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Biomolecules, Volume 13, Issue 3 (March 2023) – 176 articles

Cover Story (view full-size image): The actin cytoskeleton is involved in many cellular processes, including cell migration, adhesion, invasion, endo- and phagocytosis, and division. Actin bundles are the main constituent of actin-rich structures involved in these processes. Recent advances in high-resolution techniques pave the way to a better understanding of physiological bundles formation. Here, we overview the physical and biochemical properties of four families of highly conserved and abundant actin-bundling proteins, namely α-actinin, fimbrin/plastin, fascin, and espin. We describe their role in forming physiological actin bundles and the properties they bestow—both related and unrelated to their bundling abilities. We also review some aspects of the general mechanism of actin bundle formation. View this paper
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17 pages, 3974 KiB  
Article
Purification and Biological Properties of Raniseptins-3 and -6, Two Antimicrobial Peptides from Boana raniceps (Cope, 1862) Skin Secretion
by Gabriel Gonçalves de Freitas, João Martins Barbosa, Carlos José Correia de Santana, Ana Carolina Martins Magalhães, Keven Wender Rodrigues Macedo, Jéssica Oliveira de Souza, Jessica Schneider de Castro, Isadora Alves de Vasconcelos, Amanda Araújo Souza, Sonia Maria de Freitas, Sônia Nair Báo, Samuel Ribeiro Costa, Guilherme Dotto Brand, Ian de Meira Chaves, Vivian Vasconcelos Costa, Wagner Fontes, Osmindo Rodrigues Pires Júnior and Mariana S. Castro
Biomolecules 2023, 13(3), 576; https://doi.org/10.3390/biom13030576 - 22 Mar 2023
Cited by 2 | Viewed by 1618
Abstract
The number of multidrug-resistant pathogenic microorganisms has been growing in recent years, most of which is due to the inappropriate use of the commercial antibiotics that are currently available. The dissemination of antimicrobial resistance represents a serious global public health problem. Thus, it [...] Read more.
The number of multidrug-resistant pathogenic microorganisms has been growing in recent years, most of which is due to the inappropriate use of the commercial antibiotics that are currently available. The dissemination of antimicrobial resistance represents a serious global public health problem. Thus, it is necessary to search for and develop new drugs that can act as antimicrobial agents. Antimicrobial peptides are a promising alternative for the development of new therapeutic drugs. Anurans’ skin glands are a rich source of broad-spectrum antimicrobial compounds and hylids, a large and diverse family of tree frogs, are known as an important source of antimicrobial peptides. In the present study, two novel antimicrobial peptides, named Raniseptins-3 and -6, were isolated from Boana raniceps skin secretion and their structural and biological properties were evaluated. Raniseptins-3 and -6 are cationic, rich in hydrophobic residues, and adopt an α-helix conformation in the presence of SDS (35 mM). Both peptides are active against Gram-negative bacteria and Gram-positive pathogens, with low hemolytic activity at therapeutic concentrations. No activity was observed for yeasts, but the peptides are highly cytotoxic against B16F10 murine melanoma cells and NIH3T3 mouse fibroblast cells. None of the tested compounds showed improvement trends in the MTT and LDH parameters of MHV-3 infected cells at the concentrations tested. Full article
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15 pages, 1699 KiB  
Review
Heme Scavenging and Delivery: The Role of Human Serum Albumin
by Giovanna De Simone, Romualdo Varricchio, Tommaso Francesco Ruberto, Alessandra di Masi and Paolo Ascenzi
Biomolecules 2023, 13(3), 575; https://doi.org/10.3390/biom13030575 - 22 Mar 2023
Cited by 5 | Viewed by 3366
Abstract
Heme is the reactive center of several metal-based proteins that are involved in multiple biological processes. However, free heme, defined as the labile heme pool, has toxic properties that are derived from its hydrophobic nature and the Fe-atom. Therefore, the heme concentration must [...] Read more.
Heme is the reactive center of several metal-based proteins that are involved in multiple biological processes. However, free heme, defined as the labile heme pool, has toxic properties that are derived from its hydrophobic nature and the Fe-atom. Therefore, the heme concentration must be tightly controlled to maintain cellular homeostasis and to avoid pathological conditions. Therefore, different systems have been developed to scavenge either Hb (i.e., haptoglobin (Hp)) or the free heme (i.e., high-density lipoproteins (HDL), low-density lipoproteins (LDL), hemopexin (Hx), and human serum albumin (HSA)). In the first seconds after heme appearance in the plasma, more than 80% of the heme binds to HDL and LDL, and only the remaining 20% binds to Hx and HSA. Then, HSA slowly removes most of the heme from HDL and LDL, and finally, heme transits to Hx, which releases it into hepatic parenchymal cells. The Hx:heme or HSA:heme complexes are internalized via endocytosis mediated by the CD91 and CD71 receptors, respectively. As heme constitutes a major iron source for pathogens, bacteria have evolved hemophores that can extract and uptake heme from host proteins, including HSA:heme. Here, the molecular mechanisms underlying heme scavenging and delivery from HSA are reviewed. Moreover, the relevance of HSA in disease states associated with increased heme plasma concentrations are discussed. Full article
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13 pages, 782 KiB  
Review
Mechanical Properties and Functions of Elastin: An Overview
by Hanna Trębacz and Angelika Barzycka
Biomolecules 2023, 13(3), 574; https://doi.org/10.3390/biom13030574 - 22 Mar 2023
Cited by 9 | Viewed by 5847
Abstract
Human tissues must be elastic, much like other materials that work under continuous loads without losing functionality. The elasticity of tissues is provided by elastin, a unique protein of the extracellular matrix (ECM) of mammals. Its function is to endow soft tissues with [...] Read more.
Human tissues must be elastic, much like other materials that work under continuous loads without losing functionality. The elasticity of tissues is provided by elastin, a unique protein of the extracellular matrix (ECM) of mammals. Its function is to endow soft tissues with low stiffness, high and fully reversible extensibility, and efficient elastic–energy storage. Depending on the mechanical functions, the amount and distribution of elastin-rich elastic fibers vary between and within tissues and organs. The article presents a concise overview of the mechanical properties of elastin and its role in the elasticity of soft tissues. Both the occurrence of elastin and the relationship between its spatial arrangement and mechanical functions in a given tissue or organ are overviewed. As elastin in tissues occurs only in the form of elastic fibers, the current state of knowledge about their mechanical characteristics, as well as certain aspects of degradation of these fibers and their mechanical performance, is presented. The overview also outlines the latest understanding of the molecular basis of unique physical characteristics of elastin and, in particular, the origin of the driving force of elastic recoil after stretching. Full article
(This article belongs to the Section Biomacromolecules: Proteins)
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14 pages, 3224 KiB  
Article
Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing
by Antonino Puglisi, Noemi Bognanni, Graziella Vecchio, Ece Bayir, Peter van Oostrum, Dawn Shepherd, Frances Platt and Erik Reimhult
Biomolecules 2023, 13(3), 573; https://doi.org/10.3390/biom13030573 - 22 Mar 2023
Cited by 2 | Viewed by 2075
Abstract
Core–shell superparamagnetic iron oxide nanoparticles hold great promise as a theranostic platform in biological systems. Herein, we report the biological effect of multifunctional cyclodextrin-appended SPIONs (CySPION) in mutant Npc1-deficient CHO cells compared to their wild type counterparts. CySPIONs show negligible cytotoxicity while they [...] Read more.
Core–shell superparamagnetic iron oxide nanoparticles hold great promise as a theranostic platform in biological systems. Herein, we report the biological effect of multifunctional cyclodextrin-appended SPIONs (CySPION) in mutant Npc1-deficient CHO cells compared to their wild type counterparts. CySPIONs show negligible cytotoxicity while they are strongly endocytosed and localized in the lysosomal compartment. Through their bespoke pH-sensitive chemistry, these nanoparticles release appended monomeric cyclodextrins to mobilize over-accumulated cholesterol and eject it outside the cells. CySPIONs show a high rate of transport across blood–brain barrier models, indicating their promise as a therapeutic approach for cholesterol-impaired diseases affecting the brain. Full article
(This article belongs to the Special Issue Cyclodextrin-Based Drug Release and Drug Delivery Systems)
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15 pages, 3340 KiB  
Review
Modulation of Allosteric Control and Evolution of Hemoglobin
by Maurizio Brunori and Adriana Erica Miele
Biomolecules 2023, 13(3), 572; https://doi.org/10.3390/biom13030572 - 22 Mar 2023
Cited by 1 | Viewed by 1646
Abstract
Allostery arises when a ligand-induced change in shape of a binding site of a protein is coupled to a tertiary/quaternary conformational change with a consequent modulation of functional properties. The two-state allosteric model of Monod, Wyman and Changeux [J. Mol. Biol. 1965; 12, [...] Read more.
Allostery arises when a ligand-induced change in shape of a binding site of a protein is coupled to a tertiary/quaternary conformational change with a consequent modulation of functional properties. The two-state allosteric model of Monod, Wyman and Changeux [J. Mol. Biol. 1965; 12, 88–118] is an elegant and effective theory to account for protein regulation and control. Tetrameric hemoglobin (Hb), the oxygen transporter of all vertebrates, has been for decades the ideal system to test for the validity of the MWC theory. The small ligands affecting Hb’s behavior (organic phosphates, protons, bicarbonate) are produced by the red blood cell during metabolism. By binding to specific sites, these messengers make Hb sensing the environment and reacting consequently. HbI and HbIV from trout and human HbA are classical cooperative models, being similar yet different. They share many fundamental features, starting with the globin fold and the quaternary assembly, and reversible cooperative O2 binding. Nevertheless, they differ in ligand affinity, binding of allosteric effectors, and stability of the quaternary assembly. Here, we recollect essential functional properties and correlate them to the tertiary and quaternary structures available in the protein databank to infer on the molecular basis of the evolution of oxygen transporters. Full article
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38 pages, 2361 KiB  
Review
The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery
by Chenye Qiao, Zongjian Liu and Shuyan Qie
Biomolecules 2023, 13(3), 571; https://doi.org/10.3390/biom13030571 - 21 Mar 2023
Cited by 4 | Viewed by 4208
Abstract
Stroke causes varying degrees of neurological deficits, leading to corresponding dysfunctions. There are different therapeutic principles for each stage of pathological development. Neuroprotection is the main treatment in the acute phase, and functional recovery becomes primary in the subacute and chronic phases. Neuroplasticity [...] Read more.
Stroke causes varying degrees of neurological deficits, leading to corresponding dysfunctions. There are different therapeutic principles for each stage of pathological development. Neuroprotection is the main treatment in the acute phase, and functional recovery becomes primary in the subacute and chronic phases. Neuroplasticity is considered the basis of functional restoration and neurological rehabilitation after stroke, including the remodeling of dendrites and dendritic spines, axonal sprouting, myelin regeneration, synapse shaping, and neurogenesis. Spatiotemporal development affects the spontaneous rewiring of neural circuits and brain networks. Microglia are resident immune cells in the brain that contribute to homeostasis under physiological conditions. Microglia are activated immediately after stroke, and phenotypic polarization changes and phagocytic function are crucial for regulating focal and global brain inflammation and neurological recovery. We have previously shown that the development of neuroplasticity is spatiotemporally consistent with microglial activation, suggesting that microglia may have a profound impact on neuroplasticity after stroke and may be a key therapeutic target for post-stroke rehabilitation. In this review, we explore the impact of neuroplasticity on post-stroke restoration as well as the functions and mechanisms of microglial activation, polarization, and phagocytosis. This is followed by a summary of microglia-targeted rehabilitative interventions that influence neuroplasticity and promote stroke recovery. Full article
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14 pages, 835 KiB  
Article
Relationship between Brain-Derived Neurotrophic Factor and Cognitive Decline in Patients with Mild Cognitive Impairment and Dementia
by Matea Nikolac Perkovic, Fran Borovecki, Igor Filipcic, Barbara Vuic, Tina Milos, Gordana Nedic Erjavec, Marcela Konjevod, Lucija Tudor, Ninoslav Mimica, Suzana Uzun, Oliver Kozumplik, Dubravka Svob Strac and Nela Pivac
Biomolecules 2023, 13(3), 570; https://doi.org/10.3390/biom13030570 - 21 Mar 2023
Cited by 6 | Viewed by 1884
Abstract
In the last decade, increasing evidence has emerged linking alterations in the brain-derived neurotrophic factor (BDNF) expression with the development of Alzheimer’s disease (AD). Because of the important role of BDNF in cognition and its association with AD pathogenesis, the aim of this [...] Read more.
In the last decade, increasing evidence has emerged linking alterations in the brain-derived neurotrophic factor (BDNF) expression with the development of Alzheimer’s disease (AD). Because of the important role of BDNF in cognition and its association with AD pathogenesis, the aim of this study was to evaluate the potential difference in plasma BDNF concentrations between subjects with mild cognitive impairment (MCI; N = 209) and AD patients (N = 295) and to determine the possible association between BDNF plasma levels and the degree of cognitive decline in these individuals. The results showed a significantly higher (p < 0.001) concentration of plasma BDNF in subjects with AD (1.16; 0.13–21.34) compared with individuals with MCI (0.68; 0.02–19.14). The results of the present study additionally indicated a negative correlation between cognitive functions and BDNF plasma concentrations, suggesting higher BDNF levels in subjects with more pronounced cognitive decline. The correlation analysis revealed a significant negative correlation between BDNF plasma levels and both Mini-Mental State Examination (p < 0.001) and Clock Drawing test (p < 0.001) scores. In conclusion, the results of our study point towards elevated plasma BDNF levels in AD patients compared with MCI subjects, which may be due to the body’s attempt to counteract the early and middle stages of neurodegeneration. Full article
(This article belongs to the Special Issue Recent Advances in Neuropharmacology and Brain Physiology)
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15 pages, 3110 KiB  
Article
Oral Immunization with Escherichia coli Nissle 1917 Expressing SARS-CoV-2 Spike Protein Induces Mucosal and Systemic Antibody Responses in Mice
by Giovanni Sarnelli, Alessandro Del Re, Marcella Pesce, Jie Lu, Giovanni Esposito, Walter Sanseverino, Chiara Corpetti, Silvia Basili Franzin, Luisa Seguella, Irene Palenca, Sara Rurgo, Fatima Domenica Elisa De Palma, Aurora Zilli and Giuseppe Esposito
Biomolecules 2023, 13(3), 569; https://doi.org/10.3390/biom13030569 - 21 Mar 2023
Cited by 4 | Viewed by 2455
Abstract
As of October 2022, the COVID-19 pandemic continues to pose a major public health conundrum, with increased rates of symptomatic infections in vaccinated individuals. An ideal vaccine candidate for the prevention of outbreaks should be rapidly scalable, easy to administer, and able to [...] Read more.
As of October 2022, the COVID-19 pandemic continues to pose a major public health conundrum, with increased rates of symptomatic infections in vaccinated individuals. An ideal vaccine candidate for the prevention of outbreaks should be rapidly scalable, easy to administer, and able to elicit a potent mucosal immunity. Towards this aim, we proposed an engineered Escherichia coli (E. coli) Nissle 1917 (EcN) strain with SARS-CoV-2 spike protein (SP)-coding plasmid, which was able to expose SP on its cellular surface by a hybridization with the adhesin involved in diffuse adherence 1 (AIDA1). In this study, we presented the effectiveness of a 16-week intragastrically administered, engineered EcN in producing specific systemic and mucosal immunoglobulins against SARS-CoV-2 SP in mice. We observed a time-dependent increase in anti-SARS-CoV-2 SP IgG antibodies in the sera at week 4, with a titre that more than doubled by week 12 and a stable circulating titre by week 16 (+309% and +325% vs. control; both p < 0.001). A parallel rise in mucosal IgA antibody titre in stools, measured via intestinal and bronchoalveolar lavage fluids of the treated mice, reached a plateau by week 12 and until the end of the immunization protocol (+300, +47, and +150%, at week 16; all p < 0.001 vs. controls). If confirmed in animal models of infection, our data indicated that the engineered EcN may be a potential candidate as an oral vaccine against COVID-19. It is safe, inexpensive, and, most importantly, able to stimulate the production of both systemic and mucosal anti-SARS-CoV-2 spike-protein antibodies. Full article
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27 pages, 2044 KiB  
Review
MicroRNA in the Diagnosis and Treatment of Doxorubicin-Induced Cardiotoxicity
by Ziyu Kuang, Jingyuan Wu, Ying Tan, Guanghui Zhu, Jie Li and Min Wu
Biomolecules 2023, 13(3), 568; https://doi.org/10.3390/biom13030568 - 20 Mar 2023
Cited by 5 | Viewed by 2243
Abstract
Doxorubicin (DOX), a broad-spectrum chemotherapy drug, is widely applied to the treatment of cancer; however, DOX-induced cardiotoxicity (DIC) limits its clinical therapeutic utility. However, it is difficult to monitor and detect DIC at an early stage using conventional detection methods. Thus, sensitive, accurate, [...] Read more.
Doxorubicin (DOX), a broad-spectrum chemotherapy drug, is widely applied to the treatment of cancer; however, DOX-induced cardiotoxicity (DIC) limits its clinical therapeutic utility. However, it is difficult to monitor and detect DIC at an early stage using conventional detection methods. Thus, sensitive, accurate, and specific methods of diagnosis and treatment are important in clinical practice. MicroRNAs (miRNAs) belong to non-coding RNAs (ncRNAs) and are stable and easy to detect. Moreover, miRNAs are expected to become biomarkers and therapeutic targets for DIC; thus, there are currently many studies focusing on the role of miRNAs in DIC. In this review, we list the prominent studies on the diagnosis and treatment of miRNAs in DIC, explore the feasibility and difficulties of using miRNAs as diagnostic biomarkers and therapeutic targets, and provide recommendations for future research. Full article
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17 pages, 1712 KiB  
Article
Association between Inflammation and Thrombotic Pathway Link with Pathogenesis of Depression and Anxiety in SLE Patients
by Liliana Duca, Nadinne Roman, Andreea Teodorescu and Petru Ifteni
Biomolecules 2023, 13(3), 567; https://doi.org/10.3390/biom13030567 - 20 Mar 2023
Cited by 3 | Viewed by 1373
Abstract
As a complication of systemic lupus erythematosus (SLE), the neuropsychiatric form may manifest with neurological and psychiatric symptoms. Diagnosing neuropsychiatric SLE can be challenging due to the heterogeneity of this disease manifestation and the possibilities of investigation. This research aims to identify the [...] Read more.
As a complication of systemic lupus erythematosus (SLE), the neuropsychiatric form may manifest with neurological and psychiatric symptoms. Diagnosing neuropsychiatric SLE can be challenging due to the heterogeneity of this disease manifestation and the possibilities of investigation. This research aims to identify the possible associations between inflammation and thrombotic biomarkers alongside anxiety and/or depression manifestations in SLE patients. A group of 65 outpatients were investigated regarding the levels of depression, anxiety, disability, quality of life and other specific serum biomarkers linked with inflammation or coagulopathies. The results showed severe depression in eight participants, moderate depression in 22 (33.85%), and 26 (40%) subjects with mild depression. Anxiety was more prevalent within 64 participants (98.46%), while a degree of disability was reported by 52 participants (80%). Quality of life evaluated by EQ5D revealed a medium value of 1.57, and EQ5D VAS health medium value was 57.95 and was correlated with anxiety. A strong positive correlation between depression, anxiety and antibodies associated with anti-cardiolipin and anti beta2 glycoprotein I antibodies, lupus anticoagulant, ICAM-1, low C4 a and anti-ribosomal P antibodies were identified. These data results suggest that autoimmune/inflammatory and ischemic/thrombotic pathways could contribute to depression and anxiety as neuropsychiatric SLE manifestations. Full article
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16 pages, 9892 KiB  
Article
Structural Insights into the Distortion of the Ribosomal Small Subunit at Different Magnesium Concentrations
by Ting Yu, Junyi Jiang, Qianxi Yu, Xin Li and Fuxing Zeng
Biomolecules 2023, 13(3), 566; https://doi.org/10.3390/biom13030566 - 20 Mar 2023
Cited by 1 | Viewed by 1950
Abstract
Magnesium ions are abundant and play indispensable functions in the ribosome. A decrease in Mg2+ concentration causes 70S ribosome dissociation and subsequent unfolding. Structural distortion at low Mg2+ concentrations has been observed in an immature pre50S, while the structural changes in [...] Read more.
Magnesium ions are abundant and play indispensable functions in the ribosome. A decrease in Mg2+ concentration causes 70S ribosome dissociation and subsequent unfolding. Structural distortion at low Mg2+ concentrations has been observed in an immature pre50S, while the structural changes in mature subunits have not yet been studied. Here, we purified the 30S subunits of E. coli cells under various Mg2+ concentrations and analyzed their structural distortion by cryo-electron microscopy. Upon systematically interrogating the structural heterogeneity within the 1 mM Mg2+ dataset, we observed 30S particles with different levels of structural distortion in the decoding center, h17, and the 30S head. Our model showed that, when the Mg2+ concentration decreases, the decoding center distorts, starting from h44 and followed by the shifting of h18 and h27, as well as the dissociation of ribosomal protein S12. Mg2+ deficiency also eliminates the interactions between h17, h10, h15, and S16, resulting in the movement of h17 towards the tip of h6. More flexible structures were observed in the 30S head and platform, showing high variability in these regions. In summary, the structures resolved here showed several prominent distortion events in the decoding center and h17. The requirement for Mg2+ in ribosomes suggests that the conformational changes reported here are likely shared due to a lack of cellular Mg2+ in all domains of life. Full article
(This article belongs to the Special Issue Ribosomal Proteins in Ribosome Assembly)
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11 pages, 2339 KiB  
Article
Design and Assembly of a Biofactory for (2S)-Naringenin Production in Escherichia coli: Effects of Oxygen Transfer on Yield and Gene Expression
by Laura E. Parra Daza, Lina Suarez Medina, Albert E. Tafur Rangel, Miguel Fernández-Niño, Luis Alberto Mejía-Manzano, José González-Valdez, Luis H. Reyes and Andrés Fernando González Barrios
Biomolecules 2023, 13(3), 565; https://doi.org/10.3390/biom13030565 - 20 Mar 2023
Cited by 1 | Viewed by 2324
Abstract
The molecule (2S)-naringenin is a scaffold molecule with several nutraceutical properties. Currently, (2S)-naringenin is obtained through chemical synthesis and plant isolation. However, these methods have several drawbacks. Thus, heterologous biosynthesis has emerged as a viable alternative to its production. [...] Read more.
The molecule (2S)-naringenin is a scaffold molecule with several nutraceutical properties. Currently, (2S)-naringenin is obtained through chemical synthesis and plant isolation. However, these methods have several drawbacks. Thus, heterologous biosynthesis has emerged as a viable alternative to its production. Recently, (2S)-naringenin production studies in Escherichia coli have used different tools to increase its yield up to 588 mg/L. In this study, we designed and assembled a bio-factory for (2S)-naringenin production. Firstly, we used several parametrized algorithms to identify the shortest pathway for producing (2S)-naringenin in E. coli, selecting the genes phenylalanine ammonia lipase (pal), 4-coumarate: CoA ligase (4cl), chalcone synthase (chs), and chalcone isomerase (chi) for the biosynthetic pathway. Then, we evaluated the effect of oxygen transfer on the production of (2S)-naringenin at flask (50 mL) and bench (4 L culture) scales. At the flask scale, the agitation rate varied between 50 rpm and 250 rpm. At the bench scale, the dissolved oxygen was kept constant at 5% DO (dissolved oxygen) and 40% DO, obtaining the highest (2S)-naringenin titer (3.11 ± 0.14 g/L). Using genome-scale modeling, gene expression analysis (RT-qPCR) of oxygen-sensitive genes was obtained. Full article
(This article belongs to the Section Natural and Bio-inspired Molecules)
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11 pages, 596 KiB  
Communication
Association between Serum Levels of Interleukin-25/Thymic Stromal Lymphopoietin and the Risk of Exacerbation of Chronic Obstructive Pulmonary Disease
by Joon Young Choi, Tae-Hyung Kim, Sung-Yoon Kang, Hye Jung Park, Seong Yong Lim, Sang Hyuk Kim, Ki-Suck Jung, Kwang Ha Yoo, Hyoung Kyu Yoon and Chin Kook Rhee
Biomolecules 2023, 13(3), 564; https://doi.org/10.3390/biom13030564 - 20 Mar 2023
Viewed by 1400
Abstract
Th2 inflammation is associated with various characteristics of patients with chronic obstructive pulmonary disease (COPD). In this study, we analyzed the COPD exacerbation risk associated with serum levels of interleukin (IL)-25/thymic stromal lymphopoietin (TSLP) and eosinophils. We studied the KOCOSS cohort, a multicenter [...] Read more.
Th2 inflammation is associated with various characteristics of patients with chronic obstructive pulmonary disease (COPD). In this study, we analyzed the COPD exacerbation risk associated with serum levels of interleukin (IL)-25/thymic stromal lymphopoietin (TSLP) and eosinophils. We studied the KOCOSS cohort, a multicenter COPD cohort created by 54 medical centers in South Korea. We extracted data collected between April 2012 and August 2020. We measured serum levels of TSLP and IL-25 in those who agreed to provide blood, and assessed exacerbation risk according to each. In all, 562 patients were enrolled. The IL-25-high group had a lower St. George’s Respiratory Questionnaire score than others, and the TSLP-high group had a poorer exercise capacity than the TSLP-low group. There were no significant differences in the forced expiratory volume in 1 s (FEV1), the levels of Th2 inflammatory biomarkers, or the exacerbation histories between the two groups. The 3-year decline in FEV1 was not significantly affected by IL-25 or TSLP levels. In terms of 1-year exacerbation risk, individuals in the IL-25-high group were at lower risk for moderate-to-severe exacerbation than others. A high TSLP level was associated with a lower risk of severe exacerbation but only in the eosinophil-low group. Serum levels of IL-25 are negatively correlated with moderate-to-severe exacerbation risk in this cohort. A negative correlation between severe exacerbation risk and TSLP level was apparent only in the eosinophil-low group. Full article
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26 pages, 2794 KiB  
Review
Potential Treatment Options for Neuroblastoma with Polyphenols through Anti-Proliferative and Apoptotic Mechanisms
by Aisha Kafoud, Zoya Salahuddin, Raghad Sabaawi Ibrahim, Reem Al-Janahi, Alena Mazurakova, Peter Kubatka and Dietrich Büsselberg
Biomolecules 2023, 13(3), 563; https://doi.org/10.3390/biom13030563 - 20 Mar 2023
Cited by 2 | Viewed by 2256
Abstract
Neuroblastoma (NB) is an extracranial tumor of the peripheral nervous system arising from neural crest cells. It is the most common malignancy in infants and the most common extracranial solid tumor in children. The current treatment for high-risk NB involves chemotherapy and surgical [...] Read more.
Neuroblastoma (NB) is an extracranial tumor of the peripheral nervous system arising from neural crest cells. It is the most common malignancy in infants and the most common extracranial solid tumor in children. The current treatment for high-risk NB involves chemotherapy and surgical resection followed by high-dose chemotherapy with autologous stem-cell rescue and radiation treatment. However, those with high-risk NB are susceptible to relapse and the long-term side effects of standard chemotherapy. Polyphenols, including the sub-class of flavonoids, contain more than one aromatic ring with hydroxyl groups. The literature demonstrates their utility in inducing the apoptosis of neuroblastoma cells, mostly in vitro and some in vivo. This review explores the use of various polyphenols outlined in primary studies, underlines the pathways involved in apoptotic activity, and discusses the dosage and delivery of these polyphenols. Primary studies were obtained from multiple databases with search the terms “neuroblastoma”, “flavonoid”, and “apoptosis”. The in vitro studies showed that polyphenols exert an apoptotic effect on several NB cell lines. These polyphenols include apigenin, genistein, didymin, rutin, quercetin, curcumin, resveratrol, butein, bisphenols, and various plant extracts. The mechanisms of the therapeutic effects include calpain-dependent pathways, receptor-mediated apoptosis, and, notably, and most frequently, mitochondrial apoptosis pathways, including the mitochondrial proteins Bax and Bcl-2. Overall, polyphenols demonstrate potency in decreasing NB proliferation and inducing apoptosis, indicating significant potential for further in vivo research. Full article
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11 pages, 3708 KiB  
Opinion
Glaucoma and Myopia: Diagnostic Challenges
by Michelle T. Sun, Matthew Tran, Kuldev Singh, Robert Chang, Huaizhou Wang and Yang Sun
Biomolecules 2023, 13(3), 562; https://doi.org/10.3390/biom13030562 - 20 Mar 2023
Cited by 2 | Viewed by 4824
Abstract
The rising global prevalence of myopia is a growing concern for clinicians, as it predisposes patients to severe ocular pathologies including glaucoma. High myopia can be associated with clinical features that resemble glaucomatous damage, which make an accurate glaucoma diagnosis challenging, particularly among [...] Read more.
The rising global prevalence of myopia is a growing concern for clinicians, as it predisposes patients to severe ocular pathologies including glaucoma. High myopia can be associated with clinical features that resemble glaucomatous damage, which make an accurate glaucoma diagnosis challenging, particularly among patients with normal intraocular pressures. These patients may also present with established visual field defects which can mimic glaucoma, and standard imaging technology is less useful in disease detection and monitoring due to the lack of normative data for these anatomically unique eyes. Progression over time remains the most critical factor in facilitating the detection of early glaucomatous changes, and thus careful longitudinal follow-up of high-risk myopic patients is the most important aspect of management. Here, we review our current understanding of the complex relationship between myopia and glaucoma, and the diagnostic challenges and limitations of current testing protocols including visual field, intraocular pressure, and imaging. Furthermore, we discuss the clinical findings of two highly myopic patients with suspected glaucoma. Full article
(This article belongs to the Special Issue New Insights into the Molecular Mechanisms of Myopia and Glaucoma)
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14 pages, 1278 KiB  
Review
Alternative mRNA Splicing and Promising Therapies in Cancer
by James D. Fackenthal
Biomolecules 2023, 13(3), 561; https://doi.org/10.3390/biom13030561 - 20 Mar 2023
Cited by 5 | Viewed by 2353
Abstract
Cancer is among the leading causes of mortality worldwide. While considerable attention has been given to genetic and epigenetic sources of cancer-specific cellular activities, the role of alternative mRNA splicing has only recently received attention as a major contributor to cancer initiation and [...] Read more.
Cancer is among the leading causes of mortality worldwide. While considerable attention has been given to genetic and epigenetic sources of cancer-specific cellular activities, the role of alternative mRNA splicing has only recently received attention as a major contributor to cancer initiation and progression. The distribution of alternate mRNA splicing variants in cancer cells is different from their non-cancer counterparts, and cancer cells are more sensitive than non-cancer cells to drugs that target components of the splicing regulatory network. While many of the alternatively spliced mRNAs in cancer cells may represent “noise” from splicing dysregulation, certain recurring splicing variants have been shown to contribute to tumor progression. Some pathogenic splicing disruption events result from mutations in cis-acting splicing regulatory sequences in disease-associated genes, while others may result from shifts in balance among naturally occurring alternate splicing variants among mRNAs that participate in cell cycle progression and the regulation of apoptosis. This review provides examples of cancer-related alternate splicing events resulting from each step of mRNA processing and the promising therapies that may be used to address them. Full article
(This article belongs to the Special Issue The Functions and Mechanisms of Microenvironment in Cancer)
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19 pages, 1994 KiB  
Review
LncRNA and circRNA in Patients with Non-Alcoholic Fatty Liver Disease: A Systematic Review
by Qingmin Zeng, Chang-Hai Liu, Dongbo Wu, Wei Jiang, Nannan Zhang and Hong Tang
Biomolecules 2023, 13(3), 560; https://doi.org/10.3390/biom13030560 - 20 Mar 2023
Cited by 9 | Viewed by 2571
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide. Early identification and prompt treatment are critical to optimize patient management and improve long-term prognosis. Long non-coding RNA (lncRNA) and circular RNA (circRNA) are recently emerging non-coding [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease worldwide. Early identification and prompt treatment are critical to optimize patient management and improve long-term prognosis. Long non-coding RNA (lncRNA) and circular RNA (circRNA) are recently emerging non-coding RNAs, and are highly stable and easily detected in the circulation, representing a promising non-invasive approach for predicting NAFLD. A literature search of the Pubmed, Embase, Web of Science, and Cochrane Library databases was performed and 36 eligible studies were retrieved, including 18 on NAFLD, 13 on nonalcoholic steatohepatitis (NASH), and 11 on fibrosis and/or cirrhosis. Dynamic changes in lncRNA expression were associated with the occurrence and progression of NAFLD, among which lncRNA NEAT1, MEG3, and MALAT1 exhibited great potential as biomarkers for NAFLD. Moreover, mitochondria-located circRNA SCAR can drive metaflammation and its inhibition might be a promising therapeutic target for NASH. In this systematic review, we highlight the great potential of lncRNA/circRNA for early diagnosis and progression assessment of NAFLD. To further verify their clinical value, large-cohort studies incorporating lncRNA and circRNA expression both in liver tissue and blood should be conducted. Additionally, detailed studies on the functional mechanisms of NEAT1, MEG3, and MALAT1 will be essential for elucidating their roles in diagnosing and treating NAFLD, NASH, and fibrosis. Full article
(This article belongs to the Section Molecular Medicine)
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14 pages, 2231 KiB  
Article
The Association between Infant Colic and the Multi-Omic Composition of Human Milk
by Desirae Chandran, Kaitlyn Warren, Daniel McKeone and Steven D. Hicks
Biomolecules 2023, 13(3), 559; https://doi.org/10.3390/biom13030559 - 18 Mar 2023
Cited by 1 | Viewed by 2219
Abstract
Infant colic is a common condition with unclear biologic underpinnings and limited treatment options. We hypothesized that complex molecular networks within human milk (i.e., microbes, micro-ribonucleic acids (miRNAs), cytokines) would contribute to colic risk, while controlling for medical, social, and nutritional variables. This [...] Read more.
Infant colic is a common condition with unclear biologic underpinnings and limited treatment options. We hypothesized that complex molecular networks within human milk (i.e., microbes, micro-ribonucleic acids (miRNAs), cytokines) would contribute to colic risk, while controlling for medical, social, and nutritional variables. This hypothesis was tested in a cohort of 182 breastfed infants, assessed with a modified Infant Colic Scale at 1 month. RNA sequencing was used to interrogate microbial and miRNA features. Luminex assays were used to measure growth factors and cytokines. Milk from mothers of infants with colic (n = 28) displayed higher levels of Staphylococcus (adj. p = 0.038, d = 0.30), miR-224-3p (adj. p = 0.023, d = 0.33), miR-125b-5p (adj. p = 0.028, d = 0.29), let-7a-5p (adj. p = 0.028, d = 0.27), and miR-205-5p (adj. p = 0.029, d = 0.26) compared to milk from non-colic mother–infant dyads (n = 154). Colic symptom severity was directly associated with milk hepatocyte growth factor levels (R = 0.21, p = 0.025). A regression model involving let-7a-5p, miR-29a-3p, and Lactobacillus accurately modeled colic risk (X2 = 16.7, p = 0.001). Molecular factors within human milk may impact colic risk, and provide support for a dysbiotic/inflammatory model of colic pathophysiology. Full article
(This article belongs to the Collection Metabolomics and Integrated Multi-Omics in Health and Disease)
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18 pages, 1380 KiB  
Review
High-Fat Diet Related Lung Fibrosis-Epigenetic Regulation Matters
by Juntang Yang, Chenxi Liang, Lulu Liu, Lan Wang and Guoying Yu
Biomolecules 2023, 13(3), 558; https://doi.org/10.3390/biom13030558 - 18 Mar 2023
Cited by 5 | Viewed by 2383
Abstract
Pulmonary fibrosis (PF) is an interstitial lung disease characterized by the destruction of the pulmonary parenchyma caused by excessive extracellular matrix deposition. Despite the well-known etiological factors such as senescence, aberrant epithelial cell and fibroblast activation, and chronic inflammation, PF has recently been [...] Read more.
Pulmonary fibrosis (PF) is an interstitial lung disease characterized by the destruction of the pulmonary parenchyma caused by excessive extracellular matrix deposition. Despite the well-known etiological factors such as senescence, aberrant epithelial cell and fibroblast activation, and chronic inflammation, PF has recently been recognized as a metabolic disease and abnormal lipid signature was observed both in serum and bronchoalveolar lavage fluid (BALF) of PF patients and mice PF model. Clinically, observational studies suggest a significant link between high-fat diet (HFD) and PF as manifested by high intake of saturated fatty acids (SFAs) and meat increases the risk of PF and mice lung fibrosis. However, the possible mechanisms between HFD and PF remain unclear. In the current review we emphasize the diversity effects of the epigenetic dysregulation induced by HFD on the fibrotic factors such as epithelial cell injury, abnormal fibroblast activation and chronic inflammation. Finally, we discuss the potential ways for patients to improve their conditions and emphasize the prospect of targeted therapy based on epigenetic regulation for scientific researchers or drug developers. Full article
(This article belongs to the Special Issue The Role of Epigenetic Regulation in Cancer)
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14 pages, 3055 KiB  
Article
Ablation of GPR56 Causes β-Cell Dysfunction by ATP Loss through Mistargeting of Mitochondrial VDAC1 to the Plasma Membrane
by Israa Mohammad Al-Amily, Marie Sjögren, Pontus Duner, Mohammad Tariq, Claes B. Wollheim and Albert Salehi
Biomolecules 2023, 13(3), 557; https://doi.org/10.3390/biom13030557 - 18 Mar 2023
Viewed by 2022
Abstract
The activation of G Protein-Coupled Receptor 56 (GPR56), also referred to as Adhesion G-Protein-Coupled Ceceptor G1 (ADGRG1), by Collagen Type III (Coll III) prompts cell growth, proliferation, and survival, among other attributes. We investigated the signaling cascades mediating this functional effect in relation [...] Read more.
The activation of G Protein-Coupled Receptor 56 (GPR56), also referred to as Adhesion G-Protein-Coupled Ceceptor G1 (ADGRG1), by Collagen Type III (Coll III) prompts cell growth, proliferation, and survival, among other attributes. We investigated the signaling cascades mediating this functional effect in relation to the mitochondrial outer membrane voltage-dependent anion Channel-1 (VDAC1) expression in pancreatic β-cells. GPR56KD attenuated the Coll III-induced suppression of P70S6K, JNK, AKT, NFκB, STAT3, and STAT5 phosphorylation/activity in INS-1 cells cultured at 20 mM glucose (glucotoxicity) for 72 h. GPR56-KD also increased Chrebp, Txnip, and Vdac1 while decreasing Vdac2 mRNA expression. In GPR56-KD islet β-cells, Vdac1 was co-localized with SNAP-25, demonstrating its plasma membrane translocation. This resulted in ATP loss, reduced cAMP production and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 and human EndoC βH1 cells. The latter defects were reversed by an acute inhibition of VDAC1 with an antibody or the VDAC1 inhibitor VBIT-4. We demonstrate that Coll III potentiates GSIS by increasing cAMP and preserving β-cell functionality under glucotoxic conditions in a GPR56-dependent manner by attenuating the inflammatory response. These results emphasize GPR56 and VDAC1 as drug targets in conditions with impaired β-cell function. Full article
(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)
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17 pages, 2954 KiB  
Article
Genome-Wide Identification and Expression Analysis of Rosa roxburghii Autophagy-Related Genes in Response to Top-Rot Disease
by Kaisha Luo, Jiaohong Li, Min Lu, Huaming An and Xiaomao Wu
Biomolecules 2023, 13(3), 556; https://doi.org/10.3390/biom13030556 - 17 Mar 2023
Cited by 4 | Viewed by 1487
Abstract
Autophagy is a highly conserved process in eukaryotes that degrades and recycles damaged cells in plants and is involved in plant growth, development, senescence, and resistance to external stress. Top-rot disease (TRD) in Rosa roxburghii fruits caused by Colletotrichum fructicola often leads to [...] Read more.
Autophagy is a highly conserved process in eukaryotes that degrades and recycles damaged cells in plants and is involved in plant growth, development, senescence, and resistance to external stress. Top-rot disease (TRD) in Rosa roxburghii fruits caused by Colletotrichum fructicola often leads to huge yield losses. However, little information is available about the autophagy underlying the defense response to TRD. Here, we identified a total of 40 R. roxburghii autophagy-related genes (RrATGs), which were highly homologous to Arabidopsis thaliana ATGs. Transcriptomic data show that RrATGs were involved in the development and ripening processes of R. roxburghii fruits. Gene expression patterns in fruits with different degrees of TRD occurrence suggest that several members of the RrATGs family responded to TRD, of which RrATG18e was significantly up-regulated at the initial infection stage of C. fructicola. Furthermore, exogenous calcium (Ca2+) significantly promoted the mRNA accumulation of RrATG18e and fruit resistance to TRD, suggesting that this gene might be involved in the calcium-mediated TRD defense response. This study provided a better understanding of R. roxburghii autophagy-related genes and their potential roles in disease resistance. Full article
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12 pages, 6261 KiB  
Article
Comparisons of Cytokines, Growth Factors and Clinical Efficacy between Platelet-Rich Plasma and Autologous Conditioned Serum for Knee Osteoarthritis Management
by Pen-Gang Cheng, Kuender D. Yang, Liang-Gie Huang, Chi-Hui Wang and Wang-Sheng Ko
Biomolecules 2023, 13(3), 555; https://doi.org/10.3390/biom13030555 - 17 Mar 2023
Cited by 2 | Viewed by 2089
Abstract
This study aimed to directly compare the contents and the clinical efficacy of the two autologous blood-derived products, platelet-rich plasma (PRP) and autologous conditioned serum (ACS) for osteoarthritis (OA) treatment. The contents of standard-prepared PRP and ACS prepared at 37 °C for 1 [...] Read more.
This study aimed to directly compare the contents and the clinical efficacy of the two autologous blood-derived products, platelet-rich plasma (PRP) and autologous conditioned serum (ACS) for osteoarthritis (OA) treatment. The contents of standard-prepared PRP and ACS prepared at 37 °C for 1 h, 3 h, 6 h, and 24 h from healthy volunteers were compared. The clinical efficacy of pain relief in patients with Stage III knee OA was evaluated by a patient-reported visual analog scale (VAS) pain rating. PDGF-BB levels in ACS 1 h were significantly higher than those in PRP, and the levels in ACS preparations remained stable. IGF-1 level of ACS 24 h showed a significant increase compared to those of other ACS preparations and PRP. ACS 3 h showed a turning of IL-1Ra level and revealed a time-dependent increase up to 24 h. ACS 6 h showed a turning increase in TNF-α levels. ACS 3 h was chosen for clinical comparison with PRP. The reduction in pain VAS in the ACS group was significantly more compared to those of the PRP group (p = 0.028). However, PRP showed significant earlier improvement (p < 0.001). Conclusion: ACS contained higher levels of PDGF-BB and IL-1Ra and provided better improvement in pain relief compared to PRP. Full article
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18 pages, 3974 KiB  
Article
Roles of miR-196a and miR-196b in Zebrafish Motor Function
by Chunyan Yuan, Huaping Xie, Xiangding Chen and Shunling Yuan
Biomolecules 2023, 13(3), 554; https://doi.org/10.3390/biom13030554 - 17 Mar 2023
Viewed by 1402
Abstract
Background: The exertion of motor function depends on various tissues, such as bones and muscles. miR-196 has been widely studied in cancer and other fields, but its effect on bone and skeletal muscle is rarely reported. In order to explore the role of [...] Read more.
Background: The exertion of motor function depends on various tissues, such as bones and muscles. miR-196 has been widely studied in cancer and other fields, but its effect on bone and skeletal muscle is rarely reported. In order to explore the role of miR-196 family in bone and skeletal muscle, we used the previously successfully constructed miR-196a-1 and miR-196b gene knockout zebrafish animal models for research. Methods: The behavioral trajectories of zebrafish from 4 days post-fertilization (dpf) to 7 dpf were detected to analyze the effect of miR-196a-1 and miR-196b on motor ability. Hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) were used to detect the dorsal muscle tissue of zebrafish. The bone tissue of zebrafish was detected by microcomputed tomography (micro-CT). Real-time PCR was used to detect the expression levels of related genes, including vcp, dpm1, acta1b, mylpfb, col1a1a, bmp8a, gdf6a, and fgfr3. Results: The behavioral test showed that the total behavioral trajectory, movement time, and movement speed of zebrafish larvae were decreased in the miR-196a-1 and miR-196b gene knockout lines. Muscle tissue analysis showed that the structure of muscle fibers in the zebrafish lacking miR-196a-1 and miR-196b was abnormal and was characterized by vacuolar degeneration of muscle fibers, intranuclear migration, melanin deposition, and inflammatory cell infiltration. Bone CT examination revealed decreased bone mineral density and trabecular bone number. The real-time PCR results showed that the expression levels of vcp, dpm1, gdf6a, fgfr3, and col1a1a were decreased in the miR-196b gene knockout group. The expression levels of dpm1, acta1b, mylpfb, gdf6a, and col1a1a were decreased, and the expression level of fgfr3 was increased in the miR-196b gene knockout group compared with the wild-type group. Conclusions: miR-196a-1 and miR-196b play an important role in muscle fiber structure, bone mineral density, and bone trabecular quantity by affecting the expression of vcp, dpm1, acta1b, mylpfb, gdf6a, fgfr3, and col1a1a and then affect the function of the motor system Full article
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13 pages, 3811 KiB  
Article
Host Feeding Patterns of Mansonia (Diptera, Culicidae) in Rural Settlements near Porto Velho, State of Rondonia, Brazil
by Diego Peres Alonso, Jandui Almeida Amorim, Tatiane Marques Porangaba de Oliveira, Ivy Luizi Rodrigues de Sá, Fábio Sossai Possebon, Dario Pires de Carvalho, Kaio Augusto Nabas Ribeiro, Paulo Eduardo Martins Ribolla and Maria Anice Mureb Sallum
Biomolecules 2023, 13(3), 553; https://doi.org/10.3390/biom13030553 - 17 Mar 2023
Cited by 3 | Viewed by 1309
Abstract
Mosquito females of the genus Mansonia (Blanchard) can be a nuisance to humans and animals since they are voraciously hematophagous and feed on the blood of a variety of vertebrates. Despite their relevance, there is a lack of investigation into the blood-feeding patterns [...] Read more.
Mosquito females of the genus Mansonia (Blanchard) can be a nuisance to humans and animals since they are voraciously hematophagous and feed on the blood of a variety of vertebrates. Despite their relevance, there is a lack of investigation into the blood-feeding patterns of the Mansonia species. Knowledge of the host preference is crucial in establishing the public health importance of a mosquito species and its potential to be involved in the transmission dynamics of pathogens. Species that are primarily anthropophilic can be more effective in spreading vector-borne pathogens to humans. In this study, we used an Illumina Nextera sequencing protocol and the QIIME2 workflow to assess the diversity of DNA sequences extracted in the ingested blood of mosquito species to evaluate the overall and local host choices for three species: Ma. titillans, Ma. Amazonensis, and Ma. humeralis, in rural areas alongside the Madeira River in the vicinities of the Santo Antonio Energia (SAE) reservoir in the municipality of Porto Velho, Rondônia, Western Brazil. By performing our analysis pipeline, we have found that host diversity per collection site showed a significant heterogeneity across the sample sites. In addition, in rural areas, Ma. amazonensis present a high affinity for B. taurus, Ma. humeralis shows an overall preference for C. familiaris and B. taurus, but also H. sapiens and E. caballus in urban areas, and Ma. titillans showed more opportunistic behavior in rural areas, feeding on wild animals and G. gallus, though with an overall preference for H. sapiens. Full article
(This article belongs to the Special Issue New Insight into Vector Borne Diseases)
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22 pages, 9479 KiB  
Article
Feasibility of Transport of 26 Biologically Active Ultrashort Peptides via LAT and PEPT Family Transporters
by Vladimir Khatskelevich Khavinson, Natalia Sergeevna Linkova, Andrey Ivanovich Rudskoy and Michael Gennadievich Petukhov
Biomolecules 2023, 13(3), 552; https://doi.org/10.3390/biom13030552 - 17 Mar 2023
Cited by 1 | Viewed by 1399
Abstract
The aim of this work is to verify the possibility of transport of 26 biologically active ultrashort peptides (USPs) into cells via LAT and PEPT family transporters. Molecular modeling and computer-assisted docking of peptide ligands revealed that the size and structure of ligand-binding [...] Read more.
The aim of this work is to verify the possibility of transport of 26 biologically active ultrashort peptides (USPs) into cells via LAT and PEPT family transporters. Molecular modeling and computer-assisted docking of peptide ligands revealed that the size and structure of ligand-binding sites of the amino acid transporters LAT1, LAT2, and of the peptide transporter PEPT1 are sufficient for the transport of the 26 biologically active di-, tri-, and tetra-peptides. Comparative analysis of the binding of all possible di- and tri-peptides (8400 compounds) at the binding sites of the LAT and PEPT family transporters has been carried out. The 26 biologically active USPs systematically showed higher binding scores to LAT1, LAT2, and PEPT1, as compared with di- and tri-peptides, for which no biological activity has been established. This indicates an important possible role which LAT and PEPT family transporters may play in a variety of biological activities of the 26 biologically active peptides under investigation in this study. Most of the 26 studied USPs were found to bind to the LAT1, LAT2, and PEPT1 transporters more efficiently than the known substrates or inhibitors of these transporters. Peptides ED, DS, DR, EDR, EDG, AEDR, AEDL, KEDP, and KEDG, and peptoids DS7 and KE17 with negatively charged Asp or Glu amino acid residues at the N-terminus and neutral or positively charged residues at the C-terminus of the peptide are found to be the most effective ligands of the transporters under investigation. It can be assumed that the antitumor effect of the KE, EW, EDG, and AEDG peptides could be associated with their ability to inhibit the LAT1, LAT2, and PEPT1 amino acid transporters. The data obtained lead to new prospects for further study of the mechanisms of transport of USP-based drugs into the cell and design of new antitumor drugs. Full article
(This article belongs to the Section Bioinformatics and Systems Biology)
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13 pages, 1680 KiB  
Article
Nanobodies Selectively Binding to the Idiotype of a Dengue Virus Neutralizing Antibody Do Not Necessarily Mimic the Viral Epitope
by Monica Poggianella, Robert Bernedo, Sandra Oloketuyi and Ario de Marco
Biomolecules 2023, 13(3), 551; https://doi.org/10.3390/biom13030551 - 17 Mar 2023
Cited by 2 | Viewed by 1516
Abstract
Vaccination against dengue virus is challenged by the fact that a generic immune response can induce antibody-dependent-enhancement (ADE) in secondary infections. Only some antibodies targeting a quaternary epitope formed by the dimerization of the virus protein E possess sufficient neutralizing capacity. Therefore, the [...] Read more.
Vaccination against dengue virus is challenged by the fact that a generic immune response can induce antibody-dependent-enhancement (ADE) in secondary infections. Only some antibodies targeting a quaternary epitope formed by the dimerization of the virus protein E possess sufficient neutralizing capacity. Therefore, the immunization with anti-idiotypic antibodies of neutralizing antibodies might represent a safe vaccination strategy. Starting from a large pre-immune library, we succeeded in isolating a wide set of anti-idiotypic nanobodies characterized by selective and strong binding to the paratope of the neutralizing antibody 1C10. However, the mice immunized with such constructs did not produce effective antibodies, despite at least some of them eliciting an immune response selective for the nanobody variable regions. The results suggest that complex conformational epitopes might be difficult to be recreated by anti-idiotypic structures. The selection process of the anti-idiotypic candidates might be optimized by applying epitope mapping and modeling approaches aimed at identifying the key residues that is necessary to bind to trigger selective immune response. Full article
(This article belongs to the Collection Feature Papers in Section Molecular Medicine)
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18 pages, 8946 KiB  
Article
Enhancement of AFB1 Removal Efficiency via Adsorption/Photocatalysis Synergy Using Surface-Modified Electrospun PCL-g-C3N4/CQDs Membranes
by Liangtao Yao, Changpo Sun, Hui Lin, Guisheng Li, Zichao Lian, Ruixin Song, Songlin Zhuang and Dawei Zhang
Biomolecules 2023, 13(3), 550; https://doi.org/10.3390/biom13030550 - 17 Mar 2023
Cited by 15 | Viewed by 1932
Abstract
Aflatoxin B1 (AFB1) is a highly toxic mycotoxin produced by aspergillus species under specific conditions as secondary metabolites. In this study, types of PCL (Polycaprolactone) membranes anchored (or not) to g-C3N4/CQDs composites were prepared using electrospinning [...] Read more.
Aflatoxin B1 (AFB1) is a highly toxic mycotoxin produced by aspergillus species under specific conditions as secondary metabolites. In this study, types of PCL (Polycaprolactone) membranes anchored (or not) to g-C3N4/CQDs composites were prepared using electrospinning technology with (or without) the following surface modification treatment to remove AFB1. These membranes and g-C3N4/CQDs composites were characterized by SEM, TEM, UV-vis, XRD, XPS and FTIR to analyze their physical and chemical properties. Among them, the modified PCL-g-C3N4/CQDs electrospun membranes exhibited an excellent ability to degrade AFB1 via synergistic effects of adsorption and photocatalysis, and the degradation rate of 0.5 μg/mL AFB1 solution was observed to be up to 96.88% in 30 min under visible light irradiation. Moreover, the modified PCL-g-C3N4/CQDs electrospun membranes could be removed directly after the reaction process without centrifugal or magnetic separation, and the regeneration was a green approach synchronized with the reaction under visible light avoiding physical or chemical treatment. The mechanism of adsorption by electrostatic attraction and hydrogen bonding interaction was revealed and the mechanism of photodegradation of AFB1 was also proposed based on active species trapping experiments. This study illuminated the highly synergic adsorption and photocatalytic AFB1 removal efficiency without side effects from the modified PCL-g-C3N4/CQDs electrospun membranes, thereby offering a continual and green solution to AFB1 removal in practical application. Full article
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14 pages, 828 KiB  
Review
The Role of the Transcription Factor Nrf2 in Alzheimer’s Disease: Therapeutic Opportunities
by Laura Maria De Plano, Giovanna Calabrese, Maria Giovanna Rizzo, Salvatore Oddo and Antonella Caccamo
Biomolecules 2023, 13(3), 549; https://doi.org/10.3390/biom13030549 - 17 Mar 2023
Cited by 8 | Viewed by 2439
Abstract
Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly. One of the key features of AD is the accumulation of reactive oxygen species (ROS), which leads to an overall increase in oxidative damage. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) [...] Read more.
Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly. One of the key features of AD is the accumulation of reactive oxygen species (ROS), which leads to an overall increase in oxidative damage. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of the antioxidant response in cells. Under low ROS levels, Nrf2 is kept in the cytoplasm. However, an increase in ROS production leads to a translocation of Nrf2 into the nucleus, where it activates the transcription of several genes involved in the cells’ antioxidant response. Additionally, Nrf2 activation increases autophagy function. However, in AD, the accumulation of Aβ and tau reduces Nrf2 levels, decreasing the antioxidant response. The reduced Nrf2 levels contribute to the further accumulation of Aβ and tau by impairing their autophagy-mediated turnover. In this review, we discuss the overwhelming evidence indicating that genetic or pharmacological activation of Nrf2 is as a potential approach to mitigate AD pathology. Full article
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14 pages, 2997 KiB  
Article
Spatiotemporal Regulation of FMNL2 by N-Terminal Myristoylation and C-Terminal Phosphorylation Drives Rapid Filopodia Formation
by Lina Lorenzen, Dennis Frank, Carsten Schwan and Robert Grosse
Biomolecules 2023, 13(3), 548; https://doi.org/10.3390/biom13030548 - 17 Mar 2023
Cited by 1 | Viewed by 1549
Abstract
The actin nucleating and polymerizing formin-like 2 (FMNL2) is upregulated in several cancers and has been shown to play important roles in cell migration, invasion, cell–cell adhesion and filopodia formation. Here, using structured illumination microscopy we show that FMNL2 promotes rapid and highly [...] Read more.
The actin nucleating and polymerizing formin-like 2 (FMNL2) is upregulated in several cancers and has been shown to play important roles in cell migration, invasion, cell–cell adhesion and filopodia formation. Here, using structured illumination microscopy we show that FMNL2 promotes rapid and highly dynamic filopodia formation in epithelial cells while remaining on the tip of the growing filopodia. This filopodia tip localization depends fully on its N-terminal myristoylation. We further show that FMNL2-dependent filopodia formation requires its serine 1072 phosphorylation within the diaphanous-autoregulatory domain (DAD) by protein kinase C (PKC) α. Consistent with this, filopodia formation depends on PKC activity and PKCα localizes to the base of growing filopodia. Thus, a PKCα–FMNL2 signaling module spatiotemporally controls dynamic filopodia formation. Full article
(This article belongs to the Special Issue Actin and Its Associates: Biophysical Aspects in Functional Roles)
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4 pages, 190 KiB  
Editorial
An Editorial on the Special Issue ‘Hsp90 Structure, Mechanism and Disease’
by Chrisostomos Prodromou
Biomolecules 2023, 13(3), 547; https://doi.org/10.3390/biom13030547 - 17 Mar 2023
Viewed by 962
Abstract
Hsp90 is known for its role in the activation of an eclectic set of regulatory and signal transduction proteins [...] Full article
(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)
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