Biomolecules

22 pages, 3658 KiB

Open AccessEditor’s ChoiceArticle

The Metallodrug BOLD-100 Is a Potent Inhibitor of SARS-CoV-2 Replication and Has Broad-Acting Antiviral Activity

by Daniel S. Labach, Hinissan P. Kohio, Edwin A. Tse, Ermela Paparisto, Nicole J. Friesen, Jim Pankovich, Mark Bazett and Stephen D. Barr

Biomolecules 2023, 13(7), 1095; https://doi.org/10.3390/biom13071095 - 8 Jul 2023

Cited by 4 | Viewed by 2630

Abstract

The COVID-19 pandemic has highlighted an urgent need to discover and test new drugs to treat patients. Metal-based drugs are known to interact with DNA and/or a variety of proteins such as enzymes and transcription factors, some of which have been shown to [...] Read more.

The COVID-19 pandemic has highlighted an urgent need to discover and test new drugs to treat patients. Metal-based drugs are known to interact with DNA and/or a variety of proteins such as enzymes and transcription factors, some of which have been shown to exhibit anticancer and antimicrobial effects. BOLD-100 (sodium trans-[tetrachlorobis(1H-indazole)ruthenate(III)]dihydrate) is a novel ruthenium-based drug currently being evaluated in a Phase 1b/2a clinical trial for the treatment of advanced gastrointestinal cancer. Given that metal-based drugs are known to exhibit antimicrobial activities, we asked if BOLD-100 exhibits antiviral activity towards SARS-CoV-2. We demonstrated that BOLD-100 potently inhibits SARS-CoV-2 replication and cytopathic effects in vitro. An RNA sequencing analysis showed that BOLD-100 inhibits virus-induced transcriptional changes in infected cells. In addition, we showed that the antiviral activity of BOLD-100 is not specific for SARS-CoV-2, but also inhibits the replication of the evolutionarily divergent viruses Human Immunodeficiency Virus type 1 and Human Adenovirus type 5. This study identifies BOLD-100 as a potentially novel broad-acting antiviral drug. Full article

(This article belongs to the Special Issue Viral Drug Targets and Discovery of Antiviral Agents)

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23 pages, 1444 KiB

Open AccessEditor’s ChoiceArticle

Xanthine–Dopamine Hybrid Molecules as Multitarget Drugs with Potential for the Treatment of Neurodegenerative Diseases

by Michał Załuski, Tadeusz Karcz, Anna Drabczyńska, Christin Vielmuth, Agnieszka Olejarz-Maciej, Monika Głuch-Lutwin, Barbara Mordyl, Agata Siwek, Grzegorz Satała, Christa E. Müller and Katarzyna Kieć-Kononowicz

Biomolecules 2023, 13(7), 1079; https://doi.org/10.3390/biom13071079 - 5 Jul 2023

Cited by 7 | Viewed by 2818

Abstract

Multitarget drugs based on a hybrid dopamine–xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A_2A adenosine receptor (A_2AAR) antagonistic properties were further developed to exhibit additional [...] Read more.

Multitarget drugs based on a hybrid dopamine–xanthine core were designed as potential drug candidates for the treatment of neurodegenerative diseases. Monoamine oxidase B (MAO-B) inhibitors with significant ancillary A_2A adenosine receptor (A_2AAR) antagonistic properties were further developed to exhibit additional phosphodiesterase-4 and -10 (PDE4/10) inhibition and/or dopamine D₂ receptor (D₂R) agonistic activity. While all of the designed compounds showed MAO-B inhibition in the nanomolar range mostly combined with submicromolar A_2AAR affinity, significant enhancement of PDE-inhibitory and D₂R-agonistic activity was additionally reached for some compounds through various structural modifications. The final multitarget drugs also showed promising antioxidant properties in vitro. In order to evaluate their potential neuroprotective effect, representative ligands were tested in a cellular model of toxin-induced neurotoxicity. As a result, protective effects against oxidative stress in neuroblastoma cells were observed, confirming the utility of the applied strategy. Further evaluation of the newly developed multitarget ligands in preclinical models of Alzheimer’s and Parkinson’s diseases is warranted. Full article

(This article belongs to the Special Issue Current Progress in Protein Studies in the Context of Civilization Problems: From In Silico to In Vivo)

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23 pages, 9441 KiB

Open AccessEditor’s ChoiceArticle

Quantitative Spatial Analysis of Neuroligin-3 mRNA Expression in the Enteric Nervous System Reveals a Potential Role in Neuronal–Glial Synapses and Reduced Expression in Nlgn3^R451C Mice

by Madushani Herath, Ellie Cho, Ulrika Marklund, Ashley E. Franks, Joel C. Bornstein and Elisa L. Hill-Yardin

Biomolecules 2023, 13(7), 1063; https://doi.org/10.3390/biom13071063 - 30 Jun 2023

Cited by 7 | Viewed by 2930

Abstract

Mutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction, but cellular Nlgn3 expression in the enteric nervous system remains to be characterised. We combined RNAScope in situ hybridization and immunofluorescence to measure Nlgn3 [...] Read more.

Mutations in the Neuroligin-3 (Nlgn3) gene are implicated in autism spectrum disorder (ASD) and gastrointestinal (GI) dysfunction, but cellular Nlgn3 expression in the enteric nervous system remains to be characterised. We combined RNAScope in situ hybridization and immunofluorescence to measure Nlgn3 mRNA expression in cholinergic and VIP-expressing submucosal neurons, nitrergic and calretinin-containing myenteric neurons and glial cells in both WT and Nlgn3^R451C mutant mice. We measured Nlgn3 mRNA neuronal and glial expression via quantitative three-dimensional image analysis. To validate dual RNAScope/immunofluorescence data, we interrogated available single-cell RNA sequencing (scRNASeq) data to assess for Nlgn3, Nlgn1, Nlgn2 and their binding partners, Nrxn1-3, MGDA1 and MGDA2, in enteric neural subsets. Most submucosal and myenteric neurons expressed Nlgn3 mRNA. In contrast to other Nlgns and binding partners, Nlgn3 was strongly expressed in enteric glia, suggesting a role for neuroligin-3 in mediating enteric neuron–glia interactions. The autism-associated R451C mutation reduces Nlgn3 mRNA expression in cholinergic but not in VIPergic submucosal neurons. In the myenteric plexus, Nlgn3 mRNA levels are reduced in calretinin, nNOS-labelled neurons and S100 β -labelled glia. We provide a comprehensive cellular profile for neuroligin-3 expression in ileal neuronal subpopulations of mice expressing the R451C autism-associated mutation in Nlgn3, which may contribute to the understanding of the pathophysiology of GI dysfunction in ASD. Full article

(This article belongs to the Special Issue Neuroimmune Interactions in Neuropsychiatric Diseases)

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18 pages, 2548 KiB

Open AccessEditor’s ChoiceArticle

Activation of Metabotropic Glutamate Receptor (mGlu₂) and Muscarinic Receptors (M₁, M₄, and M₅), Alone or in Combination, and Its Impact on the Acquisition and Retention of Learning in the Morris Water Maze, NMDA Expression and cGMP Synthesis

by Joanna M. Wierońska, Paulina Cieślik, Grzegorz Burnat and Leszek Kalinowski

Biomolecules 2023, 13(7), 1064; https://doi.org/10.3390/biom13071064 - 30 Jun 2023

Cited by 7 | Viewed by 2450

Abstract

The Morris water maze (MWM) is regarded as one of the most popular tests for detecting spatial memory in rodents. Long-term potentiation and cGMP synthesis seem to be among the crucial factors involved in this type of learning. Muscarinic (M₁, M [...] Read more.

The Morris water maze (MWM) is regarded as one of the most popular tests for detecting spatial memory in rodents. Long-term potentiation and cGMP synthesis seem to be among the crucial factors involved in this type of learning. Muscarinic (M₁, M₄, and M₅ receptors) and metabotropic glutamate (mGlu) receptors are important targets in the search for antipsychotic drugs with the potency to treat cognitive disabilities associated with the disorder. Here, we show that muscarinic receptor activators (VU0357017, VU0152100, and VU0238429) and an mGlu₂ receptor activator, LY487379, dose-dependently prevented the development of cognitive disorders as a result of MK-801 administration in the MWM. The dose-ranges of the compounds were as follows: VU0357017, 0.25, 0.5, and 1 mg/kg; VU0152100, 0.05, 0.25, and 1 mg/kg; VU0238429, 1, 5, and 20 mg/kg; and LY487379, 0.5, 3, and 5 mg/kg. The co-administration of LY487379 with each of the individual muscarinic receptor ligands showed no synergistic effect, which contradicts the results obtained earlier in the novel object recognition (NOR) test. MWM learning resulted in increased cGMP synthesis, both in the cortex and hippocampi, when compared to that in intact animals, which was prevented by MK-801 administration. The investigated compounds at the highest doses reversed this MK-801-induced effect. Neither the procedure nor the treatment resulted in changes in GluN2B-NMDA expression. Full article

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

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23 pages, 4070 KiB

Open AccessEditor’s ChoiceArticle

Bioinspired Synthesis of Silver Nanoparticles for the Remediation of Toxic Pollutants and Enhanced Antibacterial Activity

by Sujata Mandal, Sangchul Hwang, Sreekar B. Marpu, Mohammad A. Omary, Victor Prybutok and Sheldon Q. Shi

Biomolecules 2023, 13(7), 1054; https://doi.org/10.3390/biom13071054 - 29 Jun 2023

Cited by 11 | Viewed by 2561

Abstract

This research presents a novel and environmentally friendly approach for the synthesis of multifunctional nanobiocomposites for the efficient removal of toxic heavy metal and dye, as well as the disinfection of wastewater microorganisms. The nanobiocomposites (KAC-CS-AgNPs) were prepared by incorporating photochemically generated silver [...] Read more.

This research presents a novel and environmentally friendly approach for the synthesis of multifunctional nanobiocomposites for the efficient removal of toxic heavy metal and dye, as well as the disinfection of wastewater microorganisms. The nanobiocomposites (KAC-CS-AgNPs) were prepared by incorporating photochemically generated silver nanoparticles (AgNPs) within a chitosan (CS)-modified, high-surface-area activated carbon derived from kenaf (KAC), using a unique self-activation method. The even distribution of AgNPs was visible in the scanning electron microscopy images and a Fourier transform infra red study demonstrated major absorption peaks. The experimental results revealed that KA-CS-AgNPs exhibited exceptional adsorption efficiency for copper (Cu²⁺), lead (Pb²⁺), and Congo Red dye (CR), and showed potent antibacterial activity against Staphylococcus aureus and Escherichia coli. The maximum adsorption capacity (mg g⁻¹) of KAC-CS-AgNPs was 71.5 for Cu²⁺, 72.3 for Pb²⁺, and 75.9 for CR, and the adsorption phenomena followed on the Freundlich and Langmuir isotherm models and the second-order kinetic model (R² > 0.99). KAC-CS-AgNPs also exhibited excellent reusability of up to four consecutive cycles with minor losses in adsorption ability. The thermodynamic parameters indicated that the adsorption process was spontaneous and endothermic in nature. The bacterial inactivation tests demonstrated that KAC-CS-AgNPs had a strong bactericidal effect on both E. coli and S. aureus, with MIC calculated for E. coli and S. aureus as 32 µg mL⁻¹ and 44 µg mL⁻¹, respectively. The synthesized bioinspired nanocomposite KAC-CS-AgNPs could be an innovative solution for effective and sustainable wastewater treatment and has great potential for commercial applications. Full article

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26 pages, 2714 KiB

Open AccessEditor’s ChoiceReview

Nuclear Phosphoinositides as Key Determinants of Nuclear Functions

by Magdalena C. Vidalle, Bhavwanti Sheth, Antonietta Fazio, Maria Vittoria Marvi, Stefano Leto, Foteini-Dionysia Koufi, Irene Neri, Irene Casalin, Giulia Ramazzotti, Matilde Y. Follo, Stefano Ratti, Lucia Manzoli, Sonakshi Gehlot, Nullin Divecha and Roberta Fiume

Biomolecules 2023, 13(7), 1049; https://doi.org/10.3390/biom13071049 - 28 Jun 2023

Cited by 15 | Viewed by 3801

Abstract

Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are [...] Read more.

Polyphosphoinositides (PPIns) are signalling messengers representing less than five per cent of the total phospholipid concentration within the cell. Despite their low concentration, these lipids are critical regulators of various cellular processes, including cell cycle, differentiation, gene transcription, apoptosis and motility. PPIns are generated by the phosphorylation of the inositol head group of phosphatidylinositol (PtdIns). Different pools of PPIns are found at distinct subcellular compartments, which are regulated by an array of kinases, phosphatases and phospholipases. Six of the seven PPIns species have been found in the nucleus, including the nuclear envelope, the nucleoplasm and the nucleolus. The identification and characterisation of PPIns interactor and effector proteins in the nucleus have led to increasing interest in the role of PPIns in nuclear signalling. However, the regulation and functions of PPIns in the nucleus are complex and are still being elucidated. This review summarises our current understanding of the localisation, biogenesis and physiological functions of the different PPIns species in the nucleus. Full article

(This article belongs to the Special Issue Versatility of a Cellular Signaling Scaffold: The Inositol Ring Rules! – Honorary Special Issue Commemorating the Work of Prof. Lucio I. M. Cocco)

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18 pages, 2809 KiB

Open AccessEditor’s ChoiceArticle

Tissue Inhibitor of Matrix Metalloproteinases-1 (TIMP-1) and Pulmonary Involvement in COVID-19 Pneumonia

by Maria Antonella Zingaropoli, Tiziana Latronico, Patrizia Pasculli, Giorgio Maria Masci, Roberta Merz, Federica Ciccone, Federica Dominelli, Cosmo Del Borgo, Miriam Lichtner, Franco Iafrate, Gioacchino Galardo, Francesco Pugliese, Valeria Panebianco, Paolo Ricci, Carlo Catalano, Maria Rosa Ciardi, Grazia Maria Liuzzi and Claudio Maria Mastroianni

Biomolecules 2023, 13(7), 1040; https://doi.org/10.3390/biom13071040 - 26 Jun 2023

Cited by 10 | Viewed by 2604

Abstract

Background: The aim of the study was to longitudinally evaluate the association between MMP-2, MMP-9, TIMP-1 and chest radiological findings in COVID-19 patients. Methods: COVID-19 patients were evaluated based on their hospital admission (baseline) and three months after hospital discharge (T post) and [...] Read more.

Background: The aim of the study was to longitudinally evaluate the association between MMP-2, MMP-9, TIMP-1 and chest radiological findings in COVID-19 patients. Methods: COVID-19 patients were evaluated based on their hospital admission (baseline) and three months after hospital discharge (T post) and were stratified into ARDS and non-ARDS groups. As a control group, healthy donors (HD) were enrolled. Results: At the baseline, compared to HD (n = 53), COVID-19 patients (n = 129) showed higher plasma levels of MMP-9 (p < 0.0001) and TIMP-1 (p < 0.0001) and the higher plasma activity of MMP-2 (p < 0.0001) and MMP-9 (p < 0.0001). In the ARDS group, higher plasma levels of MMP-9 (p = 0.0339) and TIMP-1 (p = 0.0044) and the plasma activity of MMP-2 (p = 0.0258) and MMP-9 (p = 0.0021) compared to non-ARDS was observed. A positive correlation between the plasma levels of TIMP-1 and chest computed tomography (CT) score (ρ = 0.2302, p = 0.0160) was observed. At the T post, a reduction in plasma levels of TIMP-1 (p < 0.0001), whereas an increase in the plasma levels of MMP-9 was observed (p = 0.0088). Conclusions: The positive correlation between TIMP-1 with chest CT scores highlights its potential use as a marker of fibrotic burden. At T post, the increase in plasma levels of MMP-9 and the reduction in plasma levels of TIMP-1 suggested that inflammation and fibrosis resolution were still ongoing. Full article

(This article belongs to the Special Issue Matrix Metalloproteinases in Health and Disease 3.0)

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13 pages, 2921 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Shapes and Patterns of Heme-Binding Motifs in Mammalian Heme-Binding Proteins

by Dhruv C. Rathod, Sonali M. Vaidya, Marie-T. Hopp, Toni Kühl and Diana Imhof

Biomolecules 2023, 13(7), 1031; https://doi.org/10.3390/biom13071031 - 23 Jun 2023

Cited by 11 | Viewed by 4153

Abstract

Heme is a double-edged sword. On the one hand, it has a pivotal role as a prosthetic group of hemoproteins in many biological processes ranging from oxygen transport and storage to miRNA processing. On the other hand, heme can transiently associate with proteins, [...] Read more.

Heme is a double-edged sword. On the one hand, it has a pivotal role as a prosthetic group of hemoproteins in many biological processes ranging from oxygen transport and storage to miRNA processing. On the other hand, heme can transiently associate with proteins, thereby regulating biochemical pathways. During hemolysis, excess heme, which is released into the plasma, can bind to proteins and regulate their activity and function. The role of heme in these processes is under-investigated, with one problem being the lack of knowledge concerning recognition mechanisms for the initial association of heme with the target protein and the formation of the resulting complex. A specific heme-binding sequence motif is a prerequisite for such complex formation. Although numerous short signature sequences indicating a particular protein function are known, a comprehensive analysis of the heme-binding motifs (HBMs) which have been identified in proteins, concerning specific patterns and structural peculiarities, is missing. In this report, we focus on the evaluation of known mammalian heme-regulated proteins concerning specific recognition and structural patterns in their HBMs. The Cys-Pro dipeptide motifs are particularly emphasized because of their more frequent occurrence. This analysis presents a comparative insight into the sequence and structural anomalies observed during transient heme binding, and consequently, in the regulation of the relevant protein. Full article

(This article belongs to the Special Issue Unraveling Mysteries of Heme Metabolism)

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16 pages, 2286 KiB

Open AccessEditor’s ChoiceReview

A Review on Pathophysiology, and Molecular Mechanisms of Bacterial Chondronecrosis and Osteomyelitis in Commercial Broilers

by Venkata Sesha Reddy Choppa and Woo Kyun Kim

Biomolecules 2023, 13(7), 1032; https://doi.org/10.3390/biom13071032 - 23 Jun 2023

Cited by 11 | Viewed by 3401

Abstract

Modern day broilers have a great genetic potential to gain heavy bodyweights with a huge metabolic demand prior to their fully mature ages. Moreover, this made the broilers prone to opportunistic pathogens which may enter the locomotory organs under stress causing bacterial chondronecrosis [...] Read more.

Modern day broilers have a great genetic potential to gain heavy bodyweights with a huge metabolic demand prior to their fully mature ages. Moreover, this made the broilers prone to opportunistic pathogens which may enter the locomotory organs under stress causing bacterial chondronecrosis and osteomyelitis (BCO). Such pathogenic colonization is further accelerated by microfractures and clefts that are formed in the bones due to rapid growth rate of the broilers along with ischemia of blood vessels. Furthermore, there are several pathways which alter bone homeostasis like acute phase response, and intrinsic and extrinsic cell death pathways. In contrast, all the affected birds may not exhibit clinical lameness even with the presence of lameness associated factors causing infection. Although Staphylococcus, E. coli, and Enterococcus are considered as common bacterial pathogens involved in BCO, but there exist several other non-culturable bacteria. Any deviation from maintaining a homeostatic environment in the gut might lead to bacterial translocation through blood followed by proliferation of pathogenic bacteria in respective organs including bones. It is important to alleviate dysbiosis of the blood which is analogous to dysbiosis in the gut. This can be achieved by supplementing pro, pre, and synbiotics which helps in providing a eubiotic environment abating the bacterial translocation that was studied to the incidence of BCO. This review focused on potential and novel biomarkers, pathophysiological mechanism, the economic significance of BCO, immune mechanisms, and miscellaneous factors causing BCO. In addition, the role of gut microbiomes along with their diversity and cell culture models from compact bones of chicken in better understanding of BCO were explored. Full article

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

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16 pages, 2707 KiB

Open AccessEditor’s ChoiceArticle

Enzymatic Modification of Pomace Olive Oil with Natural Antioxidants: Effect on Oxidative Stability

by Renia Fotiadou, Dimitrios Lefas, Despina Vougiouklaki, Aliki Tsakni, Dimitra Houhoula and Haralambos Stamatis

Biomolecules 2023, 13(7), 1034; https://doi.org/10.3390/biom13071034 - 23 Jun 2023

Cited by 8 | Viewed by 2278

Abstract

Enzymatic lipophilization has been proposed as a cost-effective strategy to produce new liposoluble antioxidant compounds. In this study, modified oils rich in structured phenolipids were prepared via one-pot enzymatic acylation of hydroxytyrosol (HTYR), vanillyl alcohol (VA) and homovanillyl alcohol (HVA) with pomace olive [...] Read more.

Enzymatic lipophilization has been proposed as a cost-effective strategy to produce new liposoluble antioxidant compounds. In this study, modified oils rich in structured phenolipids were prepared via one-pot enzymatic acylation of hydroxytyrosol (HTYR), vanillyl alcohol (VA) and homovanillyl alcohol (HVA) with pomace olive oil (POO) in solvent-free conditions using immobilized lipase on biogenic nanoparticles. The effect of temperature (30–70 °C) and enzyme concentration (0.1–1%, w/w) on the efficiency of the bioprocess as well as the reusability of the nanobiocatalyst were thoroughly investigated. The modified oils exhibited increased antioxidant activity compared to the control oil according to DPPH and CUPRAC assays (p < 0.05). The oxidative stability of pomace olive oil was also significantly enhanced after modification, as depicted by the K₂₃₂ values and TBARS contents under accelerated oxidation at 60 °C (p < 0.05). Moreover, a fortified mayonnaise containing modified oil with HTYR was prepared that was noticeably stable compared to the control mayonnaise at 28 °C for 5 months (p < 0.05). Enzymatically modified oils have great potential for application in the nutraceutical and food industry, encouraging the exploitation of immobilized lipases as effective and green catalytic tools. Full article

(This article belongs to the Topic Antioxidant Activity of Natural Products)

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16 pages, 3866 KiB

Open AccessEditor’s ChoiceArticle

Chemical Composition and Bioactivity of Laboratory-Fermented Bee Pollen in Comparison with Natural Bee Bread

by Michał Miłek, Mateusz Mołoń, Monika Kula-Maximenko, Ewelina Sidor, Grzegorz Zaguła and Małgorzata Dżugan

Biomolecules 2023, 13(7), 1025; https://doi.org/10.3390/biom13071025 - 22 Jun 2023

Cited by 8 | Viewed by 3729

Abstract

Bee bread is a valuable product obtained from the hive on a relatively small scale, while bee pollen is more easily available. Therefore, an effective laboratory method of converting pollen into a bee bread substitute is desired. The aim of the research was [...] Read more.

Bee bread is a valuable product obtained from the hive on a relatively small scale, while bee pollen is more easily available. Therefore, an effective laboratory method of converting pollen into a bee bread substitute is desired. The aim of the research was to verify the influence of selected factors (temperature, ultrasound) on the quality of obtained product using Lactobacillus rhamnosus inoculum. The composition of the fermented pollen was analyzed using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES), Raman spectroscopy, and SDS-PAGE and compared to natural bee bread and the original pollen. In vitro biological activity was assessed as antioxidant activity using a yeast model (BY4741 and sod1∆ strains). Fermentation of pollen occurred spontaneously and after inoculation, as demonstrated by lower pH and higher lactic acid content. Raman spectroscopy and ICP-OES confirmed changes in composition compared to the initial pollen. Compared to bee bread, the fermented pollen showed a higher content of polyphenols and comparable antioxidant activity; moreover, it accelerated yeast growth rate. In addition, a protective effect was observed for Cu/Zn-superoxide dismutase 1 (sod1∆ yeast mutant exposed to hydrogen peroxide-induced oxidative stress). The higher fermentation temperature (25 °C) produces a more bee-bread-like product, while the use of ultrasound and starter culture seems to have no positive effect. Full article

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15 pages, 1888 KiB

Open AccessEditor’s ChoiceArticle

Dynamics of Urinary Extracellular DNA in Urosepsis

by Michaela Mihaľová, Nadja Šupčíková, Alexandra Gaál Kovalčíková, Ján Breza, Jr., Ľubomíra Tóthová, Peter Celec and Ján Breza, Sr.

Biomolecules 2023, 13(6), 1008; https://doi.org/10.3390/biom13061008 - 17 Jun 2023

Cited by 3 | Viewed by 2540

Abstract

Extracellular DNA (ecDNA) is a promising candidate marker for the early diagnosis and monitoring of urinary tract infections (UTIs). The aim of our study is to describe the dynamics of ecDNA in the plasma and urine of patients with urosepsis as well as [...] Read more.

Extracellular DNA (ecDNA) is a promising candidate marker for the early diagnosis and monitoring of urinary tract infections (UTIs). The aim of our study is to describe the dynamics of ecDNA in the plasma and urine of patients with urosepsis as well as in a mouse model of UTI. Samples of blood and urine were collected from adult patients with UTIs and obstructive uropathy (n = 36) during the first 3 days at the hospital and during a follow-up. Bacterial burden and urinary ecDNA were evaluated in a mouse UTI model (n = 26) at baseline; 24, 48, and 72 h after UTI induction; and 7 days after UTI induction. The plasma ecDNA did not change during urosepsis, but the plasma DNase activity increased significantly at the follow-up. The urinary ecDNA decreased significantly during hospitalization and remained low until the follow-up (90% lower vs. admission). No change was seen in the urinary DNase activity. C-reactive protein (CRP) and procalcitonin are positively correlated with plasma and urinary ecDNA. A UTI caused sepsis in 23% of mice. The urinary ecDNA decreased by three-fold and remained low until day 7 post-infection. Urinary bacterial burden is correlated with urinary ecDNA. Urinary ecDNA is a potential non-invasive marker for monitoring the effects of treatment during urosepsis and is related to UTI progression in the experimental animal model. Full article

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

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17 pages, 1356 KiB

Open AccessEditor’s ChoiceReview

Aldosterone: Essential for Life but Damaging to the Vascular Endothelium

by Michael Crompton, Laura J. Skinner, Simon C. Satchell and Matthew J. Butler

Biomolecules 2023, 13(6), 1004; https://doi.org/10.3390/biom13061004 - 17 Jun 2023

Cited by 13 | Viewed by 6108

Abstract

The renin angiotensin aldosterone system is a key regulator of blood pressure. Aldosterone is the final effector of this pathway, acting predominantly via mineralocorticoid receptors. Aldosterone facilitates the conservation of sodium and, with it, water and acts as a powerful stimulus for potassium [...] Read more.

The renin angiotensin aldosterone system is a key regulator of blood pressure. Aldosterone is the final effector of this pathway, acting predominantly via mineralocorticoid receptors. Aldosterone facilitates the conservation of sodium and, with it, water and acts as a powerful stimulus for potassium excretion. However, evidence for the pathological impact of excess mineralocorticoid receptor stimulation is increasing. Here, we discussed how in the heart, hyperaldosteronism is associated with fibrosis, cardiac dysfunction, and maladaptive hypertrophy. In the kidney, aldosterone was shown to cause proteinuria and fibrosis and may contribute to the progression of kidney disease. More recently, studies suggested that aldosterone excess damaged endothelial cells. Here, we reviewed how damage to the endothelial glycocalyx may contribute to this process. The endothelial glycocalyx is a heterogenous, negatively charged layer on the luminal surface of cells. Aldosterone exposure alters this layer. The resulting structural changes reduced endothelial reactivity in response to protective shear stress, altered permeability, and increased immune cell trafficking. Finally, we reviewed current therapeutic strategies for limiting endothelial damage and suggested that preventing glycocalyx remodelling in response to aldosterone exposure may provide a novel strategy, free from the serious adverse effect of hyperkalaemia seen in response to mineralocorticoid blockade. Full article

(This article belongs to the Special Issue Molecular Aspect of Cardiovascular Risk Factors)

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27 pages, 8490 KiB

Open AccessEditor’s ChoiceArticle

The Ubiquitin-Proteasome System Participates in Sperm Surface Subproteome Remodeling during Boar Sperm Capacitation

by Michal Zigo, Karl Kerns and Peter Sutovsky

Biomolecules 2023, 13(6), 996; https://doi.org/10.3390/biom13060996 - 15 Jun 2023

Cited by 9 | Viewed by 4021

Abstract

Sperm capacitation is a complex process endowing biological and biochemical changes to a spermatozoon for a successful encounter with an oocyte. The present study focused on the role of the ubiquitin–proteasome system (UPS) in the remodeling of the sperm surface subproteome. The sperm [...] Read more.

Sperm capacitation is a complex process endowing biological and biochemical changes to a spermatozoon for a successful encounter with an oocyte. The present study focused on the role of the ubiquitin–proteasome system (UPS) in the remodeling of the sperm surface subproteome. The sperm surface subproteome from non-capacitated and in vitro capacitated (IVC) porcine spermatozoa, with and without proteasomal inhibition, was selectively isolated. The purified sperm surface subproteome was analyzed using high-resolution, quantitative liquid chromatography–mass spectrometry (LC-MS) in four replicates. We identified 1680 HUGO annotated proteins, out of which we found 91 to be at least 1.5× less abundant (p < 0.05) and 141 to be at least 1.5× more abundant (p < 0.05) on the surface of IVC spermatozoa. These proteins were associated with sperm capacitation, hyperactivation, metabolism, acrosomal exocytosis, and fertilization. Abundances of 14 proteins were found to be significantly different (p < 0.05), exceeding a 1.5-fold abundance between the proteasomally inhibited (100 µM MG132) and vehicle control (0.2% ethanol) groups. The proteins NIF3L1, CSE1L, NDUFB7, PGLS, PPP4C, STK39, and TPRG1L were found to be more abundant; while BPHL, GSN, GSPT1, PFDN4, STYXL1, TIMM10, and UBXN4 were found to be less abundant in proteasomally inhibited IVC spermatozoa. Despite the UPS having a narrow range of targets, it modulated sperm metabolism and binding by regulating susceptible surface proteins. Changes in CSE1L, PFDN4, and STK39 during in vitro capacitation were confirmed using immunocytochemistry, image-based flow cytometry, and Western blotting. The results confirmed the active participation of the UPS in the extensive sperm surface proteome remodeling that occurs during boar sperm capacitation. This work will help us to identify new pharmacological mechanisms to positively or negatively modulate sperm fertilizing ability in food animals and humans. Full article

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

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27 pages, 2635 KiB

Open AccessEditor’s ChoiceReview

Deciphering Plant-Insect-Microorganism Signals for Sustainable Crop Production

by Gareth Thomas, Quint Rusman, William R. Morrison III, Diego M. Magalhães, Jordan A. Dowell, Esther Ngumbi, Jonathan Osei-Owusu, Jessica Kansman, Alexander Gaffke, Kamala Jayanthi Pagadala Damodaram, Seong Jong Kim and Nurhayat Tabanca

Biomolecules 2023, 13(6), 997; https://doi.org/10.3390/biom13060997 - 15 Jun 2023

Cited by 21 | Viewed by 10234

Abstract

Agricultural crop productivity relies on the application of chemical pesticides to reduce pest and pathogen damage. However, chemical pesticides also pose a range of ecological, environmental and economic penalties. This includes the development of pesticide resistance by insect pests and pathogens, rendering pesticides [...] Read more.

Agricultural crop productivity relies on the application of chemical pesticides to reduce pest and pathogen damage. However, chemical pesticides also pose a range of ecological, environmental and economic penalties. This includes the development of pesticide resistance by insect pests and pathogens, rendering pesticides less effective. Alternative sustainable crop protection tools should therefore be considered. Semiochemicals are signalling molecules produced by organisms, including plants, microbes, and animals, which cause behavioural or developmental changes in receiving organisms. Manipulating semiochemicals could provide a more sustainable approach to the management of insect pests and pathogens across crops. Here, we review the role of semiochemicals in the interaction between plants, insects and microbes, including examples of how they have been applied to agricultural systems. We highlight future research priorities to be considered for semiochemicals to be credible alternatives to the application of chemical pesticides. Full article

(This article belongs to the Topic Advances in Chemical Ecology)

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25 pages, 2917 KiB

Open AccessEditor’s ChoiceReview

Fungal Drug Discovery for Chronic Disease: History, New Discoveries and New Approaches

by Thomas A. K. Prescott, Rowena Hill, Eduard Mas-Claret, Ester Gaya and Edie Burns

Biomolecules 2023, 13(6), 986; https://doi.org/10.3390/biom13060986 - 14 Jun 2023

Cited by 32 | Viewed by 7334

Abstract

Fungal-derived drugs include some of the most important medicines ever discovered, and have proved pivotal in treating chronic diseases. Not only have they saved millions of lives, but they have in some cases changed perceptions of what is medically possible. However, now the [...] Read more.

Fungal-derived drugs include some of the most important medicines ever discovered, and have proved pivotal in treating chronic diseases. Not only have they saved millions of lives, but they have in some cases changed perceptions of what is medically possible. However, now the low-hanging fruit have been discovered it has become much harder to make the kind of discoveries that have characterised past eras of fungal drug discovery. This may be about to change with new commercial players entering the market aiming to apply novel genomic tools to streamline the discovery process. This review examines the discovery history of approved fungal-derived drugs, and those currently in clinical trials for chronic diseases. For key molecules, we discuss their possible ecological functions in nature and how this relates to their use in human medicine. We show how the conservation of drug receptors between fungi and humans means that metabolites intended to inhibit competitor fungi often interact with human drug receptors, sometimes with unintended benefits. We also plot the distribution of drugs, antimicrobial compounds and psychoactive mushrooms onto a fungal tree and compare their distribution to those of all fungal metabolites. Finally, we examine the phenomenon of self-resistance and how this can be used to help predict metabolite mechanism of action and aid the drug discovery process. Full article

(This article belongs to the Special Issue Naturally-Sourced Biomolecules, Their Regulatory Actions, and Applications in Chronic Disease Management)

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25 pages, 3926 KiB

Open AccessEditor’s ChoiceReview

Non-Canonical Amino Acids as Building Blocks for Peptidomimetics: Structure, Function, and Applications

by Tarsila G. Castro, Manuel Melle-Franco, Cristina E. A. Sousa, Artur Cavaco-Paulo and João C. Marcos

Biomolecules 2023, 13(6), 981; https://doi.org/10.3390/biom13060981 - 12 Jun 2023

Cited by 26 | Viewed by 8165

Abstract

This review provides a fresh overview of non-canonical amino acids and their applications in the design of peptidomimetics. Non-canonical amino acids appear widely distributed in nature and are known to enhance the stability of specific secondary structures and/or biological function. Contrary to the [...] Read more.

This review provides a fresh overview of non-canonical amino acids and their applications in the design of peptidomimetics. Non-canonical amino acids appear widely distributed in nature and are known to enhance the stability of specific secondary structures and/or biological function. Contrary to the ubiquitous DNA-encoded amino acids, the structure and function of these residues are not fully understood. Here, results from experimental and molecular modelling approaches are gathered to classify several classes of non-canonical amino acids according to their ability to induce specific secondary structures yielding different biological functions and improved stability. Regarding side-chain modifications, symmetrical and asymmetrical α,α-dialkyl glycines, Cα to Cα cyclized amino acids, proline analogues, β-substituted amino acids, and α,β-dehydro amino acids are some of the non-canonical representatives addressed. Backbone modifications were also examined, especially those that result in retro-inverso peptidomimetics and depsipeptides. All this knowledge has an important application in the field of peptidomimetics, which is in continuous progress and promises to deliver new biologically active molecules and new materials in the near future. Full article

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19 pages, 3901 KiB

Open AccessEditor’s ChoiceArticle

Unconventional Source of Neurotoxic Protein Aggregation from Organelle Off-Target Bax∆2 in Alzheimer’s Disease

by Qi Yao, Anne Caroline Mascarenhas dos Santos, Huaiyuan Zhang, Adriana Mañas, Ammarah Hussaini, Ujin Kim, Congtai Xu, Sana Basheer, Shinya Tasaki and Jialing Xiang

Biomolecules 2023, 13(6), 970; https://doi.org/10.3390/biom13060970 - 10 Jun 2023

Cited by 3 | Viewed by 2585

Abstract

Protein aggregates are a hallmark of Alzheimer’s disease (AD). Extensive studies have focused on β-amyloid plaques and Tau tangles. Here, we illustrate a novel source of protein aggregates in AD neurons from organelle off-target proteins. Bax is a mitochondrial pore-forming pro-death protein. What [...] Read more.

Protein aggregates are a hallmark of Alzheimer’s disease (AD). Extensive studies have focused on β-amyloid plaques and Tau tangles. Here, we illustrate a novel source of protein aggregates in AD neurons from organelle off-target proteins. Bax is a mitochondrial pore-forming pro-death protein. What happens to Bax if it fails to target mitochondria? We previously showed that a mitochondrial target-deficient alternatively spliced variant, Bax∆2, formed large cytosolic protein aggregates and triggered caspase 8-mediated cell death. Bax∆2 protein levels were low in most normal organs and the proteins were quickly degraded in cancer. Here, we found that 85% of AD patients had Bax∆2 required alternative splicing. Increased Bax∆2 proteins were mostly accumulated in neurons of AD-susceptible brain regions. Intracellularly, Bax∆2 aggregates distributed independently of Tau tangles. Interestingly, Bax∆2 aggregates triggered the formation of stress granules (SGs), a large protein-RNA complex involved in AD pathogenesis. Although the functional domains required for aggregation and cell death are the same as in cancer cells, Bax∆2 relied on SGs, not caspase 8, for neuronal cell death. These results imply that the aggregation of organelle off-target proteins, such as Bax∆2, broadens the scope of traditional AD pathogenic proteins that contribute to the neuronal stress responses and AD pathogenesis. Full article

(This article belongs to the Special Issue Advances in Brain Development and Disease)

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15 pages, 1018 KiB

Open AccessEditor’s ChoiceReview

Caffeine for Prevention of Alzheimer’s Disease: Is the A_2A Adenosine Receptor Its Target?

by Stefania Merighi, Alessia Travagli, Manuela Nigro, Silvia Pasquini, Martina Cappello, Chiara Contri, Katia Varani, Fabrizio Vincenzi, Pier Andrea Borea and Stefania Gessi

Biomolecules 2023, 13(6), 967; https://doi.org/10.3390/biom13060967 - 8 Jun 2023

Cited by 17 | Viewed by 5862

Abstract

Alzheimer’s disease (AD) is the most prevalent kind of dementia with roughly 135 million cases expected in the world by 2050. Unfortunately, current medications for the treatment of AD can only relieve symptoms but they do not act as disease-modifying agents that can [...] Read more.

Alzheimer’s disease (AD) is the most prevalent kind of dementia with roughly 135 million cases expected in the world by 2050. Unfortunately, current medications for the treatment of AD can only relieve symptoms but they do not act as disease-modifying agents that can stop the course of AD. Caffeine is one of the most widely used drugs in the world today, and a number of clinical studies suggest that drinking coffee may be good for health, especially in the fight against neurodegenerative conditions such as AD. Experimental works conducted “in vivo” and “in vitro” provide intriguing evidence that caffeine exerts its neuroprotective effects by antagonistically binding to A_2A receptors (A_2ARs), a subset of GPCRs that are triggered by the endogenous nucleoside adenosine. This review provides a summary of the scientific data supporting the critical role that A_2ARs play in memory loss and cognitive decline, as well as the evidence supporting the protective benefits against neurodegeneration that may be attained by caffeine’s antagonistic action on these receptors. They are a novel and fascinating target for regulating and enhancing synaptic activity, achieving symptomatic and potentially disease-modifying effects, and protecting against neurodegeneration. Full article

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

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13 pages, 1469 KiB

Open AccessEditor’s ChoiceArticle

Anti-TNF Biologicals Enhance the Anti-Inflammatory Properties of IgG N-Glycome in Crohn’s Disease

by Maja Hanić, Frano Vučković, Helena Deriš, Claire Bewshea, Simeng Lin, James R. Goodhand, Tariq Ahmad, Irena Trbojević-Akmačić, Nicholas A. Kennedy, Gordan Lauc and PANTS Consortium

Biomolecules 2023, 13(6), 954; https://doi.org/10.3390/biom13060954 - 7 Jun 2023

Cited by 8 | Viewed by 2564

Abstract

Crohn’s disease (CD) is a chronic inflammation of the digestive tract that significantly impairs patients’ quality of life and well-being. Anti-TNF biologicals revolutionised the treatment of CD, yet many patients do not adequately respond to such therapy. Previous studies have demonstrated a pro-inflammatory [...] Read more.

Crohn’s disease (CD) is a chronic inflammation of the digestive tract that significantly impairs patients’ quality of life and well-being. Anti-TNF biologicals revolutionised the treatment of CD, yet many patients do not adequately respond to such therapy. Previous studies have demonstrated a pro-inflammatory pattern in the composition of CD patients’ immunoglobulin G (IgG) N-glycome compared to healthy individuals. Here, we utilised the high-throughput UHPLC method for N-glycan analysis to explore the longitudinal effect of the anti-TNF drugs infliximab and adalimumab on N-glycome composition of total serum IgG in 198 patients, as well as the predictive potential of IgG N-glycans at baseline to detect primary non-responders to anti-TNF therapy in 1315 patients. We discovered a significant decrease in IgG agalactosylation and an increase in monogalactosylation, digalactosylation and sialylation during the 14 weeks of anti-TNF treatment, regardless of therapy response, all of which suggested a diminished inflammatory environment in CD patients treated with anti-TNF therapy. Furthermore, we observed that IgG N-glycome might contain certain information regarding the anti-TNF therapy outcome before initiating the treatment. However, it is impossible to predict future primary non-responders to anti-TNF therapy based solely on IgG N-glycome composition at baseline. Full article

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

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20 pages, 2711 KiB

Open AccessEditor’s ChoiceArticle

Administration of Warfarin Inhibits the Development of Cerulein-Induced Edematous Acute Pancreatitis in Rats

by Katarzyna Konarska-Bajda, Piotr Ceranowicz, Jakub Cieszkowski, Grzegorz Ginter, Agnieszka Stempniewicz, Krystyna Gałązka, Beata Kuśnierz-Cabala, Paulina Dumnicka, Joanna Bonior and Zygmunt Warzecha

Biomolecules 2023, 13(6), 948; https://doi.org/10.3390/biom13060948 - 6 Jun 2023

Cited by 4 | Viewed by 2673

Abstract

Acute pancreatitis (AP) is a severe disease with high morbidity and mortality in which inflammation and coagulation play crucial roles. The development of inflammation leads to vascular injury, endothelium and leukocytes stimulation, and an increased level of tissue factor, which results in the [...] Read more.

Acute pancreatitis (AP) is a severe disease with high morbidity and mortality in which inflammation and coagulation play crucial roles. The development of inflammation leads to vascular injury, endothelium and leukocytes stimulation, and an increased level of tissue factor, which results in the activation of the coagulation process. For this reason, anticoagulants may be considered as a therapeutic option in AP. Previous studies have shown that pretreatment with heparin, low-molecular-weight heparin (LMWH), or acenocoumarol inhibits the development of AP. The aim of the present study was to check if pretreatment with warfarin affects the development of edematous pancreatitis evoked by cerulein. Warfarin (90, 180, or 270 µg/kg/dose) or saline were administered intragastrically once a day for 7 days consecutively before the induction of AP. AP was evoked by the intraperitoneal administration of cerulein. The pre-administration of warfarin at doses of 90 or 180 µg/kg/dose reduced the histological signs of pancreatic damage in animals with the induction of AP. Additionally, other parameters of AP, such as an increase in the serum activity of lipase and amylase, the plasma concentration of D-dimer, and interleukin-1β, were decreased. In addition, pretreatment with warfarin administered at doses of 90 or 180 µg/kg/dose reversed the limitation of pancreatic blood flow evoked by AP development. Warfarin administered at a dose of 270 µg/kg/dose did not exhibit a preventive effect in cerulein-induced AP. Conclusion: Pretreatment with low doses of warfarin inhibits the development of AP evoked by the intraperitoneal administration of cerulein. Full article

(This article belongs to the Special Issue Biomarkers for Pancreatitis and Its Complications)

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13 pages, 3156 KiB

Open AccessEditor’s ChoiceArticle

Ribosomal Protein S12 Hastens Nucleation of Co-Transcriptional Ribosome Assembly

by Margaret L. Rodgers, Yunsheng Sun and Sarah A. Woodson

Biomolecules 2023, 13(6), 951; https://doi.org/10.3390/biom13060951 - 6 Jun 2023

Cited by 2 | Viewed by 2291

Abstract

Ribosomal subunits begin assembly during transcription of the ribosomal RNA (rRNA), when the rRNA begins to fold and associate with ribosomal proteins (RPs). In bacteria, the first steps of ribosome assembly depend upon recognition of the properly folded rRNA by primary assembly proteins [...] Read more.

Ribosomal subunits begin assembly during transcription of the ribosomal RNA (rRNA), when the rRNA begins to fold and associate with ribosomal proteins (RPs). In bacteria, the first steps of ribosome assembly depend upon recognition of the properly folded rRNA by primary assembly proteins such as S4, which nucleates assembly of the 16S 5′ domain. Recent evidence, however, suggests that initial recognition by S4 is delayed due to variable folding of the rRNA during transcription. Here, using single-molecule colocalization co-transcriptional assembly (smCoCoA), we show that the late-binding RP S12 specifically promotes the association of S4 with the pre-16S rRNA during transcription, thereby accelerating nucleation of 30S ribosome assembly. Order of addition experiments suggest that S12 helps chaperone the rRNA during transcription, particularly near the S4 binding site. S12 interacts transiently with the rRNA during transcription and, consequently, a high concentration is required for its chaperone activity. These results support a model in which late-binding RPs moonlight as RNA chaperones during transcription in order to facilitate rapid assembly. Full article

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

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17 pages, 9304 KiB

Open AccessEditor’s ChoiceArticle

Quantifying Yeast Microtubules and Spindles Using the Toolkit for Automated Microtubule Tracking (TAMiT)

by Saad Ansari, Zachary R. Gergely, Patrick Flynn, Gabriella Li, Jeffrey K. Moore and Meredith D. Betterton

Biomolecules 2023, 13(6), 939; https://doi.org/10.3390/biom13060939 - 4 Jun 2023

Cited by 1 | Viewed by 2013

Abstract

Fluorescently labeled proteins absorb and emit light, appearing as Gaussian spots in fluorescence imaging. When fluorescent tags are added to cytoskeletal polymers such as microtubules, a line of fluorescence and even non-linear structures results. While much progress has been made in techniques for [...] Read more.

Fluorescently labeled proteins absorb and emit light, appearing as Gaussian spots in fluorescence imaging. When fluorescent tags are added to cytoskeletal polymers such as microtubules, a line of fluorescence and even non-linear structures results. While much progress has been made in techniques for imaging and microscopy, image analysis is less well-developed. Current analysis of fluorescent microtubules uses either manual tools, such as kymographs, or automated software. As a result, our ability to quantify microtubule dynamics and organization from light microscopy remains limited. Despite the development of automated microtubule analysis tools for in vitro studies, analysis of images from cells often depends heavily on manual analysis. One of the main reasons for this disparity is the low signal-to-noise ratio in cells, where background fluorescence is typically higher than in reconstituted systems. Here, we present the Toolkit for Automated Microtubule Tracking (TAMiT), which automatically detects, optimizes, and tracks fluorescent microtubules in living yeast cells with sub-pixel accuracy. Using basic information about microtubule organization, TAMiT detects linear and curved polymers using a geometrical scanning technique. Images are fit via an optimization problem for the microtubule image parameters that are solved using non-linear least squares in Matlab. We benchmark our software using simulated images and show that it reliably detects microtubules, even at low signal-to-noise ratios. Then, we use TAMiT to measure monopolar spindle microtubule bundle number, length, and lifetime in a large dataset that includes several S. pombe mutants that affect microtubule dynamics and bundling. The results from the automated analysis are consistent with previous work and suggest a direct role for CLASP/Cls1 in bundling spindle microtubules. We also illustrate automated tracking of single curved astral microtubules in S. cerevisiae, with measurement of dynamic instability parameters. The results obtained with our fully-automated software are similar to results using hand-tracked measurements. Therefore, TAMiT can facilitate automated analysis of spindle and microtubule dynamics in yeast cells. Full article

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

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20 pages, 7260 KiB

Open AccessEditor’s ChoiceArticle

Cyclosporines Antagonize the Antiviral Activity of IFITMProteins by Redistributing Them toward the Golgi Apparatus

by David Prikryl, Mariana Marin, Tanay M. Desai, Yuhong Du, Haian Fu and Gregory B. Melikyan

Biomolecules 2023, 13(6), 937; https://doi.org/10.3390/biom13060937 - 3 Jun 2023

Cited by 1 | Viewed by 2706

Abstract

Interferon-induced transmembrane proteins (IFITMs) block the fusion of diverse enveloped viruses, likely through increasing the cell membrane’s rigidity. Previous studies have reported that the antiviral activity of the IFITM family member, IFITM3, is antagonized by cell pretreatment with rapamycin derivatives and cyclosporines A [...] Read more.

Interferon-induced transmembrane proteins (IFITMs) block the fusion of diverse enveloped viruses, likely through increasing the cell membrane’s rigidity. Previous studies have reported that the antiviral activity of the IFITM family member, IFITM3, is antagonized by cell pretreatment with rapamycin derivatives and cyclosporines A and H (CsA and CsH) that promote the degradation of IFITM3. Here, we show that CsA and CsH potently enhance virus fusion with IFITM1- and IFITM3-expressing cells by inducing their rapid relocalization from the plasma membrane and endosomes, respectively, towards the Golgi. This relocalization is not associated with a significant degradation of IFITMs. Although prolonged exposure to CsA induces IFITM3 degradation in cells expressing low endogenous levels of this protein, its levels remain largely unchanged in interferon-treated cells or cells ectopically expressing IFITM3. Importantly, the CsA-mediated redistribution of IFITMs to the Golgi occurs on a much shorter time scale than degradation and thus likely represents the primary mechanism of enhancement of virus entry. We further show that rapamycin also induces IFITM relocalization toward the Golgi, albeit less efficiently than cyclosporines. Our findings highlight the importance of regulation of IFITM trafficking for its antiviral activity and reveal a novel mechanism of the cyclosporine-mediated modulation of cell susceptibility to enveloped virus infection. Full article

(This article belongs to the Special Issue Molecular Mechanism Investigations into Membrane Fusion)

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19 pages, 4790 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Disease-Specific α-Synuclein Seeding in Lewy Body Disease and Multiple System Atrophy Are Preserved in Formaldehyde-Fixed Paraffin-Embedded Human Brain

by Ain Kim, Ivan Martinez-Valbuena, Jun Li, Anthony E. Lang and Gabor G. Kovacs

Biomolecules 2023, 13(6), 936; https://doi.org/10.3390/biom13060936 - 2 Jun 2023

Cited by 4 | Viewed by 3433

Abstract

Recent studies have been able to detect α-synuclein (αSyn) seeding in formaldehyde-fixed paraffin-embedded (FFPE) tissues from patients with synucleinopathies using seed amplification assays (SAAs), but with relatively low sensitivity due to limited protein extraction efficiency. With the aim of introducing an alternative option [...] Read more.

Recent studies have been able to detect α-synuclein (αSyn) seeding in formaldehyde-fixed paraffin-embedded (FFPE) tissues from patients with synucleinopathies using seed amplification assays (SAAs), but with relatively low sensitivity due to limited protein extraction efficiency. With the aim of introducing an alternative option to frozen tissues, we developed a streamlined protein extraction protocol for evaluating disease-specific seeding in FFPE human brain. We evaluated the protein extraction efficiency of different tissue preparations, deparaffinizations, and protein extraction buffers using formaldehyde-fixed and FFPE tissue of a single Lewy body disease (LBD) subject. Alternatively, we incorporated heat-induced antigen retrieval and dissociation using a commercially available kit. Our novel protein extraction protocol has been optimized to work with 10 sections of 4.5-µm-thickness or 2-mm-diameter micro-punch of FFPE tissue that can be used to seed SAAs. We demonstrated that extracted proteins from FFPE still preserve seeding potential and further show disease-specific seeding in LBD and multiple system atrophy. To the best of our knowledge, our study is the first to recapitulate disease-specific αSyn seeding behaviour in FFPE human brain. Our findings open new perspectives in re-evaluating archived human brain tissue, extending the disease-specific seeding assays to larger cohorts to facilitate molecular subtyping of synucleinopathies. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Alpha-Synuclein in Parkinson's Disease and Other Synucleinopathies)

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16 pages, 896 KiB

Open AccessEditor’s ChoiceArticle

Hyperactivity in Mice Induced by Opioid Agonists with Partial Intrinsic Efficacy and Biased Agonism Administered Alone and in Combination with Morphine

by Agnes Acevedo-Canabal, Travis W. Grim, Cullen L. Schmid, Nina McFague, Edward L. Stahl, Nicole M. Kennedy, Thomas D. Bannister and Laura M. Bohn

Biomolecules 2023, 13(6), 935; https://doi.org/10.3390/biom13060935 - 2 Jun 2023

Cited by 4 | Viewed by 3537

Abstract

Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using ³⁵S-GTPγS binding assays. While all of the agonists act as [...] Read more.

Opioid analgesics such as morphine and fentanyl induce mu-opioid receptor (MOR)-mediated hyperactivity in mice. Herein, we show that morphine, fentanyl, SR-17018, and oliceridine have submaximal intrinsic efficacy in the mouse striatum using ³⁵S-GTPγS binding assays. While all of the agonists act as partial agonists for stimulating G protein coupling in striatum, morphine, fentanyl, and oliceridine are fully efficacious in stimulating locomotor activity; meanwhile, the noncompetitive biased agonists SR-17018 and SR-15099 produce submaximal hyperactivity. Moreover, the combination of SR-17018 and morphine attenuates hyperactivity while antinociceptive efficacy is increased. The combination of oliceridine with morphine increases hyperactivity, which is maintained over time. These findings provide evidence that noncompetitive agonists at MOR can be used to suppress morphine-induced hyperactivity while enhancing antinociceptive efficacy; moreover, they demonstrate that intrinsic efficacy measured at the receptor level is not directly proportional to drug efficacy in the locomotor activity assay. Full article

(This article belongs to the Special Issue Biogenic Amines, Their Receptors and Transporters in Health and Disease: Commemorative Issue in Honor of Professor Marc G. Caron (1946–2022))

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24 pages, 840 KiB

Open AccessEditor’s ChoiceReview

Mechanisms Suggesting a Relationship between Vitamin D and Erectile Dysfunction: An Overview

by Andrea Crafa, Rossella Cannarella, Federica Barbagallo, Claudia Leanza, Roberto Palazzolo, Hunter Ausley Flores, Sandro La Vignera, Rosita A. Condorelli and Aldo E. Calogero

Biomolecules 2023, 13(6), 930; https://doi.org/10.3390/biom13060930 - 1 Jun 2023

Cited by 14 | Viewed by 15798

Abstract

Vitamin D deficiency (VDD) and erectile dysfunction (ED) heavily burden the male population. The higher prevalence of both conditions in the elderly suggests a possible relationship between the two conditions. In addition, in vitro, animal, and human studies have revealed several mechanisms that [...] Read more.

Vitamin D deficiency (VDD) and erectile dysfunction (ED) heavily burden the male population. The higher prevalence of both conditions in the elderly suggests a possible relationship between the two conditions. In addition, in vitro, animal, and human studies have revealed several mechanisms that may relate VDD to ED. The main mechanism by which vitamin D might exert its action on sexual function appears to be through the regulation of endothelial function. Indeed, VDD correlates with several markers of endothelial function. The action of vitamin D on the endothelium would be exercised both indirectly through its intervention in inflammatory processes and through the production of oxygen free radicals, and directly through the regulation of vascular stiffness, the production of nitric oxide, and the regulation of vessel permeability. Furthermore, the ubiquitous distribution of the vitamin D receptor in the human body means that this hormone can also exert a beneficial effect on erectile function by interfering with those comorbidities significantly associated with ED, such as hypertension, diabetes mellitus, hypercholesterolemia, chronic kidney disease, and hypogonadism. In this review, we thoroughly and carefully presented the evidence and mechanisms that would appear to relate vitamin D levels to erectile function. Furthermore, we have summarized the meta-analytic evidence for and against this association to provide a true representation of this topic. Data published to date suggest that low levels of vitamin D could contribute to worsening erectile function through several mechanisms. Therefore, vitamin D levels should be measured in patients with ED and maintained at adequate levels by specific supplementation in case of deficiency. However, the low quality and heterogeneity of clinical trials evaluating the effects of vitamin D administration on erectile function and ED-associated comorbidities do not allow for a univocal conclusion, and indicate the need for further studies to analyze these aspects. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

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26 pages, 2667 KiB

Open AccessEditor’s ChoiceArticle

Protein Biomarker Discovery Studies on Urinary sEV Fractions Separated with UF-SEC for the First Diagnosis and Detection of Recurrence in Bladder Cancer Patients

by Stephanie Jordaens, Eline Oeyen, Hanny Willems, Filip Ameye, Stefan De Wachter, Patrick Pauwels and Inge Mertens

Biomolecules 2023, 13(6), 932; https://doi.org/10.3390/biom13060932 - 1 Jun 2023

Cited by 9 | Viewed by 3177

Abstract

Urinary extracellular vesicles (EVs) are an attractive source of bladder cancer biomarkers. Here, a protein biomarker discovery study was performed on the protein content of small urinary EVs (sEVs) to identify possible biomarkers for the primary diagnosis and recurrence of non-muscle-invasive bladder cancer [...] Read more.

Urinary extracellular vesicles (EVs) are an attractive source of bladder cancer biomarkers. Here, a protein biomarker discovery study was performed on the protein content of small urinary EVs (sEVs) to identify possible biomarkers for the primary diagnosis and recurrence of non-muscle-invasive bladder cancer (NMIBC). The sEVs were isolated by ultrafiltration (UF) in combination with size-exclusion chromatography (SEC). The first part of the study compared healthy individuals with NMIBC patients with a primary diagnosis. The second part compared tumor-free patients with patients with a recurrent NMIBC diagnosis. The separated sEVs were in the size range of 40 to 200 nm. Based on manually curated high quality mass spectrometry (MS) data, the statistical analysis revealed 69 proteins that were differentially expressed in these sEV fractions of patients with a first bladder cancer tumor vs. an age- and gender-matched healthy control group. When the discriminating power between healthy individuals and first diagnosis patients is taken into account, the biomarkers with the most potential are MASP2, C3, A2M, CHMP2A and NHE-RF1. Additionally, two proteins (HBB and HBA1) were differentially expressed between bladder cancer patients with a recurrent diagnosis vs. tumor-free samples of bladder cancer patients, but their biological relevance is very limited. Full article

(This article belongs to the Special Issue The Next Generation of Proteomics for Precision Medicine)

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14 pages, 1115 KiB

Open AccessEditor’s ChoiceReview

Microglia NLRP3 Inflammasome and Neuroimmune Signaling in Substance Use Disorders

by Ming-Lei Guo, Soheil Kazemi Roodsari, Yan Cheng, Rachael Elizabeth Dempsey and Wenhui Hu

Biomolecules 2023, 13(6), 922; https://doi.org/10.3390/biom13060922 - 31 May 2023

Cited by 18 | Viewed by 5000

Abstract

During the last decade, substance use disorders (SUDs) have been increasingly recognized as neuroinflammation-related brain diseases. Various types of abused drugs (cocaine, methamphetamine, alcohol, opiate-like drugs, marijuana, etc.) can modulate the activation status of microglia and neuroinflammation levels which are involved in the [...] Read more.

During the last decade, substance use disorders (SUDs) have been increasingly recognized as neuroinflammation-related brain diseases. Various types of abused drugs (cocaine, methamphetamine, alcohol, opiate-like drugs, marijuana, etc.) can modulate the activation status of microglia and neuroinflammation levels which are involved in the pathogenesis of SUDs. Several neuroimmune signaling pathways, including TLR/NF-кB, reactive oxygen species, mitochondria dysfunction, as well as autophagy defection, etc., have been implicated in promoting SUDs. Recently, inflammasome-mediated signaling has been identified as playing critical roles in the microglia activation induced by abused drugs. Among the family of inflammasomes, NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) serves the primary research target due to its abundant expression in microglia. NLRP3 has the capability of integrating multiple external and internal inputs and coordinately determining the intensity of microglia activation under various pathological conditions. Here, we summarize the effects of abused drugs on NLRP3 inflammasomes, as well as others, if any. The research on this topic is still at an infant stage; however, the readily available findings suggest that NLRP3 inflammasome could be a common downstream effector stimulated by various types of abused drugs and play critical roles in determining abused-drug-mediated biological effects through enhancing glia–neuron communications. NLRP3 inflammasome might serve as a novel target for ameliorating the development of SUDs. Full article

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

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20 pages, 4362 KiB

Open AccessEditor’s ChoiceArticle

Mucoadhesive Rifampicin-Liposomes for the Treatment of Pulmonary Infection by Mycobacterium abscessus: Chitosan or ε-Poly-L-Lysine Decoration

by Jacopo Forte, Patrizia Nadia Hanieh, Noemi Poerio, Tommaso Olimpieri, Maria Grazia Ammendolia, Maurizio Fraziano, Maria Gioia Fabiano, Carlotta Marianecci, Maria Carafa, Federico Bordi, Simona Sennato and Federica Rinaldi

Biomolecules 2023, 13(6), 924; https://doi.org/10.3390/biom13060924 - 31 May 2023

Cited by 7 | Viewed by 2844

Abstract

Mycobacterium abscessus (Mabs) is a dangerous non-tubercular mycobacterium responsible for severe pulmonary infections in immunologically vulnerable patients, due to its wide resistance to many different antibiotics which make its therapeutic management extremely difficult. Drug nanocarriers as liposomes may represent a promising delivery strategy [...] Read more.

Mycobacterium abscessus (Mabs) is a dangerous non-tubercular mycobacterium responsible for severe pulmonary infections in immunologically vulnerable patients, due to its wide resistance to many different antibiotics which make its therapeutic management extremely difficult. Drug nanocarriers as liposomes may represent a promising delivery strategy against pulmonary Mabs infection, due to the possibility to be aerosolically administrated and to tune their properties in order to increase nebulization resistance and retainment of encapsulated drug. In fact, liposome surface can be modified by decoration with mucoadhesive polymers to enhance its stability, mucus penetration and prolong its residence time in the lung. The aim of this work is to employ Chitosan or ε-poly-L-lysine decoration for improving the properties of a novel liposomes composed by hydrogenated phosphatidyl-choline from soybean (HSPC) and anionic 1,2-Dipalmitoyl-sn-glycero-3-phosphorylglycerol sodium salt (DPPG) able to entrap Rifampicin. A deep physicochemical characterization of polymer-decorated liposomes shows that both polymers improve mucoadhesion without affecting liposome features and Rifampicin entrapment efficiency. Therapeutic activity on Mabs-infected macrophages demonstrates an effective antibacterial effect of ε-poly-L-lysine liposomes with respect to chitosan-decorated ones. Altogether, these results suggest a possible use of ε-PLL liposomes to improve antibiotic delivery in the lung. Full article

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

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56 pages, 2374 KiB

Open AccessEditor’s ChoiceReview

The Janus-Faced Role of Lipid Droplets in Aging: Insights from the Cellular Perspective

by Nikolaus Bresgen, Melanie Kovacs, Angelika Lahnsteiner, Thomas Klaus Felder and Mark Rinnerthaler

Biomolecules 2023, 13(6), 912; https://doi.org/10.3390/biom13060912 - 30 May 2023

Cited by 17 | Viewed by 7467

Abstract

It is widely accepted that nine hallmarks—including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis—exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be [...] Read more.

It is widely accepted that nine hallmarks—including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis—exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be regarded as a further aging-associated process. Independently of their essential role as fat stores, lipid droplets are also able to control cell integrity by mitigating lipotoxic and proteotoxic insults. As we will show in this review, numerous longevity interventions (such as mTOR inhibition) also lead to strong accumulation of lipid droplets in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mammalian cells, just to name a few examples. In mammals, due to the variety of different cell types and tissues, the role of lipid droplets during the aging process is much more complex. Using selected diseases associated with aging, such as Alzheimer’s disease, Parkinson’s disease, type II diabetes, and cardiovascular disease, we show that lipid droplets are “Janus”-faced. In an early phase of the disease, lipid droplets mitigate the toxicity of lipid peroxidation and protein aggregates, but in a later phase of the disease, a strong accumulation of lipid droplets can cause problems for cells and tissues. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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16 pages, 13956 KiB

Open AccessEditor’s ChoiceArticle

xProtCAS: A Toolkit for Extracting Conserved Accessible Surfaces from Protein Structures

by Hazem M. Kotb and Norman E. Davey

Biomolecules 2023, 13(6), 906; https://doi.org/10.3390/biom13060906 - 30 May 2023

Cited by 2 | Viewed by 4732

Abstract

The identification of protein surfaces required for interaction with other biomolecules broadens our understanding of protein function, their regulation by post-translational modification, and the deleterious effect of disease mutations. Protein interaction interfaces are often identifiable as patches of conserved residues on a protein’s [...] Read more.

The identification of protein surfaces required for interaction with other biomolecules broadens our understanding of protein function, their regulation by post-translational modification, and the deleterious effect of disease mutations. Protein interaction interfaces are often identifiable as patches of conserved residues on a protein’s surface. However, finding conserved accessible surfaces on folded regions requires an understanding of the protein structure to discriminate between functional and structural constraints on residue conservation. With the emergence of deep learning methods for protein structure prediction, high-quality structural models are now available for any protein. In this study, we introduce tools to identify conserved surfaces on AlphaFold2 structural models. We define autonomous structural modules from the structural models and convert these modules to a graph encoding residue topology, accessibility, and conservation. Conserved surfaces are then extracted using a novel eigenvector centrality-based approach. We apply the tool to the human proteome identifying hundreds of uncharacterised yet highly conserved surfaces, many of which contain clinically significant mutations. The xProtCAS tool is available as open-source Python software and an interactive web server. Full article

(This article belongs to the Special Issue Bioinformatics in Protein Evolution)

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14 pages, 2074 KiB

Open AccessEditor’s ChoiceArticle

Pharmacological Characterization of P626, a Novel Dual Adenosine A_2A/A_2B Receptor Antagonist, on Synaptic Plasticity and during an Ischemic-like Insult in CA1 Rat Hippocampus

by Martina Venturini, Federica Cherchi, Clara Santalmasi, Lucia Frulloni, Ilaria Dettori, Daniela Catarzi, Felicita Pedata, Vittoria Colotta, Flavia Varano, Elisabetta Coppi and Anna Maria Pugliese

Biomolecules 2023, 13(6), 894; https://doi.org/10.3390/biom13060894 - 27 May 2023

Cited by 1 | Viewed by 2613

Abstract

In recent years, the use of multi-target compounds has become an increasingly pursued strategy to treat complex pathologies, including cerebral ischemia. Adenosine and its receptors (A₁AR, A_2AAR, A_2BAR, A₃AR) are known to play a crucial [...] Read more.

In recent years, the use of multi-target compounds has become an increasingly pursued strategy to treat complex pathologies, including cerebral ischemia. Adenosine and its receptors (A₁AR, A_2AAR, A_2BAR, A₃AR) are known to play a crucial role in synaptic transmission either in normoxic or ischemic-like conditions. Previous data demonstrate that the selective antagonism of A_2AAR or A_2BAR delays anoxic depolarization (AD) appearance, an unequivocal sign of neuronal injury induced by a severe oxygen-glucose deprivation (OGD) insult in the hippocampus. Furthermore, the stimulation of A_2AARs or A_2BARs by respective selective agonists, CGS21680 and BAY60-6583, increases pre-synaptic neurotransmitter release, as shown by the decrease in paired-pulse facilitation (PPF) at Schaffer collateral-CA1 synapses. In the present research, we investigated the effect/s of the newly synthesized dual A_2AAR/A_2BAR antagonist, P626, in preventing A_2AAR- and/or A_2BAR-mediated effects by extracellular recordings of synaptic potentials in the CA1 rat hippocampal slices. We demonstrated that P626 prevented PPF reduction induced by CGS21680 or BAY60-6583 and delayed, in a concentration-dependent manner, AD appearance during a severe OGD. In conclusion, P626 may represent a putative neuroprotective compound for stroke treatment with the possible translational advantage of reducing side effects and bypassing differences in pharmacokinetics due to combined treatment. Full article

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

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18 pages, 2907 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 4 | Viewed by 3189

Abstract

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

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

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

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34 pages, 2973 KiB

Open AccessEditor’s ChoiceReview

The Role of Extracellular Vesicles in the Pathogenesis of Hematological Malignancies: Interaction with Tumor Microenvironment; a Potential Biomarker and Targeted Therapy

by Kaushik Das, Tanmoy Mukherjee and Prem Shankar

Biomolecules 2023, 13(6), 897; https://doi.org/10.3390/biom13060897 - 27 May 2023

Cited by 17 | Viewed by 4115

Abstract

The tumor microenvironment (TME) plays an important role in the development and progression of hematological malignancies. In recent years, studies have focused on understanding how tumor cells communicate within the TME. In addition to several factors, such as growth factors, cytokines, extracellular matrix [...] Read more.

The tumor microenvironment (TME) plays an important role in the development and progression of hematological malignancies. In recent years, studies have focused on understanding how tumor cells communicate within the TME. In addition to several factors, such as growth factors, cytokines, extracellular matrix (ECM) molecules, etc., a growing body of evidence has indicated that extracellular vesicles (EVs) play a crucial role in the communication of tumor cells within the TME, thereby contributing to the pathogenesis of hematological malignancies. The present review focuses on how EVs derived from tumor cells interact with the cells in the TME, such as immune cells, stromal cells, endothelial cells, and ECM components, and vice versa, in the context of various hematological malignancies. EVs recovered from the body fluids of cancer patients often carry the bioactive molecules of the originating cells and hence can be considered new predictive biomarkers for specific types of cancer, thereby also acting as potential therapeutic targets. Here, we discuss how EVs influence hematological tumor progression via tumor–host crosstalk and their use as biomarkers for hematological malignancies, thereby benefiting the development of potential therapeutic targets. Full article

(This article belongs to the Special Issue The Role of Tumor Microenvironment in the Pathogenesis and Progression of Hematological Malignancies)

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18 pages, 3951 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 5 | Viewed by 2440

Abstract

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

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

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

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15 pages, 612 KiB

Open AccessEditor’s ChoiceReview

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

by Masayo Nagai and Hidesuke Kaji

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

Cited by 15 | Viewed by 2739

Abstract

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

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

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

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17 pages, 5746 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 6 | Viewed by 3180

Abstract

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

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

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

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19 pages, 3251 KiB

Open AccessEditor’s ChoiceArticle

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

by Kouji Fukuyama, Eishi Motomura and Motohiro Okada

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

Cited by 5 | Viewed by 2623

Abstract

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

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

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

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18 pages, 977 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 20 | Viewed by 8210

Abstract

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

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

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

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26 pages, 9848 KiB

Open AccessEditor’s ChoiceReview

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

by Kavan Gor and Olivier Duss

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

Cited by 7 | Viewed by 5011

Abstract

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

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

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

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18 pages, 3411 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 13 | Viewed by 3861

Abstract

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

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

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

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19 pages, 1589 KiB

Open AccessEditor’s ChoiceReview

Altered Purinergic Signaling in Neurodevelopmental Disorders: Focus on P2 Receptors

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

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

Cited by 6 | Viewed by 3217

Abstract

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

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

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

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41 pages, 4159 KiB

Open AccessEditor’s ChoiceReview

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

by Günter A. Müller and Timo D. Müller

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

Cited by 19 | Viewed by 5918

Abstract

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

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

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

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26 pages, 1574 KiB

Open AccessEditor’s ChoiceReview

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

by Rawan Tarawneh

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

Cited by 8 | Viewed by 7445

Abstract

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

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

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

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12 pages, 1454 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 7 | Viewed by 2806

Abstract

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

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

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

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26 pages, 816 KiB

Open AccessEditor’s ChoiceReview

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

by Kenneth Maiese

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

Cited by 20 | Viewed by 5396

Abstract

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

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

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19 pages, 4128 KiB

Open AccessEditor’s ChoiceArticle

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

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

Biomolecules 2023, 13(5), 801; https://doi.org/10.3390/biom13050801 - 8 May 2023

Cited by 4 | Viewed by 3785

Abstract

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

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

(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)

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20 pages, 1556 KiB

Open AccessEditor’s ChoiceReview

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

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

Biomolecules 2023, 13(5), 787; https://doi.org/10.3390/biom13050787 - 2 May 2023

Cited by 20 | Viewed by 7716

Abstract

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

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

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

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29 pages, 2633 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Strategies for Spinocerebellar Ataxia Type 1

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

Biomolecules 2023, 13(5), 788; https://doi.org/10.3390/biom13050788 - 2 May 2023

Cited by 6 | Viewed by 7792

Abstract

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

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

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

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