Biomolecules

12 pages, 4703 KiB

Open AccessReview

Exploring Biomolecular Self-Assembly with Far-Infrared Radiation

by Takayasu Kawasaki, Yuusuke Yamaguchi, Hideaki Kitahara, Akinori Irizawa and Masahiko Tani

Biomolecules 2022, 12(9), 1326; https://doi.org/10.3390/biom12091326 - 19 Sep 2022

Cited by 2 | Viewed by 2237

Physical engineering technology using far-infrared radiation has been gathering attention in chemical, biological, and material research fields. In particular, the high-power radiation at the terahertz region can give remarkable effects on biological materials distinct from a simple thermal treatment. Self-assembly of biological molecules [...] Read more.

Physical engineering technology using far-infrared radiation has been gathering attention in chemical, biological, and material research fields. In particular, the high-power radiation at the terahertz region can give remarkable effects on biological materials distinct from a simple thermal treatment. Self-assembly of biological molecules such as amyloid proteins and cellulose fiber plays various roles in medical and biomaterials fields. A common characteristic of those biomolecular aggregates is a sheet-like fibrous structure that is rigid and insoluble in water, and it is often hard to manipulate the stacking conformation without heating, organic solvents, or chemical reagents. We discovered that those fibrous formats can be conformationally regulated by means of intense far-infrared radiations from a free-electron laser and gyrotron. In this review, we would like to show the latest and the past studies on the effects of far-infrared radiation on the fibrous biomaterials and to suggest the potential use of the far-infrared radiation for regulation of the biomolecular self-assembly. Full article

(This article belongs to the Topic Fibrous Proteins and Self-Assembling Peptides: From Structure and Assembly to Applications)

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15 pages, 626 KiB

Open AccessArticle

RetroComposer: Composing Templates for Template-Based Retrosynthesis Prediction

by Chaochao Yan, Peilin Zhao, Chan Lu, Yang Yu and Junzhou Huang

Biomolecules 2022, 12(9), 1325; https://doi.org/10.3390/biom12091325 - 19 Sep 2022

Cited by 7 | Viewed by 1979

Abstract

The main target of retrosynthesis is to recursively decompose desired molecules into available building blocks. Existing template-based retrosynthesis methods follow a template selection stereotype and suffer from limited training templates, which prevents them from discovering novel reactions. To overcome this limitation, we propose [...] Read more.

The main target of retrosynthesis is to recursively decompose desired molecules into available building blocks. Existing template-based retrosynthesis methods follow a template selection stereotype and suffer from limited training templates, which prevents them from discovering novel reactions. To overcome this limitation, we propose an innovative retrosynthesis prediction framework that can compose novel templates beyond training templates. As far as we know, this is the first method that uses machine learning to compose reaction templates for retrosynthesis prediction. Besides, we propose an effective reactant candidate scoring model that can capture atom-level transformations, which helps our method outperform previous methods on the USPTO-50K dataset. Experimental results show that our method can produce novel templates for 15 USPTO-50K test reactions that are not covered by training templates. We have released our source implementation. Full article

(This article belongs to the Special Issue Biomolecular Data Science—in Honor of Professor Philip E. Bourne)

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15 pages, 1887 KiB

Open AccessReview

Myocarditis-like Episodes in Patients with Arrhythmogenic Cardiomyopathy: A Systematic Review on the So-Called Hot-Phase of the Disease

by Riccardo Bariani, Ilaria Rigato, Alberto Cipriani, Maria Bueno Marinas, Rudy Celeghin, Cristina Basso, Domenico Corrado, Kalliopi Pilichou and Barbara Bauce

Biomolecules 2022, 12(9), 1324; https://doi.org/10.3390/biom12091324 - 19 Sep 2022

Cited by 17 | Viewed by 2229

Abstract

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease, characterized by myocytes necrosis with fibrofatty substitution and ventricular arrhythmias that can even lead to sudden cardiac death. The presence of inflammatory cell infiltrates in endomyocardial biopsies or in autoptic specimens of ACM patients [...] Read more.

Arrhythmogenic cardiomyopathy (ACM) is a genetically determined myocardial disease, characterized by myocytes necrosis with fibrofatty substitution and ventricular arrhythmias that can even lead to sudden cardiac death. The presence of inflammatory cell infiltrates in endomyocardial biopsies or in autoptic specimens of ACM patients has been reported, suggesting a possible role of inflammation in the pathophysiology of the disease. Furthermore, chest pain episodes accompanied by electrocardiographic changes and troponin release have been observed and defined as the “hot-phase” phenomenon. The aim of this critical systematic review was to assess the clinical features of ACM patients presenting with “hot-phase” episodes. According to PRISMA guidelines, a search was run in the PubMed, Scopus and Web of Science electronic databases using the following keywords: “arrhythmogenic cardiomyopathy”; “myocarditis” or “arrhythmogenic cardiomyopathy”; “troponin” or “arrhythmogenic cardiomyopathy”; and “hot-phase”. A total of 1433 titles were retrieved, of which 65 studies were potentially relevant to the topic. Through the application of inclusion and exclusion criteria, 9 papers reporting 103 ACM patients who had experienced hot-phase episodes were selected for this review. Age at time of episodes was available in 76% of cases, with the mean age reported being 26 years ± 14 years (min 2–max 71 years). Overall, 86% of patients showed left ventricular epicardial LGE. At the time of hot-phase episodes, 49% received a diagnosis of ACM (Arrhythmogenic left ventricular cardiomyopathy in the majority of cases), 19% of dilated cardiomyopathy and 26% of acute myocarditis. At the genetic study, Desmoplakin (DSP) was the more represented disease-gene (69%), followed by Plakophillin-2 (9%) and Desmoglein-2 (6%). In conclusion, ACM patients showing hot-phase episodes are usually young, and DSP is the most common disease gene, accounting for 69% of cases. Currently, the role of “hot-phase” episodes in disease progression and arrhythmic risk stratification remains to be clarified. Full article

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

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13 pages, 2424 KiB

Open AccessArticle

Generation and Validation of an Anti-Human PANK3 Mouse Monoclonal Antibody

by Sunada Khadka, Long Vien, Paul Leonard, Laura Bover and Florian Muller

Biomolecules 2022, 12(9), 1323; https://doi.org/10.3390/biom12091323 - 19 Sep 2022

Cited by 2 | Viewed by 1672

Abstract

Coenzyme A (CoA) is an essential co-factor at the intersection of diverse metabolic pathways. Cellular CoA biosynthesis is regulated at the first committed step—phosphorylation of pantothenic acid—catalyzed by pantothenate kinases (PANK1,2,3 in humans, PANK3 being the most highly expressed). Despite the critical importance [...] Read more.

Coenzyme A (CoA) is an essential co-factor at the intersection of diverse metabolic pathways. Cellular CoA biosynthesis is regulated at the first committed step—phosphorylation of pantothenic acid—catalyzed by pantothenate kinases (PANK1,2,3 in humans, PANK3 being the most highly expressed). Despite the critical importance of CoA in metabolism, the differential roles of PANK isoforms remain poorly understood. Our investigations of PANK proteins as potential precision oncology collateral lethality targets (PANK1 is co-deleted as part of the PTEN locus in some highly aggressive cancers) were severely hindered by a dearth of commercial antibodies that can reliably detect endogenous PANK3 protein. While we successfully validated commercial antibodies for PANK1 and PANK2 using CRISPR knockout cell lines, we found no commercial antibody that could detect endogenous PANK3. We therefore set out to generate a mouse monoclonal antibody against human PANK3 protein. We demonstrate that a clone (Clone MDA-299-62A) can reliably detect endogenous PANK3 protein in cancer cell lines, with band-specificity confirmed by CRISPR PANK3 knockout and knockdown cell lines. Sub-cellular fractionation shows that PANK3 is overwhelmingly cytosolic and expressed broadly across cancer cell lines. PANK3 monoclonal antibody MDA-299-62A should prove a valuable tool for researchers investigating this understudied family of metabolic enzymes in health and disease. Full article

(This article belongs to the Section Molecular Biology)

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14 pages, 1334 KiB

Open AccessArticle

Biphasic Response of Astrocytic Brain-Derived Neurotrophic Factor Expression following Corticosterone Stimulation

by Alexandros Tsimpolis, Maria Kokkali, Aris Logothetis, Konstantinos Kalafatakis and Ioannis Charalampopoulos

Biomolecules 2022, 12(9), 1322; https://doi.org/10.3390/biom12091322 - 18 Sep 2022

Cited by 2 | Viewed by 1786

Abstract

Novel research studies indicate multivarious interactions of glucocorticoid hormones (GCs) with the brain-derived neurotrophic factor (BDNF), regulating important aspects of neuronal cell physiology. While there is recent evidence of the chronic effects of GC stimulation on BDNF levels, as well as of the [...] Read more.

Novel research studies indicate multivarious interactions of glucocorticoid hormones (GCs) with the brain-derived neurotrophic factor (BDNF), regulating important aspects of neuronal cell physiology. While there is recent evidence of the chronic effects of GC stimulation on BDNF levels, as well as of the role of BDNF stimulation in the type of genomic effects following activation of GC-sensitive receptors, no data exist concerning the acute effects of GC stimulation on BDNF/TrkB gene expression. To address this question, we conducted a chrono-pharmacological study on rodent glial cells, astrocytes, which express the BDNF receptor, TrkB, following corticosterone administration. mRNA levels of BDNF and TrkB were estimated 1, 6, 12 and 24 h post-treatment. Selective inhibitors for GC-sensitive receptors and TrkB were used to decipher the molecular pathways of the effects observed. Our data support a biphasic response of BDNF expression after corticosterone stimulation. This response is characterized by a rapid TrkB phosphorylation-dependent upregulation of BDNF mRNA within the first hour, followed by a glucocorticoid receptor (GR)-dependent downregulation of BDNF mRNA, evident at 6, 12 and 24 h, with a direct impact on the protein levels of mature BDNF. Finally, a second pulse of corticosterone administration 1 h prior to the 6, 12 or 24 h timepoints normalized BDNF expression for the corresponding timepoint (i.e., mRNA levels became indifferent from baseline). These results present for the first time a biphasic regulation of the neurotrophin system based on glucocorticoid rhythmicity, further indicating complex trophic responses to temporal hormonal mechanisms in the brain microenvironment. Full article

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

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20 pages, 1127 KiB

Open AccessEditor’s ChoiceReview

Roles of Two-Component Signal Transduction Systems in Shigella Virulence

by Martina Pasqua, Marco Coluccia, Yoko Eguchi, Toshihide Okajima, Milena Grossi, Gianni Prosseda, Ryutaro Utsumi and Bianca Colonna

Biomolecules 2022, 12(9), 1321; https://doi.org/10.3390/biom12091321 - 18 Sep 2022

Cited by 11 | Viewed by 3600

Abstract

Two-component signal transduction systems (TCSs) are widespread types of protein machinery, typically consisting of a histidine kinase membrane sensor and a cytoplasmic transcriptional regulator that can sense and respond to environmental signals. TCSs are responsible for modulating genes involved in a multitude of [...] Read more.

Two-component signal transduction systems (TCSs) are widespread types of protein machinery, typically consisting of a histidine kinase membrane sensor and a cytoplasmic transcriptional regulator that can sense and respond to environmental signals. TCSs are responsible for modulating genes involved in a multitude of bacterial functions, including cell division, motility, differentiation, biofilm formation, antibiotic resistance, and virulence. Pathogenic bacteria exploit the capabilities of TCSs to reprogram gene expression according to the different niches they encounter during host infection. This review focuses on the role of TCSs in regulating the virulence phenotype of Shigella, an intracellular pathogen responsible for severe human enteric syndrome. The pathogenicity of Shigella is the result of the complex action of a wide number of virulence determinants located on the chromosome and on a large virulence plasmid. In particular, we will discuss how five TCSs, EnvZ/OmpR, CpxA/CpxR, ArcB/ArcA, PhoQ/PhoP, and EvgS/EvgA, contribute to linking environmental stimuli to the expression of genes related to virulence and fitness within the host. Considering the relevance of TCSs in the expression of virulence in pathogenic bacteria, the identification of drugs that inhibit TCS function may represent a promising approach to combat bacterial infections. Full article

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

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14 pages, 601 KiB

Open AccessReview

Role of circRNA in E3 Modification under Human Disease

by Zishuo Chen, Minkai Song, Ting Wang, Jiawen Gao, Fei Lin, Hui Dai and Chao Zhang

Biomolecules 2022, 12(9), 1320; https://doi.org/10.3390/biom12091320 - 18 Sep 2022

Cited by 1 | Viewed by 2233

Abstract

Circular RNA (circRNA) is often regarded as a special kind of non-coding RNA, involved in the regulation mechanism of various diseases, such as tumors, neurological diseases, and inflammation. In a broad spectrum of biological processes, the modification of the 76-amino acid ubiquitin protein [...] Read more.

Circular RNA (circRNA) is often regarded as a special kind of non-coding RNA, involved in the regulation mechanism of various diseases, such as tumors, neurological diseases, and inflammation. In a broad spectrum of biological processes, the modification of the 76-amino acid ubiquitin protein generates a large number of signals with different cellular results. Each modification may change the result of signal transduction and participate in the occurrence and development of diseases. Studies have found that circRNA-mediated ubiquitination plays an important role in a variety of diseases. This review first introduces the characteristics of circRNA and ubiquitination and summarizes the mechanism of circRNA in the regulation of ubiquitination in various diseases. It is hoped that the emergence of circRNA-mediated ubiquitination can broaden the diagnosis and prognosis of the disease. Full article

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

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19 pages, 3498 KiB

Open AccessArticle

Controversial Role of Transferrin in the Transport of Ruthenium Anticancer Drugs

by Aviva Levina, Anthony R. M. Chetcuti and Peter A. Lay

Biomolecules 2022, 12(9), 1319; https://doi.org/10.3390/biom12091319 - 18 Sep 2022

Cited by 9 | Viewed by 1881

Abstract

Ruthenium complexes are at the forefront of developments in metal-based anticancer drugs, but many questions remain open regarding their reactivity in biological media, including the role of transferrin (Tf) in their transport and cellular uptake. A well-known anticancer drug, KP1019 ((IndH)[Ru^IIICl [...] Read more.

Ruthenium complexes are at the forefront of developments in metal-based anticancer drugs, but many questions remain open regarding their reactivity in biological media, including the role of transferrin (Tf) in their transport and cellular uptake. A well-known anticancer drug, KP1019 ((IndH)[Ru^IIICl₄(Ind)₂], where Ind = indazole) and a reference complex, [Ru^III(nta)₂]³⁻ (nta = nitrilotriacetato(3−)) interacted differently with human apoTf, monoFeTf, or Fe₂Tf. These reactions were studied by biolayer interferometry (BLI) measurements of Ru–Fe–Tf binding to recombinant human transferrin receptor 1 (TfR1) in conjunction with UV-vis spectroscopy and particle size analysis. Cellular Ru uptake in human hepatoma (HepG2) cells was measured under the conditions of the BLI assays. The mode of Tf binding and cellular Ru uptake were critically dependent on the nature of Ru complex, availability of Fe(III) binding sites of Tf, and the presence of proteins that competed for metal binding, particularly serum albumin. Cellular uptake of KP1019 was not Tf-mediated and occurred mostly by passive diffusion, which may also be suitable for treatments of inoperable cancers by intratumoral injections. High cellular Ru uptake from a combination of [Ru^III(nta)₂]³⁻ and Fe₂Tf in the absence of significant Ru–Tf binding was likely to be due to trapping of Ru(III) species into the endosome during TfR1-mediated endocytosis of Fe₂Tf. Full article

(This article belongs to the Topic Metalloproteins and Metalloenzymes)

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9 pages, 281 KiB

Open AccessArticle

The Paradoxical Role of Circulating Ketone Bodies in Glycemic Control of Individuals with Type 2 Diabetes: High Risk, High Reward?

by Amarens van der Vaart, Martine G. E. Knol, Martin H. de Borst, Stephan J. L. Bakker, Margery A. Connelly, Erwin Garcia, Henk J. G. Bilo, Peter R. van Dijk and Robin P. F. Dullaart

Biomolecules 2022, 12(9), 1318; https://doi.org/10.3390/biom12091318 - 18 Sep 2022

Cited by 6 | Viewed by 1793

Abstract

Introduction: Fasting plasma ketone bodies (KB) are elevated in individuals with type 2 diabetes (T2D) and could affect glycemic control and disease progression. Prolonged KB exposure may result in adaptive beneficial responses, counteracting glycemic dysregulation. In the current proof-of-concept study in adults with [...] Read more.

Introduction: Fasting plasma ketone bodies (KB) are elevated in individuals with type 2 diabetes (T2D) and could affect glycemic control and disease progression. Prolonged KB exposure may result in adaptive beneficial responses, counteracting glycemic dysregulation. In the current proof-of-concept study in adults with T2D, we hypothesized that fasting plasma KB are cross-sectionally associated with poorer glycemic control but prospectively with better glycemic control. Materials and Methods: Fasting plasma KB were measured via nuclear magnetic resonance spectroscopy in patients with T2D treated in primary care (Zodiac cohort; The Netherlands). We analyzed the associations between KB and HbA1c at baseline using linear regression analyses and HbA1c changes over time using linear mixed models. We adjusted for potential confounders, including risk factors for poor glycemic control. Individuals with T2D participating in the general population-based PREVEND study were used as a replication cohort. Results: We included 271 individuals with T2D with a total of 859 HbA1c measurements during a follow-up period of 3.0 (2.0–3.2) years. At baseline, the total amount of fasting plasma KB was independently and positively associated with HbA1c levels (regression coefficient in the fully adjusted analysis = 0.31; 95% CI 0.06–0.57, per doubling of KB; p = 0.02). In contrast, in the longitudinal analyses, fasting plasma KB were associated with a yearly HbA1c (%) decrease of −0.10 (95% CI −0.19 to −0.00 per doubling baseline KB; p = 0.05). Results were replicated in 387 individuals with T2D from a general population cohort with a total of 1115 glucose measurements during a follow-up period of 7.5 (7.2–8.0) years. A yearly decrease in fasting plasma glucose (mmol/L) of 0.09 was found per doubling of baseline KB. Conclusions: This study is the first to suggest a paradoxical role of circulating KB on glycemic control in T2D: elevated KB are associated with cross-sectionally poorer glycemic control but longitudinally with better long-term glycemic control. Full article

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

18 pages, 3536 KiB

Open AccessArticle

Injectable Peptide Hydrogel Encapsulation of Mesenchymal Stem Cells Improved Viability, Stemness, Anti-Inflammatory Effects, and Early Stage Wound Healing

by Quan Li, Guangyan Qi, Dylan Lutter, Warren Beard, Camila R. S. Souza, Margaret A. Highland, Wei Wu, Ping Li, Yuanyuan Zhang, Anthony Atala and Xiuzhi Sun

Biomolecules 2022, 12(9), 1317; https://doi.org/10.3390/biom12091317 - 17 Sep 2022

Cited by 4 | Viewed by 2636

Abstract

Human-adipose-derived mesenchymal stem cells (hADMSCs) are adult stem cells and are relatively easy to access compared to other sources of mesenchymal stem cells (MSCs). They have shown immunomodulation properties as well as effects in improving tissue regeneration. To better stimulate and preserve the [...] Read more.

Human-adipose-derived mesenchymal stem cells (hADMSCs) are adult stem cells and are relatively easy to access compared to other sources of mesenchymal stem cells (MSCs). They have shown immunomodulation properties as well as effects in improving tissue regeneration. To better stimulate and preserve the therapeutic properties of hADMSCs, biomaterials for cell delivery have been studied extensively. To date, hyaluronic acid (HA)-based materials have been most widely adopted by researchers around the world. PGmatrix is a new peptide-based hydrogel that has shown superior functional properties in 3D cell cultures. Here, we reported the in vitro and in vivo functional effects of PGmatrix on hADMSCs in comparison with HA and HA-based Hystem hydrogels. Our results showed that PGmatrix was far superior in maintaining hADMSC viability during prolonged incubation and stimulated expression of SSEA4 (stage-specific embryonic antigen-4) in hADMSCs. hADMSCs encapsulated in PGmatrix secreted more immune-responsive proteins than those in HA or Hystem, though similar VEGF-A and TGFβ1 release levels were observed in all three hydrogels. In vivo studies revealed that hADMSCs encapsulated with PGmatrix showed improved skin wound healing in diabetic-induced mice at an early stage, suggesting possible anti-inflammatory effects, though similar re-epithelialization and collagen density were observed among PGmatrix and HA or Hystem hydrogels by day 21. Full article

(This article belongs to the Section Chemical Biology)

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10 pages, 3508 KiB

Open AccessArticle

Expression of Major Lipid Raft Protein Raftlin in Chronic Rhinosinusitis with Nasal Polyps in Smoking and Non-Smoking Patients Correlated with Interleukin-17 and Tumor Necrosis Factor-α Levels

by Yu-Tsai Lin, Ming-Hsien Tsai, Yan-Ye Su, Wei-Chih Chen, Shun-Chen Huang and Chih-Yen Chien

Biomolecules 2022, 12(9), 1316; https://doi.org/10.3390/biom12091316 - 17 Sep 2022

Cited by 1 | Viewed by 1648

Abstract

Raftlin, as an inflammatory biomarker, has been previously reported in chronic inflammatory diseases. This study investigates the expression of Raftlin in cigarette smokers and in chronic rhinosinusitis with nasal polyps (CRSwNP), as well as evaluating its correlation with interleukin-17 (IL-17) and tumor necrosis [...] Read more.

Raftlin, as an inflammatory biomarker, has been previously reported in chronic inflammatory diseases. This study investigates the expression of Raftlin in cigarette smokers and in chronic rhinosinusitis with nasal polyps (CRSwNP), as well as evaluating its correlation with interleukin-17 (IL-17) and tumor necrosis factor-α (TNF-α) levels. A total of 30 CRSwNP non-smoking and 16 CRSwNP + SK (smoking) patients undergoing endoscopic sinus surgery were enrolled, while 20 middle turbinate tissue pieces were examined and performed as the control group. In nasal mucosa epithelial staining, Raftlin levels were elevated in the columnar cells and were stained much more intensely in the CRSwNP and CRSwNP + SK groups. Raftlin was located more closely to the apical region of the epithelium in the CRSwNP + SK group; however, the Raftlin levels from whole nasal tissue pieces, according to ELISA data, showed that there was no significant difference between the three different study groups. A positive relationship by Pearson correlation was found between IL-17 or TNF-α levels and Raftlin levels. Taken together, these data indicate that increasing Raftlin expression in columnar cells might involve nasal epithelial remodeling in smokers with CRSwNP. Full article

(This article belongs to the Special Issue Immune-Related Biomarkers)

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13 pages, 2349 KiB

Open AccessArticle

Plasma Kallikrein-Activated TGF-β Is Prognostic for Poor Overall Survival in Patients with Pancreatic Ductal Adenocarcinoma and Associates with Increased Fibrogenesis

by Rasmus S. Pedersen, Neel I. Nissen, Christina Jensen, Jeppe Thorlacius-Ussing, Tina Manon-Jensen, Majken L. Olesen, Lasse L. Langholm, Hadi M. H. Diab, Lars N. Jorgensen, Carsten P. Hansen, Inna M. Chen, Julia S. Johansen, Morten A. Karsdal and Nicholas Willumsen

Biomolecules 2022, 12(9), 1315; https://doi.org/10.3390/biom12091315 - 17 Sep 2022

Cited by 2 | Viewed by 2031

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive complex with a latency-associated protein (LAP) that can be [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a hard-to-treat cancer due to the collagen-rich (fibrotic) and immune-suppressed microenvironment. A major driver of this phenomenon is transforming growth factor beta (TGF-β). TGF-β is produced in an inactive complex with a latency-associated protein (LAP) that can be cleaved by plasma kallikrein (PLK), hereby releasing active TGF-β. The aim of this study was to evaluate LAP cleaved by PLK as a non-invasive biomarker for PDAC and tumor fibrosis. An ELISA was developed for the quantification of PLK-cleaved LAP-TGF-β in the serum of 34 patients with PDAC (stage 1–4) and 20 healthy individuals. Biomarker levels were correlated with overall survival (OS) and compared to serum type III collagen (PRO-C3) and type VI collagen (PRO-C6) pro-peptides. PLK-cleaved LAP-TGF-β was higher in patients with PDAC compared to healthy individuals (p < 0.0001). High levels (>median) of PLK-cleaved LAP-TGF-β were associated with poor OS in patients with PDAC independent of age and stage (HR 2.57, 95% CI: 1.22–5.44, p = 0.0135). High levels of PLK-cleaved LAP-TGF-β were associated with high PRO-C3 and PRO-C6, indicating a relationship between the PLK-cleaved LAP-TGF-β fragment, TGF-β activity, and tumor fibrosis. If these preliminary results are validated, circulating PLK-cleaved LAP-TGF-β may be a biomarker for future clinical trials. Full article

(This article belongs to the Special Issue The Role of Biomolecules in Tumor Microenvironment)

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3 pages, 190 KiB

Open AccessEditorial

Digital Pathology: New Initiative in Pathology

by William C. Cho

Biomolecules 2022, 12(9), 1314; https://doi.org/10.3390/biom12091314 - 17 Sep 2022

Cited by 2 | Viewed by 1460

Abstract

Digital pathology (DP) is an emerging field of pathology that manages information generated from digitized specimen slides [...] Full article

(This article belongs to the Special Issue Digital Pathology)

2 pages, 182 KiB

Open AccessEditorial

Glycosylation—The Most Diverse Post-Translational Modification

by Erika Staudacher, Els J. M. Van Damme and Guy Smagghe

Biomolecules 2022, 12(9), 1313; https://doi.org/10.3390/biom12091313 - 17 Sep 2022

Cited by 2 | Viewed by 1808

Abstract

This article is part of the Special Issue Glycosylation—The Most Diverse Post-Translational Modification [...] Full article

(This article belongs to the Special Issue Glycosylation—The Most Diverse Post-Translational Modification)

12 pages, 861 KiB

Open AccessArticle

Effects of RIPC on the Metabolome in Patients Undergoing Vascular Surgery: A Randomized Controlled Trial

by Kadri Eerik, Teele Kasepalu, Karl Kuusik, Jaan Eha, Mare Vähi, Kalle Kilk, Mihkel Zilmer and Jaak Kals

Biomolecules 2022, 12(9), 1312; https://doi.org/10.3390/biom12091312 - 16 Sep 2022

Cited by 2 | Viewed by 1743

Abstract

Background: remote ischemic preconditioning (RIPC) is a phenomenon in which short episodes of ischemia are applied to distant organs to prepare target organs for more prolonged ischemia and to induce protection against ischemia-reperfusion injury. This study aims to evaluate whether preoperatively performed RIPC [...] Read more.

Background: remote ischemic preconditioning (RIPC) is a phenomenon in which short episodes of ischemia are applied to distant organs to prepare target organs for more prolonged ischemia and to induce protection against ischemia-reperfusion injury. This study aims to evaluate whether preoperatively performed RIPC affects the metabolome and to assess whether metabolomic changes correlate with heart and kidney injury markers after vascular surgery. Methods: a randomized sham-controlled, double-blinded trial was conducted at Tartu University Hospital. Patients undergoing elective open vascular surgery were recruited and RIPC was applied before operation. Blood was collected preoperatively and 24 h postoperatively. The metabolome was analyzed using the AbsoluteIDQ p180 Kit. Results: final analysis included 45 patients from the RIPC group and 47 from the sham group. RIPC did not significantly alter metabolites 24 h postoperatively. There was positive correlation of change in the kynurenine/tryptophan ratio with change in hs-troponin T (r = 0.570, p < 0.001), NT-proBNP (r = 0.552, p < 0.001), cystatin C (r = 0.534, p < 0.001) and beta-2-microglobulin (r = 0.504, p < 0.001) only in the RIPC group. Conclusions: preoperative RIPC did not significantly affect the metabolome 24 h after vascular surgery. The positive linear correlation of kynurenine/tryptophan ratio with heart and kidney injury markers suggests that the kynurenine–tryptophan pathway can play a role in RIPC-associated cardio- and nephroprotective effects. Full article

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

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14 pages, 3419 KiB

Open AccessArticle

Phenolics from Defatted Black Cumin Seeds (Nigella sativa L.): Ultrasound-Assisted Extraction Optimization, Comparison, and Antioxidant Activity

by Abdelkrim Gueffai, Diego J. Gonzalez-Serrano, Marios C. Christodoulou, Jose C. Orellana-Palacios, Maria Lopez S. Ortega, Aoumria Ouldmoumna, Fatima Zohra Kiari, Georgia D. Ioannou, Constantina P. Kapnissi-Christodoulou, Andres Moreno and Milad Hadidi

Biomolecules 2022, 12(9), 1311; https://doi.org/10.3390/biom12091311 - 16 Sep 2022

Cited by 13 | Viewed by 2833

Abstract

An ultrasound-assisted method was used for the extraction of phenolics from defatted black cumin seeds (Nigella sativa L.), and the effects of several extraction factors on the total phenolic content and DPPH radical scavenging activity were investigated. To improve the extraction efficiency [...] Read more.

An ultrasound-assisted method was used for the extraction of phenolics from defatted black cumin seeds (Nigella sativa L.), and the effects of several extraction factors on the total phenolic content and DPPH radical scavenging activity were investigated. To improve the extraction efficiency of phenolics from black cumin seed by ultrasonic-assisted extraction, the optimal extraction conditions were determined as follows: ethanol concentration of 59.1%, extraction temperature of 44.6 °C and extraction time of 32.5 min. Under these conditions, the total phenolic content and DPPH radical scavenging activity increased by about 70% and 38%, respectively, compared with conventional extraction. Furthermore, a complementary quantitative analysis of individual phenolic compounds was carried out using the HPLC-UV technique. The phenolic composition revealed high amounts of epicatechin (1.88–2.37 mg/g) and rutin (0.96–1.21 mg/g) in the black cumin seed extracts. Ultrasonic-assisted extraction can be a useful extraction method for the recovery of polyphenols from defatted black cumin seeds. Full article

(This article belongs to the Special Issue Lipids, Proteins and Bioactive Peptides in Food: A Themed Issue Dedicated to Dr. José M. Lorenzo)

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28 pages, 2835 KiB

Open AccessReview

Ginsenoside and Its Therapeutic Potential for Cognitive Impairment

by Hui Feng, Mei Xue, Hao Deng, Shiqi Cheng, Yue Hu and Chunxiang Zhou

Biomolecules 2022, 12(9), 1310; https://doi.org/10.3390/biom12091310 - 16 Sep 2022

Cited by 19 | Viewed by 3350

Abstract

Cognitive impairment (CI) is one of the major clinical features of many neurodegenerative diseases. It can be aging-related or even appear in non-central nerve system (CNS) diseases. CI has a wide spectrum that ranges from the cognitive complaint with normal screening tests to [...] Read more.

Cognitive impairment (CI) is one of the major clinical features of many neurodegenerative diseases. It can be aging-related or even appear in non-central nerve system (CNS) diseases. CI has a wide spectrum that ranges from the cognitive complaint with normal screening tests to mild CI and, at its end, dementia. Ginsenosides, agents extracted from a key Chinese herbal medicine (ginseng), show great promise as a new therapeutic option for treating CI. This review covered both clinical trials and preclinical studies to summarize the possible mechanisms of how ginsenosides affect CI in different diseases. It shows that ginsenosides can modulate signaling pathways associated with oxidative stress, apoptosis, inflammation, synaptic plasticity, and neurogenesis. The involved signaling pathways mainly include the PI3K/Akt, CREB/BDNF, Keap1/Nrf2 signaling, and NF-κB/NLRP3 inflammasome pathways. We hope to provide a theoretical basis for the treatment of CI for related diseases by ginsenosides. Full article

(This article belongs to the Special Issue Advances in Ginsenosides 2.0)

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15 pages, 2227 KiB

Open AccessEditor’s ChoiceArticle

6-Furopyridine Hexamethylene Amiloride Is a Non-Selective P2X7 Receptor Antagonist

by Peter Cuthbertson, Amal Elhage, Dena Al-Rifai, Reece A. Sophocleous, Ross J. Turner, Ashraf Aboelela, Hiwa Majed, Richard S. Bujaroski, Iman Jalilian, Michael J. Kelso, Debbie Watson, Benjamin J. Buckley and Ronald Sluyter

Biomolecules 2022, 12(9), 1309; https://doi.org/10.3390/biom12091309 - 16 Sep 2022

Cited by 5 | Viewed by 1916

Abstract

P2X7 is an extracellular adenosine 5′-triphopshate (ATP)-gated cation channel present on leukocytes, where its activation induces pro-inflammatory cytokine release and ectodomain shedding of cell surface molecules. Human P2X7 can be partially inhibited by amiloride and its derivatives at micromolar concentrations. This study aimed [...] Read more.

P2X7 is an extracellular adenosine 5′-triphopshate (ATP)-gated cation channel present on leukocytes, where its activation induces pro-inflammatory cytokine release and ectodomain shedding of cell surface molecules. Human P2X7 can be partially inhibited by amiloride and its derivatives at micromolar concentrations. This study aimed to screen a library of compounds derived from amiloride or its derivative 5-(N,N-hexamethylene) amiloride (HMA) to identify a potential P2X7 antagonist. 6-Furopyridine HMA (6-FPHMA) was identified as a novel P2X7 antagonist and was characterized further. 6-FPHMA impaired ATP-induced dye uptake into human RPMI8226 multiple myeloma cells and human P2X7-HEK293 cells, in a concentration-dependent, non-competitive manner. Likewise, 6-FPHMA blocked ATP-induced Ca²⁺ fluxes in human P2X7-HEK293 cells in a concentration-dependent, non-competitive manner. 6-FPHMA inhibited ATP-induced dye uptake into human T cells, and interleukin-1β release within human blood and CD23 shedding from RPMI8226 cells. 6-FPHMA also impaired ATP-induced dye uptake into murine P2X7- and canine P2X7-HEK293 cells. However, 6-FPHMA impaired ATP-induced Ca²⁺ fluxes in human P2X4-HEK293 cells and non-transfected HEK293 cells, which express native P2Y₁, P2Y₂ and P2Y₄. In conclusion, 6-FPHMA inhibits P2X7 from multiple species. Its poor selectivity excludes its use as a specific P2X7 antagonist, but further study of amiloride derivatives as P2 receptor antagonists is warranted. Full article

(This article belongs to the Special Issue Feature Paper from Biomolecules Journal Reviewers)

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14 pages, 6692 KiB

Open AccessFeature PaperArticle

Aerosol-Administered Adelmidrol Attenuates Lung Inflammation in a Murine Model of Acute Lung Injury

by Livia Interdonato, Ramona D’amico, Marika Cordaro, Rosalba Siracusa, Roberta Fusco, Alessio Filippo Peritore, Enrico Gugliandolo, Rosalia Crupi, Stefano Coaccioli, Tiziana Genovese, Daniela Impellizzeri, Rosanna Di Paola and Salvatore Cuzzocrea

Biomolecules 2022, 12(9), 1308; https://doi.org/10.3390/biom12091308 - 16 Sep 2022

Cited by 7 | Viewed by 1985

Abstract

Acute lung injury (ALI) is a common and devastating clinical disorder with a high mortality rate and no specific therapy. The pathophysiology of ALI is characterized by increased alveolar/capillary permeability, lung inflammation, oxidative stress and structural damage to lung tissues, which can progress [...] Read more.

Acute lung injury (ALI) is a common and devastating clinical disorder with a high mortality rate and no specific therapy. The pathophysiology of ALI is characterized by increased alveolar/capillary permeability, lung inflammation, oxidative stress and structural damage to lung tissues, which can progress to acute respiratory distress syndrome (ARDS). Adelmidrol (ADM), an analogue of palmitoylethanolamide (PEA), is known for its anti-inflammatory and antioxidant functions, which are mainly due to down-modulating mast cells (MCs) and promoting endogenous antioxidant defense. The aim of this study is to evaluate the protective effects of ADM in a mice model of ALI, induced by intratracheal administration of lipopolysaccharide (LPS) at the dose of 5 mg/kg. ADM 2% was administered by aerosol 1 and 6 h after LPS instillation. In this study, we clearly demonstrated that ADM reduced lung damage and airway infiltration induced by LPS instillation. At the same time, ADM counteracted the increase in MC number and the expression of specific markers of MC activation, i.e., chymase and tryptase. Moreover, ADM reduced oxidative stress by upregulating antioxidant enzymes as well as modulating the Nf-kB pathway and the resulting pro-inflammatory cytokine release. These results suggest that ADM could be a potential candidate in the management of ALI. Full article

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

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18 pages, 9214 KiB

Open AccessArticle

Functional and Structural Impact of Deleterious Missense Single Nucleotide Polymorphisms in the NR3C1, CYP3A5, and TNF-α Genes: An In Silico Analysis

by Navakanth Raju Ramayanam, Ranjani Manickam, Vijayakumar Thangavel Mahalingam, Khang Wen Goh, Chrismawan Ardianto, Poovi Ganesan, Long Chiau Ming and Rajanandh Muhasaparur Ganesan

Biomolecules 2022, 12(9), 1307; https://doi.org/10.3390/biom12091307 - 16 Sep 2022

Cited by 5 | Viewed by 2096

Abstract

Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 [...] Read more.

Human diseases are generally influenced by SNPs (single nucleotide polymorphisms). The mutations in amino acid residues generated by deleterious SNPs contribute to the structural and functional diversity of the encoded protein. Tumor necrosis factor-α (TNF-α), Glucocorticoid receptor gene (NR3C1), and Cytochrome P450 3A5 (CYP3A5) play a key role in glucocorticoid resistance susceptibility in humans. Possible causative mutations could be used as therapeutic targets and diagnostic markers for glucocorticoid resistance. This study evaluated the missense SNPs of TNF-α, NR3C1, and CYP3A5 to predict their impact on amino acid changes, protein interaction, and functional stability. The protein sequence of dbSNP was obtained and used online in silico method to screen deleterious mutants for the in silico analysis. In the coding regions of TNF-α, NR3C1, and CYP3A5, 14 deleterious mutations were discovered. The protein functional and stability changes in the amino acid between native and mutant energy were identified by analyzing the changes in the hydrogen bonding of these mutants from native, which were all measured using Swiss PDB and PyMOL. F446S and R439K had the highest root-mean-square deviation (RMSD) values among the 14 deleterious mutants. Additionally, the conserved region of amino acid protein interaction was analyzed. This study could aid in the discovery of new detrimental mutations in TNF-α, NR3C1, and CYP3A5, as well as the development of long-term therapy for corticosteroid resistance in several inflammatory diseases. However, more research into the deleterious mutations of the TNF-α, NR3C1, and CYP3A5 genes is needed to determine their role in corticosteroid resistance. Full article

(This article belongs to the Special Issue Rare Diseases Associated with SNPs and Protein Structure Modifications)

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27 pages, 14409 KiB

Open AccessReview

Phytochemicals in Inhibition of Prostate Cancer: Evidence from Molecular Mechanisms Studies

by Qiongyu Hao, Yanyuan Wu, Jaydutt V. Vadgama and Piwen Wang

Biomolecules 2022, 12(9), 1306; https://doi.org/10.3390/biom12091306 - 16 Sep 2022

Cited by 7 | Viewed by 3167

Abstract

Prostate cancer is one of the leading causes of death for men worldwide. The development of resistance, toxicity, and side effects of conventional therapies have made prostate cancer treatment become more intensive and aggressive. Many phytochemicals isolated from plants have shown to be [...] Read more.

Prostate cancer is one of the leading causes of death for men worldwide. The development of resistance, toxicity, and side effects of conventional therapies have made prostate cancer treatment become more intensive and aggressive. Many phytochemicals isolated from plants have shown to be tumor cytotoxic. In vitro laboratory studies have revealed that natural compounds can affect cancer cell proliferation by modulating many crucial cellular signaling pathways frequently dysregulated in prostate cancer. A multitude of natural compounds have been found to induce cell cycle arrest, promote apoptosis, inhibit cancer cell growth, and suppress angiogenesis. In addition, combinatorial use of natural compounds with hormone and/or chemotherapeutic drugs seems to be a promising strategy to enhance the therapeutic effect in a less toxic manner, as suggested by pre-clinical studies. In this context, we systematically reviewed the currently available literature of naturally occurring compounds isolated from vegetables, fruits, teas, and herbs, with their relevant mechanisms of action in prostate cancer. As there is increasing data on how phytochemicals interfere with diverse molecular pathways in prostate cancer, this review discusses and emphasizes the implicated molecular pathways of cell proliferation, cell cycle control, apoptosis, and autophagy as important processes that control tumor angiogenesis, invasion, and metastasis. In conclusion, the elucidation of the natural compounds’ chemical structure-based anti-cancer mechanisms will facilitate drug development and the optimization of drug combinations. Phytochemicals, as anti-cancer agents in the treatment of prostate cancer, can have significant health benefits for humans. Full article

(This article belongs to the Special Issue Natural Products in Chemo- or Hormone Therapy)

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4 pages, 180 KiB

Open AccessEditorial

Phytohormones 2020

by Guzel Kudoyarova

Biomolecules 2022, 12(9), 1305; https://doi.org/10.3390/biom12091305 - 16 Sep 2022

Cited by 1 | Viewed by 1466

Abstract

The hormonal system plays a decisive role in the control of plant growth and development [...] Full article

(This article belongs to the Special Issue Phytohormones 2020)

13 pages, 1499 KiB

Open AccessArticle

Chitosan as an Adjuvant to Enhance the Control Efficacy of Low-Dosage Pyraclostrobin against Powdery Mildew of Rosa roxburghii and Improve Its Photosynthesis, Yield, and Quality

by Cheng Zhang, Qinju Li, Jiaohong Li, Yue Su and Xiaomao Wu

Biomolecules 2022, 12(9), 1304; https://doi.org/10.3390/biom12091304 - 16 Sep 2022

Cited by 11 | Viewed by 1555

Abstract

Powdery mildew is the most serious fungal disease of Rosa roxburghii in Guizhou Province, China. In this study, the control role of chitosan-assisted pyraclostrobin against powdery mildew of R. roxburghii and its influences on the resistance, photosynthesis, yield, quality and amino acids [...] Read more.

Powdery mildew is the most serious fungal disease of Rosa roxburghii in Guizhou Province, China. In this study, the control role of chitosan-assisted pyraclostrobin against powdery mildew of R. roxburghii and its influences on the resistance, photosynthesis, yield, quality and amino acids of R. roxburghii were evaluated. The results indicate that the foliar application of 30% pyraclostrobin suspension concentrate (SC) 100 mg L⁻¹ + chitosan 500 mg L⁻¹ displayed a superior control potential against powdery mildew, with a control efficacy of 89.30% and 94.58% after 7 d and 14 d of spraying, respectively, which significantly (p < 0.01) exceeded those of 30% pyraclostrobin SC 150 mg L⁻¹, 30% pyraclostrobin SC 100 mg L⁻¹, and chitosan 500 mg L⁻¹. Simultaneously, their co-application could effectively enhance their effect on the resistance and photosynthesis of R. roxburghii leaves compared to their application alone. Meanwhile, their co-application could also more effectively enhance the yield, quality, and amino acids of R. roxburghii fruits compared to their application alone. This work highlights that chitosan can be applied as an effective adjuvant to promote the efficacy of low-dosage pyraclostrobin against powdery mildew in R. roxburghii and improve its resistance, photosynthesis, yield, quality, and amino acids. Full article

(This article belongs to the Special Issue Plant Adaptation to Their Biotic and Abiotic Environment through the Lens of Secretomics)

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29 pages, 1573 KiB

Open AccessReview

Co-Stimulatory Receptor Signaling in CAR-T Cells

by Mackenzie M. Honikel and Scott H. Olejniczak

Biomolecules 2022, 12(9), 1303; https://doi.org/10.3390/biom12091303 - 15 Sep 2022

Cited by 12 | Viewed by 6243

Abstract

T cell engineering strategies have emerged as successful immunotherapeutic approaches for the treatment of human cancer. Chimeric Antigen Receptor T (CAR-T) cell therapy represents a prominent synthetic biology approach to re-direct the specificity of a patient’s autologous T cells toward a desired tumor [...] Read more.

T cell engineering strategies have emerged as successful immunotherapeutic approaches for the treatment of human cancer. Chimeric Antigen Receptor T (CAR-T) cell therapy represents a prominent synthetic biology approach to re-direct the specificity of a patient’s autologous T cells toward a desired tumor antigen. CAR-T therapy is currently FDA approved for the treatment of hematological malignancies, including subsets of B cell lymphoma, acute lymphoblastic leukemia (ALL) and multiple myeloma. Mechanistically, CAR-mediated recognition of a tumor antigen results in propagation of T cell activation signals, including a co-stimulatory signal, resulting in CAR-T cell activation, proliferation, evasion of apoptosis, and acquisition of effector functions. The importance of including a co-stimulatory domain in CARs was recognized following limited success of early iteration CAR-T cell designs lacking co-stimulation. Today, all CAR-T cells in clinical use contain either a CD28 or 4-1BB co-stimulatory domain. Preclinical investigations are exploring utility of including additional co-stimulatory molecules such as ICOS, OX40 and CD27 or various combinations of multiple co-stimulatory domains. Clinical and preclinical evidence implicates the co-stimulatory signal in several aspects of CAR-T cell therapy including response kinetics, persistence and durability, and toxicity profiles each of which impact the safety and anti-tumor efficacy of this immunotherapy. Herein we provide an overview of CAR-T cell co-stimulation by the prototypical receptors and discuss current and emerging strategies to modulate co-stimulatory signals to enhance CAR-T cell function. Full article

(This article belongs to the Special Issue Immunotherapy and Cancer)

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22 pages, 4209 KiB

Open AccessArticle

The Role of Disordered Regions in Orchestrating the Properties of Multidomain Proteins: The SARS-CoV-2 Nucleocapsid Protein and Its Interaction with Enoxaparin

by Marco Schiavina, Letizia Pontoriero, Giuseppe Tagliaferro, Roberta Pierattelli and Isabella C. Felli

Biomolecules 2022, 12(9), 1302; https://doi.org/10.3390/biom12091302 - 15 Sep 2022

Cited by 3 | Viewed by 2234

Abstract

Novel and efficient strategies need to be developed to interfere with the SARS-CoV-2 virus. One of the most promising pharmaceutical targets is the nucleocapsid protein (N), responsible for genomic RNA packaging. N is composed of two folded domains and three intrinsically disordered regions [...] Read more.

Novel and efficient strategies need to be developed to interfere with the SARS-CoV-2 virus. One of the most promising pharmaceutical targets is the nucleocapsid protein (N), responsible for genomic RNA packaging. N is composed of two folded domains and three intrinsically disordered regions (IDRs). The globular RNA binding domain (NTD) and the tethered IDRs are rich in positively charged residues. The study of the interaction of N with polyanions can thus help to elucidate one of the key driving forces responsible for its function, i.e., electrostatics. Heparin, one of the most negatively charged natural polyanions, has been used to contrast serious cases of COVID-19 infection, and we decided to study its interaction with N at the molecular level. We focused on the NTR construct, which comprises the NTD and two flanking IDRs, and on the NTD construct in isolation. We characterized this interaction using different nuclear magnetic resonance approaches and isothermal titration calorimetry. With these tools, we were able to identify an extended surface of NTD involved in the interaction. Moreover, we assessed the importance of the IDRs in increasing the affinity for heparin, highlighting how different tracts of these flexible regions modulate the interaction. Full article

(This article belongs to the Special Issue Structural Disorder within Viral Proteins: A Themed Issue Dedicated to Doctor Sonia Longhi)

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12 pages, 842 KiB

Open AccessArticle

The Association of Metformin, Other Antidiabetic Medications and Statins on the Prognosis of Rectal Cancer in Patients with Type 2 Diabetes: A Retrospective Cohort Study

by Sami Erkinantti, Ari Hautakoski, Reijo Sund, Martti Arffman, Elina Urpilainen, Ulla Puistola, Esa Läärä, Arja Jukkola and Peeter Karihtala

Biomolecules 2022, 12(9), 1301; https://doi.org/10.3390/biom12091301 - 15 Sep 2022

Cited by 1 | Viewed by 1687

Abstract

Metformin and statin use have been associated with an improved prognosis for colorectal cancer in persons with type 2 diabetes (T2D). Data regarding rectal cancer (RC) have been inconclusive; therefore, we investigated the issue with high-quality data and a robust study design. We [...] Read more.

Metformin and statin use have been associated with an improved prognosis for colorectal cancer in persons with type 2 diabetes (T2D). Data regarding rectal cancer (RC) have been inconclusive; therefore, we investigated the issue with high-quality data and a robust study design. We identified 1271 eligible patients with T2D and incident RC between 1998 and 2011 from the Diabetes in Finland (FinDM) database. Cox models were fitted for cause-specific mortality rates to obtain adjusted estimates of the hazard ratios (HR) with 95% confidence intervals (CI) in relation to use of antidiabetic medication (ADM) and statins before the RC diagnosis and for post-diagnostic use in a time-dependent exposure manner. No sufficient evidence was found for either pre- or post-diagnostic metformin use and RC mortality (HR 0.96, 95% CI 0.67–1.38, and 0.70, 95% CI 0.45–1.10, respectively) when compared to other oral ADMs. Both pre- and post-diagnostic statin use appeared to be inversely associated with mortality from RC (HR 0.77 95% CI 0.63–0.94, and 0.57, 95% CI 0.42–0.78, respectively). Our study was inconclusive as to the association of metformin use with the prognosis of RC, but statin use was found to predict reduced mortality, both from RC and from other causes of death in persons with T2D. Full article

(This article belongs to the Special Issue New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine)

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24 pages, 2979 KiB

Open AccessEditor’s ChoiceArticle

Oviductal Extracellular Vesicles Enhance Porcine In Vitro Embryo Development by Modulating the Embryonic Transcriptome

by Agostinho Soares de Alcântara-Neto, Cristina Cuello, Rustem Uzbekov, Stefan Bauersachs, Pascal Mermillod and Carmen Almiñana

Biomolecules 2022, 12(9), 1300; https://doi.org/10.3390/biom12091300 - 15 Sep 2022

Cited by 8 | Viewed by 2242

Abstract

Oviductal extracellular vesicles (oEVs) have been identified as important components of the oviductal fluid (OF) and have been pointed to as key modulators of gamete/embryo-maternal interactions. Here, we determined the functional impact of oEVs on embryo development and the embryonic transcriptome in porcine. [...] Read more.

Oviductal extracellular vesicles (oEVs) have been identified as important components of the oviductal fluid (OF) and have been pointed to as key modulators of gamete/embryo-maternal interactions. Here, we determined the functional impact of oEVs on embryo development and the embryonic transcriptome in porcine. Experiment 1 examined the effect of oEVs and OF on embryo development. In vitro-produced embryos were cultured with oEVs or OF for 2 or 7 days using an in vitro sequential system or without supplementation (control). Experiment 2 analyzed transcriptomic alterations of EV-treated embryos versus control and the oEVs RNA cargo by RNA-sequencing. Two days of EV treatment enhanced embryo development over time when compared to other treatments. Different RNA expression profiles between embryos treated with EVs for two or seven days and untreated controls were obtained, with 54 and 59 differentially expressed (DE) genes and six and seven DE miRNAs, respectively. In oEV RNA cargo, 12,998 RNAs and 163 miRNAs were identified. Integrative analyses pointed to specific oEV components that might act as modulators of the embryonic transcriptome, such as S100A11, ANXA2 or miR-21-5p. Overall, the findings suggested that oEVs could be a potential strategy to improve porcine IVP outcomes, particularly by using two days of EV treatment. Full article

(This article belongs to the Special Issue Biomolecules in Parental–Embryo Communication and Implantation)

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23 pages, 886 KiB

Open AccessReview

Progesterone as an Anti-Inflammatory Drug and Immunomodulator: New Aspects in Hormonal Regulation of the Inflammation

by Tatiana A. Fedotcheva, Nadezhda I. Fedotcheva and Nikolai L. Shimanovsky

Biomolecules 2022, 12(9), 1299; https://doi.org/10.3390/biom12091299 - 14 Sep 2022

Cited by 27 | Viewed by 4735

Abstract

The specific regulation of inflammatory processes by steroid hormones has been actively studied in recent years, especially by progesterone (P₄) and progestins. The mechanisms of the anti-inflammatory and immunomodulatory P₄ action are not fully clear. The anti-inflammatory effects of P [...] Read more.

The specific regulation of inflammatory processes by steroid hormones has been actively studied in recent years, especially by progesterone (P₄) and progestins. The mechanisms of the anti-inflammatory and immunomodulatory P₄ action are not fully clear. The anti-inflammatory effects of P₄ can be defined as nonspecific, associated with the inhibition of NF-κB and COX, as well as the inhibition of prostaglandin synthesis, or as specific, associated with the regulation of T-cell activation, the regulation of the production of pro- and anti-inflammatory cytokines, and the phenomenon of immune tolerance. The specific anti-inflammatory effects of P₄ and its derivatives (progestins) can also include the inhibition of proliferative signaling pathways and the antagonistic action against estrogen receptor beta-mediated signaling as a proinflammatory and mitogenic factor. The anti-inflammatory action of P₄ is accomplished through the participation of progesterone receptor (PR) chaperones HSP90, as well as immunophilins FKBP51 and FKBP52, which are the validated targets of clinically approved immunosuppressive drugs. The immunomodulatory and anti-inflammatory effects of HSP90 inhibitors, tacrolimus and cyclosporine, are manifested, among other factors, due to their participation in the formation of an active ligand–receptor complex of P₄ and their interaction with its constituent immunophilins. Pharmacological agents such as HSP90 inhibitors can restore the lost anti-inflammatory effect of glucocorticoids and P₄ in chronic inflammatory and autoimmune diseases. By regulating the activity of FKBP51 and FKBP52, it is possible to increase or decrease hormonal signaling, as well as restore it during the development of hormone resistance. The combined action of immunophilin suppressors with steroid hormones may be a promising strategy in the treatment of chronic inflammatory and autoimmune diseases, including endometriosis, stress-related disorders, rheumatoid arthritis, and miscarriages. Presumably, the hormone receptor- and immunophilin-targeted drugs may act synergistically, allowing for a lower dose of each. Full article

(This article belongs to the Section Molecular Medicine)

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11 pages, 3505 KiB

Open AccessReview

Clinical and Mechanistic Review of Amiodarone-Associated Optic Neuropathy

by Reece Mitchell and Joseph Chacko

Biomolecules 2022, 12(9), 1298; https://doi.org/10.3390/biom12091298 - 14 Sep 2022

Cited by 3 | Viewed by 1828

Abstract

Amiodarone-associated optic neuropathy (AAON) is a complex clinical diagnosis, requiring distinction from non-arteritic ischemic optic neuropathy (NAION) due to a shared at-risk patient population. Diagnosis of AAON is complicated by a varied clinical presentation and incomplete pathophysiologic mechanisms. This article reviews pertinent literature [...] Read more.

Amiodarone-associated optic neuropathy (AAON) is a complex clinical diagnosis, requiring distinction from non-arteritic ischemic optic neuropathy (NAION) due to a shared at-risk patient population. Diagnosis of AAON is complicated by a varied clinical presentation and incomplete pathophysiologic mechanisms. This article reviews pertinent literature for describing and clinically delineating AAON from NAION, as well as newly reported protective mechanisms of insulin-like growth factor 1 (IGF-1) and PI3K/Akt against amiodarone-induced oxidative and apoptotic injury in retinal ganglion and pigment epithelial cells. These studies offer a basis for exploring mechanisms of amiodarone toxicity in the optic nerve. Full article

(This article belongs to the Special Issue New Discoveries in Retinal Cell Degeneration and Retinal Diseases)

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18 pages, 831 KiB

Open AccessReview

Conservation Biology and Reproduction in a Time of Developmental Plasticity

by William V. Holt and Pierre Comizzoli

Biomolecules 2022, 12(9), 1297; https://doi.org/10.3390/biom12091297 - 14 Sep 2022

Cited by 3 | Viewed by 2015

Abstract

The objective of this review is to ask whether, and how, principles in conservation biology may need to be revisited in light of new knowledge about the power of epigenetics to alter developmental pathways. Importantly, conservation breeding programmes, used widely by zoological parks [...] Read more.

The objective of this review is to ask whether, and how, principles in conservation biology may need to be revisited in light of new knowledge about the power of epigenetics to alter developmental pathways. Importantly, conservation breeding programmes, used widely by zoological parks and aquariums, may appear in some cases to reduce fitness by decreasing animals’ abilities to cope when confronted with the ‘wild side’ of their natural habitats. Would less comfortable captive conditions lead to the selection of individuals that, despite being adapted to life in a captive environment, be better able to thrive if relocated to a more natural environment? While threatened populations may benefit from advanced reproductive technologies, these may actually induce undesirable epigenetic changes. Thus, there may be inherent risks to the health and welfare of offspring (as is suspected in humans). Advanced breeding technologies, especially those that aim to regenerate the rarest species using stem cell reprogramming and artificial gametes, may also lead to unwanted epigenetic modifications. Current knowledge is still incomplete, and therefore ethical decisions about novel breeding methods remain controversial and difficult to resolve. Full article

(This article belongs to the Special Issue Biomolecules in Parental–Embryo Communication and Implantation)

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