AAV7m8.SNCG.eGFP. However, immune cell infiltration of the optic nerve is not significantly different among all EAE groups of mice injected with either vehicle or AAV7m8.SNCG.SIRT1. We conclude that despite minimally affecting the inflammatory response in the optic nerve, AAV7m8-mediated SIRT1 transfer into RGCs has a neuroprotective potential against RGC loss, axon demyelination and vison deficits associated with EAE. Together, these data suggest that SIRT1 exerts direct effects on RGC survival and function. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Optic Neuropathies)

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32 pages, 1340 KiB

Open AccessEditor’s ChoiceReview

NAFLD: Mechanisms, Treatments, and Biomarkers

by Fatiha Nassir

Biomolecules 2022, 12(6), 824; https://doi.org/10.3390/biom12060824 - 13 Jun 2022

Cited by 227 | Viewed by 22297

Abstract

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason [...] Read more.

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is one of the most common causes of liver diseases worldwide. NAFLD is growing in parallel with the obesity epidemic. No pharmacological treatment is available to treat NAFLD, specifically. The reason might be that NAFLD is a multi-factorial disease with an incomplete understanding of the mechanisms involved, an absence of accurate and inexpensive imaging tools, and lack of adequate non-invasive biomarkers. NAFLD consists of the accumulation of excess lipids in the liver, causing lipotoxicity that might progress to metabolic-associated steatohepatitis (NASH), liver fibrosis, and hepatocellular carcinoma. The mechanisms for the pathogenesis of NAFLD, current interventions in the management of the disease, and the role of sirtuins as potential targets for treatment are discussed here. In addition, the current diagnostic tools, and the role of non-coding RNAs as emerging diagnostic biomarkers are summarized. The availability of non-invasive biomarkers, and accurate and inexpensive non-invasive diagnosis tools are crucial in the detection of the early signs in the progression of NAFLD. This will expedite clinical trials and the validation of the emerging therapeutic treatments. Full article

(This article belongs to the Special Issue Mechanisms of Nonalcoholic Liver Diseases)

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21 pages, 4098 KiB

Open AccessEditor’s ChoiceArticle

Occurrence of Lymphangiogenesis in Peripheral Nerve Autografts Contrasts Schwann Cell-Induced Apoptosis of Lymphatic Endothelial Cells In Vitro

by Carina Hromada, Jaana Hartmann, Johannes Oesterreicher, Anton Stoiber, Anna Daerr, Barbara Schädl, Eleni Priglinger, Andreas H. Teuschl-Woller, Wolfgang Holnthoner, Johannes Heinzel and David Hercher

Biomolecules 2022, 12(6), 820; https://doi.org/10.3390/biom12060820 - 12 Jun 2022

Cited by 12 | Viewed by 3675

Abstract

Peripheral nerve injuries pose a major clinical concern world-wide, and functional recovery after segmental peripheral nerve injury is often unsatisfactory, even in cases of autografting. Although it is well established that angiogenesis plays a pivotal role during nerve regeneration, the influence of lymphangiogenesis [...] Read more.

Peripheral nerve injuries pose a major clinical concern world-wide, and functional recovery after segmental peripheral nerve injury is often unsatisfactory, even in cases of autografting. Although it is well established that angiogenesis plays a pivotal role during nerve regeneration, the influence of lymphangiogenesis is strongly under-investigated. In this study, we analyzed the presence of lymphatic vasculature in healthy and regenerated murine peripheral nerves, revealing that nerve autografts contained increased numbers of lymphatic vessels after segmental damage. This led us to elucidate the interaction between lymphatic endothelial cells (LECs) and Schwann cells (SCs) in vitro. We show that SC and LEC secretomes did not influence the respective other cell types’ migration and proliferation in 2D scratch assay experiments. Furthermore, we successfully created lymphatic microvascular structures in SC-embedded 3D fibrin hydrogels, in the presence of supporting cells; whereas SCs seemed to exert anti-lymphangiogenic effects when cultured with LECs alone. Here, we describe, for the first time, increased lymphangiogenesis after peripheral nerve injury and repair. Furthermore, our findings indicate a potential lymph-repellent property of SCs, thereby providing a possible explanation for the lack of lymphatic vessels in the healthy endoneurium. Our results highlight the importance of elucidating the molecular mechanisms of SC–LEC interaction. Full article

(This article belongs to the Special Issue Recent Advances in Schwann Cells)

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21 pages, 3295 KiB

Open AccessEditor’s ChoiceReview

Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels

by Anna Ananchenko, Toka O. K. Hussein, Deepansh Mody, Mackenzie J. Thompson and John E. Baenziger

Biomolecules 2022, 12(6), 814; https://doi.org/10.3390/biom12060814 - 10 Jun 2022

Cited by 11 | Viewed by 4185

Abstract

Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function [...] Read more.

Pentameric ligand-gated ion channels (pLGICs) play a leading role in synaptic communication, are implicated in a variety of neurological processes, and are important targets for the treatment of neurological and neuromuscular disorders. Endogenous lipids and lipophilic compounds are potent modulators of pLGIC function and may help shape synaptic communication. Increasing structural and biophysical data reveal sites for lipid binding to pLGICs. Here, we update our evolving understanding of pLGIC–lipid interactions highlighting newly identified modes of lipid binding along with the mechanistic understanding derived from the new structural data. Full article

(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)

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32 pages, 9181 KiB

Open AccessEditor’s ChoiceReview

Inhibitors of the Cancer Target Ribonucleotide Reductase, Past and Present

by Sarah E. Huff, Jordan M. Winter and Chris G. Dealwis

Biomolecules 2022, 12(6), 815; https://doi.org/10.3390/biom12060815 - 10 Jun 2022

Cited by 25 | Viewed by 6175

Abstract

Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR [...] Read more.

Ribonucleotide reductase (RR) is an essential multi-subunit enzyme found in all living organisms; it catalyzes the rate-limiting step in dNTP synthesis, namely, the conversion of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. As expression levels of human RR (hRR) are high during cell replication, hRR has long been considered an attractive drug target for a range of proliferative diseases, including cancer. While there are many excellent reviews regarding the structure, function, and clinical importance of hRR, recent years have seen an increase in novel approaches to inhibiting hRR that merit an updated discussion of the existing inhibitors and strategies to target this enzyme. In this review, we discuss the mechanisms and clinical applications of classic nucleoside analog inhibitors of hRRM1 (large catalytic subunit), including gemcitabine and clofarabine, as well as inhibitors of the hRRM2 (free radical housing small subunit), including triapine and hydroxyurea. Additionally, we discuss novel approaches to targeting RR and the discovery of new classes of hRR inhibitors. Full article

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

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9 pages, 3284 KiB

Open AccessEditor’s ChoiceArticle

Efficient Viral Transduction in Fetal and Adult Human Inner Ear Explants with AAV9-PHP.B Vectors

by Edward S. A. van Beelen, Wouter H. van der Valk, Thijs O. Verhagen, John C. M. J. de Groot, Margot A. Madison, Wijs Shadmanfar, Erik F. Hensen, Jeroen C. Jansen, Peter Paul G. van Benthem, Jeffrey R. Holt and Heiko Locher

Biomolecules 2022, 12(6), 816; https://doi.org/10.3390/biom12060816 - 10 Jun 2022

Cited by 7 | Viewed by 3571

Abstract

Numerous studies have shown the recovery of auditory function in mouse models of genetic hearing loss following AAV gene therapy, yet translation to the clinic has not yet been demonstrated. One limitation has been the lack of human inner ear cell lines or [...] Read more.

Numerous studies have shown the recovery of auditory function in mouse models of genetic hearing loss following AAV gene therapy, yet translation to the clinic has not yet been demonstrated. One limitation has been the lack of human inner ear cell lines or tissues for validating viral gene therapies. Cultured human inner ear tissue could help confirm viral tropism and efficacy for driving exogenous gene expression in targeted cell types, establish promoter efficacy and perhaps selectivity for targeted cells, confirm the expression of therapeutic constructs and the subcellular localization of therapeutic proteins, and address the potential cellular toxicity of vectors or exogenous constructs. To begin to address these questions, we developed an explant culture method using native human inner ear tissue excised at either fetal or adult stages. Inner ear sensory epithelia were cultured for four days and exposed to vectors encoding enhanced green fluorescent protein (eGFP). We focused on the synthetic AAV9-PHP.B capsid, which has been demonstrated to be efficient for driving eGFP expression in the sensory hair cells of mouse and non-human primate inner ears. We report that AAV9-PHP.B also drives eGFP expression in fetal cochlear hair cells and in fetal and adult vestibular hair cells in explants of human inner ear sensory epithelia, which suggests that both the experimental paradigm and the viral capsid may be valuable for translation to clinical application. Full article

(This article belongs to the Special Issue Inner Ear Therapeutics)

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19 pages, 3172 KiB

Open AccessEditor’s ChoiceArticle

Exploring Silk Sericin for Diabetic Wounds: An In Situ-Forming Hydrogel to Protect against Oxidative Stress and Improve Tissue Healing and Regeneration

by Sara Baptista-Silva, Beatriz G. Bernardes, Sandra Borges, Ilda Rodrigues, Rui Fernandes, Susana Gomes-Guerreiro, Marta Teixeira Pinto, Manuela Pintado, Raquel Soares, Raquel Costa and Ana Leite Oliveira

Biomolecules 2022, 12(6), 801; https://doi.org/10.3390/biom12060801 - 8 Jun 2022

Cited by 30 | Viewed by 5034

Abstract

Chronic wounds are one of the most frequent complications that are associated with diabetes mellitus. The overproduction of reactive oxygen species (ROS) is a key factor in the delayed healing of a chronic wound. In the present work, we develop a novel in [...] Read more.

Chronic wounds are one of the most frequent complications that are associated with diabetes mellitus. The overproduction of reactive oxygen species (ROS) is a key factor in the delayed healing of a chronic wound. In the present work, we develop a novel in situ-forming silk sericin-based hydrogel (SSH) that is produced by a simple methodology using horseradish peroxidase (HRP) crosslinking as an advanced dressing for wound healing. The antioxidant and angiogenic effects were assessed in vitro and in vivo after in situ application using an excisional wound-healing model in a genetically-induced diabetic db/db mice and though the chick embryo choriollantoic membrane (CAM) assay, respectively. Wounds in diabetic db/db mice that were treated with SSH closed with reduced granulation tissue, decreased wound edge distance, and wound thickness, when compared to Tegaderm, a dressing that is commonly used in the clinic. The hydrogel also promoted a deposition of collagen fibers with smaller diameter which may have had a boost effect in re-epithelialization. SSH treatment slightly induced two important endogenous antioxidant defenses, superoxide dismutase and catalase. A CAM assay made it possible to observe that SSH led to an increase in the number of newly formed vessels without inducing an inflammatory reaction. The present hydrogel may result in a multi-purpose technology with angiogenic, antioxidant, and anti-inflammatory properties, while advancing efficient and organized tissue regeneration. Full article

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11 pages, 1655 KiB

Open AccessEditor’s ChoiceArticle

Characterization of DAG Binding to TRPC Channels by Target-Dependent cis–trans Isomerization of OptoDArG

by Hazel Erkan-Candag, Denis Krivic, Mathias A. F. Gsell, Mina Aleksanyan, Thomas Stockner, Rumiana Dimova, Oleksandra Tiapko and Klaus Groschner

Biomolecules 2022, 12(6), 799; https://doi.org/10.3390/biom12060799 - 7 Jun 2022

Cited by 8 | Viewed by 2828

Abstract

Azobenzene-based photochromic lipids are valuable probes for the analysis of ion channel–lipid interactions. Rapid photoisomerization of these molecules enables the analysis of lipid gating kinetics and provides information on lipid sensing. Thermal relaxation of the metastable cis conformation to the trans conformation of [...] Read more.

Azobenzene-based photochromic lipids are valuable probes for the analysis of ion channel–lipid interactions. Rapid photoisomerization of these molecules enables the analysis of lipid gating kinetics and provides information on lipid sensing. Thermal relaxation of the metastable cis conformation to the trans conformation of azobenzene photolipids is rather slow in the dark and may be modified by ligand–protein interactions. Cis photolipid-induced changes in pure lipid membranes as visualized from the morphological response of giant unilamellar vesicles indicated that thermal cis–trans isomerization of both PhoDAG-1 and OptoDArG is essentially slow in the lipid bilayer environment. While the currents activated by cis PhoDAG remained stable upon termination of UV light exposure (dark, UV-OFF), cis OptoDArG-induced TRPC3/6/7 activity displayed a striking isoform-dependent exponential decay. The deactivation kinetics of cis OptoDArG-induced currents in the dark was sensitive to mutations in the L2 lipid coordination site of TRPC channels. We conclude that the binding of cis OptoDArG to TRPC channels promotes transition of cis OptoDArG to the trans conformation. This process is suggested to provide valuable information on DAG–ion channel interactions and may enable highly selective photopharmacological interventions. Full article

(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)

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24 pages, 2138 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis

by Carla Rodriguez-Mogeda, Sabela Rodríguez-Lorenzo, Jiji Attia, Jack van Horssen, Maarten E. Witte and Helga E. de Vries

Biomolecules 2022, 12(6), 800; https://doi.org/10.3390/biom12060800 - 7 Jun 2022

Cited by 17 | Viewed by 6861

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of [...] Read more.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of anti-CD20 therapies have put B cells in the spotlight of MS research. Besides their pathological effects in the periphery in MS, B cells gain access to the CNS where they can contribute to disease pathogenesis. Specifically, B cells accumulate in perivascular infiltrates in the brain parenchyma and the subarachnoid spaces of the meninges, but are virtually absent from the choroid plexus. Hence, the possible migration of B cells over the blood–brain-, blood–meningeal-, and blood–cerebrospinal fluid (CSF) barriers appears to be a crucial step to understanding B cell-mediated pathology. To gain more insight into the molecular mechanisms that regulate B cell trafficking into the brain, we here provide a comprehensive overview of the different CNS barriers in health and in MS and how they translate into different routes for B cell migration. In addition, we review the mechanisms of action of diverse therapies that deplete peripheral B cells and/or block B cell migration into the CNS. Importantly, this review shows that studying the different routes of how B cells enter the inflamed CNS should be the next step to understanding this disease. Full article

(This article belongs to the Special Issue The Central Nervous System Barriers in Health and Disease)

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17 pages, 1813 KiB

Open AccessEditor’s ChoiceArticle

Biochemical and Thermodynamic Studies on a Novel Thermotolerant GH10 Xylanase from Bacillus safensis

by Panayiotis D. Glekas, Styliani Kalantzi, Anargiros Dalios, Dimitris G. Hatzinikolaou and Diomi Mamma

Biomolecules 2022, 12(6), 790; https://doi.org/10.3390/biom12060790 - 6 Jun 2022

Cited by 12 | Viewed by 3026

Abstract

Xylanases have a broad range of applications in agro-industrial processes. In this study, we report on the discovery and characterization of a new thermotolerant GH10 xylanase from Bacillus safensis, designated as BsXyn10. The xylanase gene (bsxyn10) was cloned from Bacillus [...] Read more.

Xylanases have a broad range of applications in agro-industrial processes. In this study, we report on the discovery and characterization of a new thermotolerant GH10 xylanase from Bacillus safensis, designated as BsXyn10. The xylanase gene (bsxyn10) was cloned from Bacillus safensis and expressed in Escherichia coli. The reduced molecular mass of BsXyn10 was 48 kDa upon SDS-PAGE. Bsxyn10 was optimally active at pH 7.0 and 60 °C, stable over a broad range of pH (5.0–8.0), and also revealed tolerance toward different modulators (metal cations, EDTA). The enzyme was active toward various xylans with no activity on the glucose-based polysaccharides. K_M, v_max, and k_cat for oat spelt xylan hydrolysis were found to be 1.96 g·L⁻¹, 58.6 μmole·min⁻¹·(mg protein)⁻¹, and 49 s⁻¹, respectively. Thermodynamic parameters for oat spelt xylan hydrolysis at 60 °C were ΔS* = −61.9 J·mol⁻¹·K⁻¹, ΔH* = 37.0 kJ·mol⁻¹ and ΔG* = 57.6 kJ·mol⁻¹. BsXyn10 retained high levels of activity at temperatures up to 60 °C. The thermodynamic parameters (ΔH*_D, ΔG*_D, ΔS*_D) for the thermal deactivation of BsXyn10 at a temperature range of 40–80 °C were: 192.5 ≤ ΔH*_D ≤ 192.8 kJ·mol⁻¹, 262.1 ≤ ΔS*_D ≤ 265.8 J·mol⁻¹·K⁻¹, and 99.9 ≤ ΔG*_D ≤ 109.6 kJ·mol⁻¹. The BsXyn10-treated oat spelt xylan manifested the catalytic release of xylooligosaccharides of 2–6 DP, suggesting that BsXyn10 represents a promising candidate biocatalyst appropriate for several biotechnological applications. Full article

(This article belongs to the Section Enzymology)

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27 pages, 2164 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Nano-Based Approved Pharmaceuticals for Cancer Treatment: Present and Future Challenges

by Francisco Rodríguez, Pablo Caruana, Noa De la Fuente, Pía Español, María Gámez, Josep Balart, Elisa Llurba, Ramón Rovira, Raúl Ruiz, Cristina Martín-Lorente, José Luis Corchero and María Virtudes Céspedes

Biomolecules 2022, 12(6), 784; https://doi.org/10.3390/biom12060784 - 4 Jun 2022

Cited by 156 | Viewed by 9995

Abstract

Cancer is one of the main causes of death worldwide. To date, and despite the advances in conventional treatment options, therapy in cancer is still far from optimal due to the non-specific systemic biodistribution of antitumor agents. The inadequate drug concentrations at the [...] Read more.

Cancer is one of the main causes of death worldwide. To date, and despite the advances in conventional treatment options, therapy in cancer is still far from optimal due to the non-specific systemic biodistribution of antitumor agents. The inadequate drug concentrations at the tumor site led to an increased incidence of multiple drug resistance and the appearance of many severe undesirable side effects. Nanotechnology, through the development of nanoscale-based pharmaceuticals, has emerged to provide new and innovative drugs to overcome these limitations. In this review, we provide an overview of the approved nanomedicine for cancer treatment and the rationale behind their designs and applications. We also highlight the new approaches that are currently under investigation and the perspectives and challenges for nanopharmaceuticals, focusing on the tumor microenvironment and tumor disseminate cells as the most attractive and effective strategies for cancer treatments. Full article

(This article belongs to the Special Issue Applications of Nanoparticles in Tumor Therapy)

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19 pages, 2670 KiB

Open AccessEditor’s ChoiceReview

TRAP1 Chaperones the Metabolic Switch in Cancer

by Laura A. Wengert, Sarah J. Backe, Dimitra Bourboulia, Mehdi Mollapour and Mark R. Woodford

Biomolecules 2022, 12(6), 786; https://doi.org/10.3390/biom12060786 - 4 Jun 2022

Cited by 25 | Viewed by 5558

Abstract

Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in [...] Read more.

Mitochondrial function is dependent on molecular chaperones, primarily due to their necessity in the formation of respiratory complexes and clearance of misfolded proteins. Heat shock proteins (Hsps) are a subset of molecular chaperones that function in all subcellular compartments, both constitutively and in response to stress. The Hsp90 chaperone TNF-receptor-associated protein-1 (TRAP1) is primarily localized to the mitochondria and controls both cellular metabolic reprogramming and mitochondrial apoptosis. TRAP1 upregulation facilitates the growth and progression of many cancers by promoting glycolytic metabolism and antagonizing the mitochondrial permeability transition that precedes multiple cell death pathways. TRAP1 attenuation induces apoptosis in cellular models of cancer, identifying TRAP1 as a potential therapeutic target in cancer. Similar to cytosolic Hsp90 proteins, TRAP1 is also subject to post-translational modifications (PTM) that regulate its function and mediate its impact on downstream effectors, or ‘clients’. However, few effectors have been identified to date. Here, we will discuss the consequence of TRAP1 deregulation in cancer and the impact of post-translational modification on the known functions of TRAP1. Full article

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

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11 pages, 303 KiB

Open AccessEditor’s ChoiceReview

Classical and Unexpected Effects of Ultra-Micronized PEA in Neuromuscular Function

by Pierangelo Cifelli, Gabriele Ruffolo, Marco Ceccanti, Chiara Cambieri, Laura Libonati, Eleonora Palma and Maurizio Inghilleri

Biomolecules 2022, 12(6), 758; https://doi.org/10.3390/biom12060758 - 29 May 2022

Cited by 4 | Viewed by 3197

Abstract

Recently, the endocannabinoid system has attracted growing attention from the scientific community for its involvement in homeostatic and pathological processes as they pertains to human physiology. Among the constituents of the endocannabinoid system, the molecule palmitoyl ethanolamide has particularly been studied for its [...] Read more.

Recently, the endocannabinoid system has attracted growing attention from the scientific community for its involvement in homeostatic and pathological processes as they pertains to human physiology. Among the constituents of the endocannabinoid system, the molecule palmitoyl ethanolamide has particularly been studied for its ability to reduce several inflammatory processes involving the central nervous system. Here, we reviewed published literature and summarized the main targets of the palmitoyl ethanolamide, along with its unique possible mechanisms for restoring correct functioning of the central nervous system. Moreover, we have highlighted a less-known characteristic of palmitoyl ethanolamide, namely its ability to modulate the function of the neuromuscular junction by binding to acetylcholine receptors in different experimental conditions. Indeed, there are several studies that have highlighted how ultra-micronized palmitoyl ethanolamide is an interesting nutraceutical support for the treatment of pathological neuromuscular conditions, specifically when the normal activity of the acetylcholine receptor is altered. Although further multicentric clinical trials are needed to confirm the efficacy of ultra-micronized palmitoyl ethanolamide in improving symptoms of neuromuscular diseases, all the literature reviewed here strongly supports the ability of this endocannabinoid-like molecule to modulate the acetylcholine receptors thus resulting as a valid support for the treatment of human neuromuscular diseases. Full article

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

15 pages, 1570 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Myristic Acid Supplementation Aggravates High Fat Diet-Induced Adipose Inflammation and Systemic Insulin Resistance in Mice

by Viswanathan Saraswathi, Narendra Kumar, Weilun Ai, Thiyagarajan Gopal, Saumya Bhatt, Edward N. Harris, Geoffrey A. Talmon and Cyrus V. Desouza

Biomolecules 2022, 12(6), 739; https://doi.org/10.3390/biom12060739 - 24 May 2022

Cited by 23 | Viewed by 4877

Abstract

Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic [...] Read more.

Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic insulin resistance (IR) in obesity are still unclear. Here, we sought to determine the effects of a high fat (HF) diet supplemented with MA on obesity-associated metabolic disorders in mice. Wild-type C57BL/6 mice were fed a HF diet in the presence or absence of 3% MA for 12 weeks. Plasma lipids, plasma adipokines, AT inflammation, systemic IR, glucose homeostasis, and hepatic steatosis were assessed. The body weight and visceral adipose tissue (VAT) mass were significantly higher in mice receiving the HF+MA diet compared to HF diet-fed controls. Plasma total cholesterol levels were marginally increased in HF+MA-fed mice compared to controls. Fasting blood glucose was comparable between HF and HF+MA-fed mice. Interestingly, the plasma insulin and HOMA-IR index, a measure of insulin resistance, were significantly higher in HF+MA-fed mice compared to HF controls. Macrophage and inflammatory markers were significantly elevated in the AT and AT-derived stromal vascular cells upon MA feeding. Moreover, the level of circulating resistin, an adipokine promoting insulin resistance, was significantly higher in HF+MA-fed mice compared with HF controls. The insulin tolerance test revealed that the IR was higher in mice receiving the MA supplementation compared to HF controls. Moreover, the glucose tolerance test showed impairment in systemic glucose homeostasis in MA-fed mice. Analyses of liver samples showed a trend towards an increase in liver TG upon MA feeding. However, markers of oxidative stress and inflammation were reduced in the liver of mice fed an MA diet compared to controls. Taken together, our data suggest that chronic administration of MA in diet exacerbates obesity-associated insulin resistance and this effect is mediated in part, via increased AT inflammation and increased secretion of resistin. Full article

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

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11 pages, 1733 KiB

Open AccessEditor’s ChoiceReview

Neuromuscular Active Zone Structure and Function in Healthy and Lambert-Eaton Myasthenic Syndrome States

by Scott P. Ginebaugh, Yomna Badawi, Tyler B. Tarr and Stephen D. Meriney

Biomolecules 2022, 12(6), 740; https://doi.org/10.3390/biom12060740 - 24 May 2022

Cited by 5 | Viewed by 3797

Abstract

The mouse neuromuscular junction (NMJ) has long been used as a model synapse for the study of neurotransmission in both healthy and disease states of the NMJ. Neurotransmission from these neuromuscular nerve terminals occurs at highly organized structures called active zones (AZs). Within [...] Read more.

The mouse neuromuscular junction (NMJ) has long been used as a model synapse for the study of neurotransmission in both healthy and disease states of the NMJ. Neurotransmission from these neuromuscular nerve terminals occurs at highly organized structures called active zones (AZs). Within AZs, the relationships between the voltage-gated calcium channels and docked synaptic vesicles govern the probability of acetylcholine release during single action potentials, and the short-term plasticity characteristics during short, high frequency trains of action potentials. Understanding these relationships is important not only for healthy synapses, but also to better understand the pathophysiology of neuromuscular diseases. In particular, we are interested in Lambert-Eaton myasthenic syndrome (LEMS), an autoimmune disorder in which neurotransmitter release from the NMJ decreases, leading to severe muscle weakness. In LEMS, the reduced neurotransmission is traditionally thought to be caused by the antibody-mediated removal of presynaptic voltage-gated calcium channels. However, recent experimental data and AZ computer simulations have predicted that a disruption in the normally highly organized active zone structure, and perhaps autoantibodies to other presynaptic proteins, contribute significantly to pathological effects in the active zone and the characteristics of chemical transmitters. Full article

(This article belongs to the Special Issue The Neuromuscular Junction in Health and Disease)

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16 pages, 3889 KiB

Open AccessEditor’s ChoiceArticle

Impairment of the Retinal Endothelial Cell Barrier Induced by Long-Term Treatment with VEGF-A₁₆₅ No Longer Depends on the Growth Factor’s Presence

by Heidrun L. Deissler, Matus Rehak and Armin Wolf

Biomolecules 2022, 12(5), 734; https://doi.org/10.3390/biom12050734 - 23 May 2022

Cited by 3 | Viewed by 2828

Abstract

As responses of immortalized endothelial cells of the bovine retina (iBREC) to VEGF-A₁₆₅ depend on exposure time to the growth factor, we investigated changes evident after long-term treatment for nine days. The cell index of iBREC cultivated on gold electrodes—determined as a [...] Read more.

As responses of immortalized endothelial cells of the bovine retina (iBREC) to VEGF-A₁₆₅ depend on exposure time to the growth factor, we investigated changes evident after long-term treatment for nine days. The cell index of iBREC cultivated on gold electrodes—determined as a measure of permeability—was persistently reduced by exposure to the growth factor. Late after addition of VEGF-A₁₆₅ protein levels of claudin-1 and CD49e were significantly lower, those of CD29 significantly higher, and the plasmalemma vesicle associated protein was no longer detected. Nuclear levels of β-catenin were only elevated on day two. Extracellular levels of VEGF-A—measured by ELISA—were very low. Similar to the binding of the growth factor by brolucizumab, inhibition of VEGFR2 by tyrosine kinase inhibitors tivozanib or nintedanib led to complete, although transient, recovery of the low cell index when added early, though was inefficient when added three or six days later. Additional inhibition of other receptor tyrosine kinases by nintedanib was similarly unsuccessful, but additional blocking of c-kit by tivozanib led to sustained recovery of the low cell index, an effect observed only when the inhibitor was added early. From these data, we conclude that several days after the addition of VEGF-A₁₆₅ to iBREC, barrier dysfunction is mainly sustained by increased paracellular flow and impaired adhesion. Even more important, these changes are most likely no longer VEGF-A-controlled. Full article

(This article belongs to the Special Issue Cell and Organ Cultures for Studying Retinal Diseases)

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17 pages, 2074 KiB

Open AccessEditor’s ChoiceArticle

Reduced Platelet MAO-B Activity Is Associated with Psychotic, Positive, and Depressive Symptoms in PTSD

by Senka Repovecki, Gordana Nedic Erjavec, Suzana Uzun, Lucija Tudor, Matea Nikolac Perkovic, Marcela Konjevod, Oliver Kozumplik, Dubravka Svob Strac, Zrnka Kovacic Petrovic, Ninoslav Mimica and Nela Pivac

Biomolecules 2022, 12(5), 736; https://doi.org/10.3390/biom12050736 - 23 May 2022

Cited by 3 | Viewed by 3684

Abstract

Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet [...] Read more.

Post-traumatic stress disorder (PTSD) is a trauma-related disorder. Platelet monoamine oxidase (MAO-B) is a peripheral biomarker associated with various symptoms in different psychopathologies, but its role in PTSD or different symptoms in PTSD is not clear. This study elucidated the association between platelet MAO-B activity and clinical symptoms occurring in PTSD. Platelet MAO-B activity was determined in 1053 male Caucasian subjects: 559 war veterans with PTSD (DSM-5 criteria), 62 combat exposed veterans who did not develop PTSD, and 432 non-combat exposed healthy controls. Clinical symptoms in PTSD were determined using CAPS and PANSS. Platelet MAO-B activity, controlled for the effect of smoking, was significantly increased in PTSD with severe versus mild and moderate traumatic symptoms, and was significantly decreased in PTSD subjects with severe versus mild positive, psychotic, and depressive symptoms. This finding was further confirmed with reduced platelet MAO-B activity in PTSD veterans with severe versus mild individual items of the PANSS-depressed, PANSS-psychotic, and PANSS-positive subscales. Altered platelet MAO-B activity, controlled for the possible confounders, was associated with the development and severity of different symptoms occurring in PTSD. These findings confirmed the role of platelet MAO-B activity as a peripheral marker of various psychopathological symptoms. Full article

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

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20 pages, 1082 KiB

Open AccessEditor’s ChoiceReview

Innate Immunity: A Balance between Disease and Adaption to Stress

by Irene Faenza and William L. Blalock

Biomolecules 2022, 12(5), 737; https://doi.org/10.3390/biom12050737 - 23 May 2022

Cited by 19 | Viewed by 5734

Abstract

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation [...] Read more.

Since first being documented in ancient times, the relation of inflammation with injury and disease has evolved in complexity and causality. Early observations supported a cause (injury) and effect (inflammation) relationship, but the number of pathologies linked to chronic inflammation suggests that inflammation itself acts as a potent promoter of injury and disease. Additionally, results from studies over the last 25 years point to chronic inflammation and innate immune signaling as a critical link between stress (exogenous and endogenous) and adaptation. This brief review looks to highlight the role of the innate immune response in disease pathology, and recent findings indicating the innate immune response to chronic stresses as an influence in driving adaptation. Full article

(This article belongs to the Special Issue Inflammatory Pathways in Neuro-Muscular Degeneration, Metabolic Syndromes, Cancer and Infection)

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20 pages, 4302 KiB

Open AccessEditor’s ChoiceArticle

Anti-Inflammatory Effects of GM1 Ganglioside on Endotoxin-Induced Uveitis in Rats

by Tzu-Heng Weng, Chang-Chih Ke and Yuahn-Sieh Huang

Biomolecules 2022, 12(5), 727; https://doi.org/10.3390/biom12050727 - 21 May 2022

Cited by 3 | Viewed by 3625

Abstract

Exogenous ganglioside GM1 has been reported to exert an immunomodulatory effect. We investigated the anti-inflammatory effect of GM1 ganglioside on endotoxin-induced uveitis (EIU) in rats and RAW 264.7 macrophages. Methods: EIU was induced in Lewis rats by administering a subcutaneous injection of lipopolysaccharide [...] Read more.

Exogenous ganglioside GM1 has been reported to exert an immunomodulatory effect. We investigated the anti-inflammatory effect of GM1 ganglioside on endotoxin-induced uveitis (EIU) in rats and RAW 264.7 macrophages. Methods: EIU was induced in Lewis rats by administering a subcutaneous injection of lipopolysaccharide (LPS). GM1 was injected intraperitoneally for three consecutive days prior to the LPS injection. Twenty-four hours after the LPS injection, the integrity of the blood-aqueous barrier was evaluated by determining the protein concentration and number of infiltrating cells in the aqueous humor (AqH). Immunohistochemical and Western blot analyses of the iris-ciliary body (ICB) were performed to evaluate the effect of GM1 on the LPS-induced expression of cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1). The effect of GM1 on proinflammatory mediators and signaling cascades was examined in LPS-stimulated RAW 264.7 cells using Western blotting and immunofluorescence staining to further clarify the underlying anti-inflammatory mechanism. Results: GM1 significantly reduced the protein concentration and number of infiltrating cells in the AqH of rats with EIU. GM1 also decreased the LPS-induced expression of the ICAM-1 and COX-2 proteins in the ICB. In RAW 264.7 cells, GM1 inhibited the proinflammatory mediators induced by LPS, including inducible nitric oxide synthase (iNOS), COX-2, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and this inhibitory effect was potentially mediated by suppressing reactive oxygen species (ROS)-mediated activation of nuclear factor-κB (NF-κB) and mitogen-activated protein kinases (MAPKs). Conclusions: Based on this study, GM1 may be a potential anti-inflammatory agent for ocular inflammatory diseases. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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