Biomolecules

25 pages, 4177 KiB

Open AccessEditor’s ChoiceReview

Piezoelectric Signals in Vascularized Bone Regeneration

by Delfo D’Alessandro, Claudio Ricci, Mario Milazzo, Giovanna Strangis, Francesca Forli, Gabriele Buda, Mario Petrini, Stefano Berrettini, Mohammed Jasim Uddin, Serena Danti and Paolo Parchi

Biomolecules 2021, 11(11), 1731; https://doi.org/10.3390/biom11111731 - 20 Nov 2021

Cited by 35 | Viewed by 5874

Abstract

The demand for bone substitutes is increasing in Western countries. Bone graft substitutes aim to provide reconstructive surgeons with off-the-shelf alternatives to the natural bone taken from humans or animal species. Under the tissue engineering paradigm, biomaterial scaffolds can be designed by incorporating [...] Read more.

The demand for bone substitutes is increasing in Western countries. Bone graft substitutes aim to provide reconstructive surgeons with off-the-shelf alternatives to the natural bone taken from humans or animal species. Under the tissue engineering paradigm, biomaterial scaffolds can be designed by incorporating bone stem cells to decrease the disadvantages of traditional tissue grafts. However, the effective clinical application of tissue-engineered bone is limited by insufficient neovascularization. As bone is a highly vascularized tissue, new strategies to promote both osteogenesis and vasculogenesis within the scaffolds need to be considered for a successful regeneration. It has been demonstrated that bone and blood vases are piezoelectric, namely, electric signals are locally produced upon mechanical stimulation of these tissues. The specific effects of electric charge generation on different cells are not fully understood, but a substantial amount of evidence has suggested their functional and physiological roles. This review summarizes the special contribution of piezoelectricity as a stimulatory signal for bone and vascular tissue regeneration, including osteogenesis, angiogenesis, vascular repair, and tissue engineering, by considering different stem cell sources entailed with osteogenic and angiogenic potential, aimed at collecting the key findings that may enable the development of successful vascularized bone replacements useful in orthopedic and otologic surgery. Full article

(This article belongs to the Special Issue New Insights into Stem Cell Regulation)

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15 pages, 2391 KiB

Open AccessEditor’s ChoiceArticle

Assaying Paenibacillus alvei CsaB-Catalysed Ketalpyruvyltransfer to Saccharides by Measurement of Phosphate Release

by Fiona F. Hager-Mair, Cordula Stefanović, Charlie Lim, Katharina Webhofer, Simon Krauter, Markus Blaukopf, Roland Ludwig, Paul Kosma and Christina Schäffer

Biomolecules 2021, 11(11), 1732; https://doi.org/10.3390/biom11111732 - 20 Nov 2021

Cited by 2 | Viewed by 2493

Abstract

Ketalpyruvyltransferases belong to a widespread but little investigated class of enzymes, which utilise phosphoenolpyruvate (PEP) for the pyruvylation of saccharides. Pyruvylated saccharides play pivotal biological roles, ranging from protein binding to virulence. Limiting factors for the characterisation of ketalpyruvyltransferases are the availability of [...] Read more.

Ketalpyruvyltransferases belong to a widespread but little investigated class of enzymes, which utilise phosphoenolpyruvate (PEP) for the pyruvylation of saccharides. Pyruvylated saccharides play pivotal biological roles, ranging from protein binding to virulence. Limiting factors for the characterisation of ketalpyruvyltransferases are the availability of cognate acceptor substrates and a straightforward enzyme assay. We report on a fast ketalpyruvyltransferase assay based on the colorimetric detection of phosphate released during pyruvyltransfer from PEP onto the acceptor via complexation with Malachite Green and molybdate. To optimise the assay for the model 4,6-ketalpyruvyl::ManNAc-transferase CsaB from Paenibacillus alvei, a β-d-ManNAc-α-d-GlcNAc-diphosphoryl-11-phenoxyundecyl acceptor mimicking an intermediate of the bacterium’s cell wall glycopolymer biosynthesis pathway, upon which CsaB is naturally active, was produced chemo-enzymatically and used together with recombinant CsaB. Optimal assay conditions were 5 min reaction time at 37 °C and pH 7.5, followed by colour development for 1 h at 37 °C and measurement of absorbance at 620 nm. The structure of the generated pyruvylated product was confirmed by NMR spectroscopy. Using the established assay, the first kinetic constants of a 4,6-ketalpyuvyl::ManNAc-transferase could be determined; upon variation of the acceptor and PEP concentrations, a K_{M, PEP} of 19.50 ± 3.50 µM and k_{cat, PEP} of 0.21 ± 0.01 s⁻¹ as well as a K_{M, Acceptor} of 258 ± 38 µM and a k_{cat, Acceptor} of 0.15 ± 0.01 s⁻¹ were revealed. P. alvei CsaB was inactive on synthetic pNP-β-d-ManNAc and β-d-ManNAc-β-d-GlcNAc-1-OMe, supporting the necessity of a complex acceptor substrate. Full article

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

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15 pages, 1675 KiB

Open AccessEditor’s ChoiceArticle

Dynamic DNA Methylation Changes in the COMT Gene Promoter Region in Response to Mental Stress and Its Modulation by Transcranial Direct Current Stimulation

by Ariane Wiegand, Arne Blickle, Christof Brückmann, Simone Weller, Vanessa Nieratschker and Christian Plewnia

Biomolecules 2021, 11(11), 1726; https://doi.org/10.3390/biom11111726 - 19 Nov 2021

Cited by 7 | Viewed by 2402

Abstract

Changes in epigenetic modifications present a mechanism how environmental factors, such as the experience of stress, can alter gene regulation. While stress-related disorders have consistently been associated with differential DNA methylation, little is known about the time scale in which these alterations emerge. [...] Read more.

Changes in epigenetic modifications present a mechanism how environmental factors, such as the experience of stress, can alter gene regulation. While stress-related disorders have consistently been associated with differential DNA methylation, little is known about the time scale in which these alterations emerge. We investigated dynamic DNA methylation changes in whole blood of 42 healthy male individuals in response to a stressful cognitive task, its association with concentration changes in cortisol, and its modulation by transcranial direct current stimulation (tDCS). We observed a continuous increase in COMT promotor DNA methylation which correlated with higher saliva cortisol levels and was still detectable one week later. However, this lasting effect was suppressed by concurrent activity-enhancing anodal tDCS to the dorsolateral prefrontal cortex. Our findings support the significance of gene-specific DNA methylation in whole blood as potential biomarkers for stress-related effects. Moreover, they suggest alternative molecular mechanisms possibly involved in lasting behavioral effects of tDCS. Full article

(This article belongs to the Special Issue Key Advances in Brain Stimulation)

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12 pages, 1373 KiB

Open AccessEditor’s ChoiceArticle

Rhamnolipids as a Tool for Eradication of Trichosporon cutaneum Biofilm

by Olga Maťátková, Irena Kolouchová, Kristýna Lokočová, Jana Michailidu, Petr Jaroš, Markéta Kulišová, Tomáš Řezanka and Jan Masák

Biomolecules 2021, 11(11), 1727; https://doi.org/10.3390/biom11111727 - 19 Nov 2021

Cited by 5 | Viewed by 1821

Abstract

Microbial biofilms formed by pathogenic and antibiotic-resistant microorganisms represent a serious threat for public health in medicine and many industrial branches. Biofilms are involved in many persistent and chronic infections, the biofouling of water and food contamination. Therefore, current research is involved in [...] Read more.

Microbial biofilms formed by pathogenic and antibiotic-resistant microorganisms represent a serious threat for public health in medicine and many industrial branches. Biofilms are involved in many persistent and chronic infections, the biofouling of water and food contamination. Therefore, current research is involved in the development of new treatment strategies. Biofilm is a complex system, and thus all aspects of the measurement and monitoring of its growth and eradication in various conditions, including static and dynamic flow, are issues of great importance. The antibiofilm character of rhamnolipid mixtures produced by four Pseudomonas aeruginosa strains was studied under different conditions. For this purpose, the biofilm of opportunistic pathogen Trichosporon cutaneum was used and treated under static conditions (microscope glass coverslip in a Petri dish) and under dynamic conditions (a single-channel flow cell). The results show that the biological activity of rhamnolipids depends both on their properties and on the conditions of the biofilm formation. Therefore, this aspect must be taken into account when planning the experimental or application design. Full article

(This article belongs to the Collection Feature Papers in Biomacromolecules: Lipids)

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18 pages, 958 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Rare Does Not Mean Worthless: How Rare Diseases Have Shaped Neurodevelopment Research in the NGS Era

by Mattia Zaghi, Federica Banfi, Edoardo Bellini and Alessandro Sessa

Biomolecules 2021, 11(11), 1713; https://doi.org/10.3390/biom11111713 - 17 Nov 2021

Cited by 4 | Viewed by 2903

Abstract

The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and [...] Read more.

The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and rare genomic variants and to perform detailed phenotypic characterizations of both physiological organs and experimental models. Recent years have seen the introduction of multiple techniques using NGS to profile transcription, DNA and chromatin modifications, protein binding, etc., that are now allowing us to profile cells in bulk or even at a single-cell level. Although rare and ultra-rare diseases only affect a few people, each of these diseases represent scholarly cases from which a great deal can be learned about the pathological and physiological function of genes, pathways, and mechanisms. Therefore, for rare diseases, state-of-the-art investigations using NGS have double valence: their genomic cause (new variants) and the characterize the underlining the mechanisms associated with them (discovery of gene function) can be found. In a non-exhaustive manner, this review will outline the main usage of NGS-based techniques for the diagnosis and characterization of neurodevelopmental disorders (NDDs), under whose umbrella many rare and ultra-rare diseases fall. Full article

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

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13 pages, 1260 KiB

Open AccessEditor’s ChoiceArticle

Late-Stage Functionalisation of Polycyclic (N-Hetero-) Aromatic Hydrocarbons by Detoxifying CYP5035S7 Monooxygenase of the White-Rot Fungus Polyporus arcularius

by Nico D. Fessner, Christopher Grimm, Wolfgang Kroutil and Anton Glieder

Biomolecules 2021, 11(11), 1708; https://doi.org/10.3390/biom11111708 - 17 Nov 2021

Cited by 4 | Viewed by 3364

Abstract

Functionalisation of polycyclic aromatic hydrocarbons (PAHs) and their N-heteroarene analogues (NPAHs) is a tedious synthetic endeavour that requires diverse bottom-up approaches. Cytochrome P450 enzymes of white-rot fungi were shown to participate in the fungal detoxification of xenobiotics and environmental hazards via hydroxylation [...] Read more.

Functionalisation of polycyclic aromatic hydrocarbons (PAHs) and their N-heteroarene analogues (NPAHs) is a tedious synthetic endeavour that requires diverse bottom-up approaches. Cytochrome P450 enzymes of white-rot fungi were shown to participate in the fungal detoxification of xenobiotics and environmental hazards via hydroxylation of PAH compounds. In this paper, the recently discovered activity of the monooxygenase CYP5035S7 towards (N)PAHs was investigated in detail, and products formed from the substrates azulene, acenaphthene, fluorene, anthracene, and phenanthrene by whole-cell biocatalysis were isolated and characterised. The observed regioselectivity of CYP5035S7 could be explained by a combination of the substrate’s electron density and steric factors influencing the substrate orientation giving insight into the active-site geometry of the enzyme. Full article

(This article belongs to the Special Issue Oxygenases: Exploiting Their Catalytic Power)

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16 pages, 2524 KiB

Open AccessEditor’s ChoiceArticle

Characterization of the Biomechanical Properties of Skin Using Vibrational Optical Coherence Tomography: Do Changes in the Biomechanical Properties of Skin Stroma Reflect Structural Changes in the Extracellular Matrix of Cancerous Lesions?

by Frederick H. Silver, Nikita Kelkar, Tanmay Deshmukh, Kelly Ritter, Nicole Ryan and Hari Nadiminti

Biomolecules 2021, 11(11), 1712; https://doi.org/10.3390/biom11111712 - 17 Nov 2021

Cited by 8 | Viewed by 2373

Abstract

Early detection of skin cancer is of critical importance since the five-year survival rate for early detected skin malignancies is 99% but drops to 27% for cancer that has spread to distant lymph nodes and other organs. Over 2.5 million benign skin biopsies [...] Read more.

Early detection of skin cancer is of critical importance since the five-year survival rate for early detected skin malignancies is 99% but drops to 27% for cancer that has spread to distant lymph nodes and other organs. Over 2.5 million benign skin biopsies (55% of the total) are performed each year in the US at an alarming cost of USD ~2.5 B. Therefore there is an unmet need for novel non-invasive diagnostic approaches to better differentiate between cancerous and non-cancerous lesions, especially in cases when there is a legitimate doubt that a biopsy may be required. The purpose of this study is to determine whether the differences in the extracellular matrices among normal skin, actinic keratosis (AK), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) can be assessed non-invasively using vibrational optical coherence tomography (VOCT). VOCT is a new diagnostic technology that uses infrared light and audible sound applied transversely to tissue to measure the resonant frequencies and elastic moduli of cells, dermal collagen, blood vessels and fibrous tissue in skin and lesion stroma without physically touching the skin. Our results indicate that the cellular, vascular and fibrotic resonant frequency peaks are altered in AK, BCC and SCC compared to those peaks observed in normal skin and can serve as physical biomarkers defining the differences between benign and cancerous skin lesions. The resonant frequency is increased from a value of 50 Hz in normal skin to a value of about 80 Hz in pre- and cancerous lesions. A new vascular peak is seen at 130 Hz in cancerous lesions that may reflect the formation of new tumor blood vessels. The peak at 260 Hz is similar to that seen in the skin of a subject with Scleroderma and skin wounds that have healed. The peak at 260 Hz appears to be associated with the deposition of large amounts of stiff fibrous collagen in the stroma surrounding cancerous lesions. Based on the results of this pilot study, VOCT can be used to non-invasively identify physical biomarkers that can help differentiate between benign and cancerous skin lesions. The appearance of new stiff cellular, fragile new vessels, and stiff fibrous material based on resonant frequency peaks and changes in the extracellular matrix can be used as a fingerprint of pre- and cancerous skin lesions. Full article

(This article belongs to the Special Issue Biomolecular Signatures in Reactive Stroma—Inflammation and Wound Healing)

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20 pages, 10229 KiB

Open AccessEditor’s ChoiceArticle

Three-Dimensional Virtual and Printed Prototypes in Complex Congenital and Pediatric Cardiac Surgery—A Multidisciplinary Team-Learning Experience

by Laszlo Kiraly, Nishant C. Shah, Osama Abdullah, Oraib Al-Ketan and Reza Rowshan

Biomolecules 2021, 11(11), 1703; https://doi.org/10.3390/biom11111703 - 16 Nov 2021

Cited by 11 | Viewed by 5817

Abstract

Three-dimensional (3D) virtual modeling and printing advances individualized medicine and surgery. In congenital cardiac surgery, 3D virtual models and printed prototypes offer advantages of better understanding of complex anatomy, hands-on preoperative surgical planning and emulation, and improved communication within the multidisciplinary team and [...] Read more.

Three-dimensional (3D) virtual modeling and printing advances individualized medicine and surgery. In congenital cardiac surgery, 3D virtual models and printed prototypes offer advantages of better understanding of complex anatomy, hands-on preoperative surgical planning and emulation, and improved communication within the multidisciplinary team and to patients. We report our single center team-learning experience about the realization and validation of possible clinical benefits of 3D-printed models in surgical planning of complex congenital cardiac surgery. CT-angiography raw data were segmented into 3D-virtual models of the heart-great vessels. Prototypes were 3D-printed as rigid “blood-volume” and flexible “hollow”. The accuracy of the models was evaluated intraoperatively. Production steps were realized in the framework of a clinical/research partnership. We produced 3D prototypes of the heart-great vessels for 15 case scenarios (nine males, median age: 11 months) undergoing complex intracardiac repairs. Parity between 3D models and intraoperative structures was within 1 mm range. Models refined diagnostics in 13/15, provided new anatomic information in 9/15. As a team-learning experience, all complex staged redo-operations (13/15; Aristotle-score mean: 10.64 ± 1.95) were rehearsed on the 3D models preoperatively. 3D-printed prototypes significantly contributed to an improved/alternative operative plan on the surgical approach, modification of intracardiac repair in 13/15. No operative morbidity/mortality occurred. Our clinical/research partnership provided coverage for the extra time/labor and material/machinery not financed by insurance. 3D-printed models provided a team-learning experience and contributed to the safety of complex congenital cardiac surgeries. A clinical/research partnership may open avenues for bioprinting of patient-specific implants. Full article

(This article belongs to the Special Issue Usefulness and Clinical Applications of 3D Printing in Cardiovascular Diseases)

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Graphical abstract

19 pages, 2572 KiB

Open AccessEditor’s ChoiceReview

Co-Evolution of Breast Milk Lipid Signaling and Thermogenic Adipose Tissue

by Tamás Röszer

Biomolecules 2021, 11(11), 1705; https://doi.org/10.3390/biom11111705 - 16 Nov 2021

Cited by 9 | Viewed by 3366

Abstract

Breastfeeding is a unique and defining behavior of mammals and has a fundamental role in nourishing offspring by supplying a lipid-rich product that is utilized to generate heat and metabolic fuel. Heat generation from lipids is a feature of newborn mammals and is [...] Read more.

Breastfeeding is a unique and defining behavior of mammals and has a fundamental role in nourishing offspring by supplying a lipid-rich product that is utilized to generate heat and metabolic fuel. Heat generation from lipids is a feature of newborn mammals and is mediated by the uncoupling of mitochondrial respiration in specific fat depots. Breastfeeding and thermogenic adipose tissue have a shared evolutionary history: both have evolved in the course of homeothermy evolution; breastfeeding mammals are termed “thermolipials”, meaning “animals with warm fat”. Beyond its heat-producing capacity, thermogenic adipose tissue is also necessary for proper lipid metabolism and determines adiposity in offspring. Recent advances have demonstrated that lipid metabolism in infants is orchestrated by breast milk lipid signals, which establish mother-to-child signaling and control metabolic development in the infant. Breastfeeding rates are declining worldwide, and are paralleled by an alarming increase in childhood obesity, which at least in part may have its roots in the impaired metabolic control by breast milk lipid signals. Full article

(This article belongs to the Special Issue Breast Milk-Derived Biomolecules in Human Health)

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22 pages, 2366 KiB

Open AccessEditor’s ChoiceReview

Expanding the Disorder-Function Paradigm in the C-Terminal Tails of Erbbs

by Louise Pinet, Nadine Assrir and Carine van Heijenoort

Biomolecules 2021, 11(11), 1690; https://doi.org/10.3390/biom11111690 - 14 Nov 2021

Cited by 2 | Viewed by 2503

Abstract

ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal [...] Read more.

ErbBs are receptor tyrosine kinases involved not only in development, but also in a wide variety of diseases, particularly cancer. Their extracellular, transmembrane, juxtamembrane, and kinase folded domains were described extensively over the past 20 years, structurally and functionally. However, their whole C-terminal tails (CTs) following the kinase domain were only described at atomic resolution in the last 4 years. They were shown to be intrinsically disordered. The CTs are known to be tyrosine-phosphorylated when the activated homo- or hetero-dimers of ErbBs are formed. Their phosphorylation triggers interaction with phosphotyrosine binding (PTB) or Src Homology 2 (SH2) domains and activates several signaling pathways controling cellular motility, proliferation, adhesion, and apoptosis. Beyond this passive role of phosphorylated domain and site display for partners, recent structural and function studies unveiled active roles in regulation of phosphorylation and interaction: the CT regulates activity of the kinase domain; different phosphorylation states have different compaction levels, potentially modulating the succession of phosphorylation events; and prolines have an important role in structure, dynamics, and possibly regulatory interactions. Here, we review both the canonical role of the disordered CT domains of ErbBs as phosphotyrosine display domains and the recent findings that expand the known range of their regulation functions linked to specific structural and dynamic features. Full article

(This article belongs to the Collection Protein Intrinsic Disorder: Role in Signaling, Regulation and Membrane-Less Organelle Formation)

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11 pages, 1607 KiB

Open AccessEditor’s ChoiceReview

An Asp to Strike Out Cancer? Therapeutic Possibilities Arising from Aspartate’s Emerging Roles in Cell Proliferation and Survival

by Iiro Taneli Helenius, Hanumantha Rao Madala and Jing-Ruey Joanna Yeh

Biomolecules 2021, 11(11), 1666; https://doi.org/10.3390/biom11111666 - 10 Nov 2021

Cited by 15 | Viewed by 3203

Abstract

A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable [...] Read more.

A better understanding of the metabolic constraints of a tumor may lead to more effective anticancer treatments. Evidence has emerged in recent years shedding light on a crucial aspartate dependency of many tumor types. As a precursor for nucleotide synthesis, aspartate is indispensable for cell proliferation. Moreover, the malate–aspartate shuttle plays a key role in redox balance, and a deficit in aspartate can lead to oxidative stress. It is now recognized that aspartate biosynthesis is largely governed by mitochondrial metabolism, including respiration and glutaminolysis in cancer cells. Therefore, under conditions that suppress mitochondrial metabolism, including mutations, hypoxia, or chemical inhibitors, aspartate can become a limiting factor for tumor growth and cancer cell survival. Notably, aspartate availability has been associated with sensitivity or resistance to various therapeutics that are presently in the clinic or in clinical trials, arguing for a critical need for more effective aspartate-targeting approaches. In this review, we present current knowledge of the metabolic roles of aspartate in cancer cells and describe how cancer cells maintain aspartate levels under different metabolic states. We also highlight several promising aspartate level-modulating agents that are currently under investigation. Full article

(This article belongs to the Special Issue Role of the Mitochondrial Stress Response in Human Cancer Progression)

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17 pages, 1711 KiB

Open AccessEditor’s ChoiceArticle

Genetic and Metabolic Determinants of Atrial Fibrillation in a General Population Sample: The CHRIS Study

by David B. Emmert, Vladimir Vukovic, Nikola Dordevic, Christian X. Weichenberger, Chiara Losi, Yuri D’Elia, Claudia Volpato, Vinicius V. Hernandes, Martin Gögele, Luisa Foco, Giulia Pontali, Deborah Mascalzoni, Francisco S. Domingues, Rupert Paulmichl, Peter P. Pramstaller, Cristian Pattaro, Alessandra Rossini, Johannes Rainer, Christian Fuchsberger and Marzia De Bortoli

Biomolecules 2021, 11(11), 1663; https://doi.org/10.3390/biom11111663 - 9 Nov 2021

Cited by 6 | Viewed by 2921

Abstract

Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health [...] Read more.

Atrial fibrillation (AF) is a supraventricular arrhythmia deriving from uncoordinated electrical activation with considerable associated morbidity and mortality. To expand the limited understanding of AF biological mechanisms, we performed two screenings, investigating the genetic and metabolic determinants of AF in the Cooperative Health Research in South Tyrol study. We found 110 AF cases out of 10,509 general population individuals. A genome-wide association scan (GWAS) identified two novel loci (p-value < 5 × 10⁻⁸) around SNPs rs745582874, next to gene PBX1, and rs768476991, within gene PCCA, with genotype calling confirmed by Sanger sequencing. Risk alleles at both SNPs were enriched in a family detected through familial aggregation analysis of the phenotype, and both rare alleles co-segregated with AF. The metabolic screening of 175 metabolites, in a subset of individuals, revealed a 41% lower concentration of lysophosphatidylcholine lysoPC a C20:3 in AF cases compared to controls (p-adj = 0.005). The genetic findings, combined with previous evidence, indicate that the two identified GWAS loci may be considered novel genetic rare determinants for AF. Considering additionally the association of lysoPC a C20:3 with AF by metabolic screening, our results demonstrate the valuable contribution of the combined genomic and metabolomic approach in studying AF in large-scale population studies. Full article

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

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12 pages, 2915 KiB

Open AccessEditor’s ChoiceArticle

Data-Driven Analysis of Fluorination of Ligands of Aminergic G Protein Coupled Receptors

by Wojciech Pietruś, Rafał Kurczab, Dagmar Stumpfe, Andrzej J. Bojarski and Jürgen Bajorath

Biomolecules 2021, 11(11), 1647; https://doi.org/10.3390/biom11111647 - 8 Nov 2021

Cited by 2 | Viewed by 1937

Abstract

Currently, G protein-coupled receptors are the targets with the highest number of drugs in many therapeutic areas. Fluorination has become a common strategy in designing highly active biological compounds, as evidenced by the steadily increasing number of newly approved fluorine-containing drugs. Herein, we [...] Read more.

Currently, G protein-coupled receptors are the targets with the highest number of drugs in many therapeutic areas. Fluorination has become a common strategy in designing highly active biological compounds, as evidenced by the steadily increasing number of newly approved fluorine-containing drugs. Herein, we identified in the ChEMBL database and analysed 1554 target-based FSAR sets (non-fluorinated compounds and their fluorinated analogues) comprising 966 unique non-fluorinated and 2457 unique fluorinated compounds active against 33 different aminergic GPCRs. Although a relatively small number of activity cliffs (defined as a pair of structurally similar compounds showing significant differences of activity −ΔpPot > 1.7) was found in FSAR sets, it is clear that appropriately introduced fluorine can increase ligand potency more than 50-fold. The analysis of matched molecular pairs (MMPs) networks indicated that the fluorination of the aromatic ring showed no clear trend towards a positive or negative effect on affinity; however, a favourable site for a positive potency effect of fluorination was the ortho position. Fluorination of aliphatic fragments more often led to a decrease in biological activity. The results may constitute the rules of thumb for fluorination of aminergic receptor ligands and provide insights into the role of fluorine substitutions in medicinal chemistry. Full article

(This article belongs to the Collection In Silico Drug Design for GPCRs: Big Data for Small Molecule Discovery)

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19 pages, 1175 KiB

Open AccessEditor’s ChoiceReview

miRNA as a Modulator of Immunotherapy and Immune Response in Melanoma

by Mai-Huong Thi Nguyen, Yueh-Hsia Luo, An-Lun Li, Jen-Chieh Tsai, Kun-Lin Wu, Pei-Jung Chung and Nianhan Ma

Biomolecules 2021, 11(11), 1648; https://doi.org/10.3390/biom11111648 - 8 Nov 2021

Cited by 16 | Viewed by 3334

Abstract

Immune checkpoint inhibitors are a promising therapy for the treatment of cancers, including melanoma, that improved benefit clinical outcomes. However, a subset of melanoma patients do not respond or acquire resistance to immunotherapy, which limits their clinical applicability. Recent studies have explored the [...] Read more.

Immune checkpoint inhibitors are a promising therapy for the treatment of cancers, including melanoma, that improved benefit clinical outcomes. However, a subset of melanoma patients do not respond or acquire resistance to immunotherapy, which limits their clinical applicability. Recent studies have explored the reasons related to the resistance of melanoma to immune checkpoint inhibitors. Of note, miRNAs are the regulators of not only cancer progression but also of the response between cancer cells and immune cells. Investigation of miRNA functions within the tumor microenvironment have suggested that miRNAs could be considered as key partners in immunotherapy. Here, we reviewed the known mechanism by which melanoma induces resistance to immunotherapy and the role of miRNAs in immune responses and the microenvironment. Full article

(This article belongs to the Special Issue MicroRNAs - Small Molecules with Great Potential in Tumorigenesis)

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12 pages, 1151 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Profiles, Bioactive Compounds, and Antioxidant Capacity in Lentinula edodes Cultivated on Log versus Sawdust Substrates

by Miso Nam, Ji Yeon Choi and Min-Sun Kim

Biomolecules 2021, 11(11), 1654; https://doi.org/10.3390/biom11111654 - 8 Nov 2021

Cited by 13 | Viewed by 2577

Abstract

Lentinula edodes (shiitake) is a popular nutritious edible mushroom with a desirable aroma and flavor. Traditional cultivation of L. edodes on beds of logs has been replaced by cultivation on sawdust, but the effects of cultivation changes on L. edodes mushrooms have not [...] Read more.

Lentinula edodes (shiitake) is a popular nutritious edible mushroom with a desirable aroma and flavor. Traditional cultivation of L. edodes on beds of logs has been replaced by cultivation on sawdust, but the effects of cultivation changes on L. edodes mushrooms have not been well characterized. We determined the metabolic profile, bioactive compounds, and antioxidant capacity in L. edodes grown on log or sawdust substrates. Metabolic profiles of L. edodes extracts were determined by ¹H nuclear magnetic resonance (NMR) and ultra-performance liquid chromatography to quadrupole time-of-flight mass spectrometry. Principal component analysis score plots from ¹H NMR analysis showed clear differences between samples. Concentrations of primary metabolites, especially amino acids, generally decreased in L. edodes grown on logs compared to sawdust. Phenolic compounds showed variations in concentration depending on the cultivation method. Bioactive compounds and their antioxidant capacity were analyzed spectrophotometrically. L. edodes cultivated on logs had high concentrations of bioactive compounds with strong antioxidant capacity compared to L. edodes cultivated on sawdust. Thus, the concentration of primary metabolites was high in L. edodes grown on sawdust, which produces a high growth rate. In contrast, log-cultivated L. edodes, which were similar to wild mushrooms, had high levels of bioactive compounds and high antioxidant capacity. This information is useful for determining optimal cultivation conditions for nutritional and medicinal uses of L. edodes mushrooms. Full article

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21 pages, 17965 KiB

Open AccessEditor’s ChoiceReview

The Synthesis and Biological Evaluation of D-Ring-Modified Vitamin D Analogues

by Fumihiro Kawagoe, Sayuri Mototani and Atsushi Kittaka

Biomolecules 2021, 11(11), 1639; https://doi.org/10.3390/biom11111639 - 4 Nov 2021

Cited by 9 | Viewed by 2258

Abstract

The vitamin D₃ structure consists of the A-ring, a linker originating from the B-ring, C-ring, D-ring, and side-chain moieties. Each unit has its unique role in expressing the biological activities of vitamin D₃. Many efforts have been made to date [...] Read more.

The vitamin D₃ structure consists of the A-ring, a linker originating from the B-ring, C-ring, D-ring, and side-chain moieties. Each unit has its unique role in expressing the biological activities of vitamin D₃. Many efforts have been made to date to assess the possible clinical use of vitamin D. Some organic chemists focused on the D-ring structure of vitamin D and synthesized D-ring-modified vitamin D analogues, and their biological activities were studied. This review summarizes the synthetic methodologies of D-ring-modified vitamin D analogues, except for seco-D, and their preliminary biological profiles. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

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15 pages, 1541 KiB

Open AccessEditor’s ChoiceReview

Revisiting the Large-Conductance Calcium-Activated Potassium (BKCa) Channels in the Pulmonary Circulation

by Divya Guntur, Horst Olschewski, Péter Enyedi, Réka Csáki, Andrea Olschewski and Chandran Nagaraj

Biomolecules 2021, 11(11), 1629; https://doi.org/10.3390/biom11111629 - 3 Nov 2021

Cited by 9 | Viewed by 3645

Abstract

Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell′s membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) [...] Read more.

Potassium ion concentrations, controlled by ion pumps and potassium channels, predominantly govern a cell′s membrane potential and the tone in the vessels. Calcium-activated potassium channels respond to two different stimuli-changes in voltage and/or changes in intracellular free calcium. Large conductance calcium-activated potassium (BKCa) channels assemble from pore forming and various modulatory and auxiliary subunits. They are of vital significance due to their very high unitary conductance and hence their ability to rapidly cause extreme changes in the membrane potential. The pathophysiology of lung diseases in general and pulmonary hypertension, in particular, show the implication of either decreased expression and partial inactivation of BKCa channel and its subunits or mutations in the genes encoding different subunits of the channel. Signaling molecules, circulating humoral molecules, vasorelaxant agents, etc., have an influence on the open probability of the channel in pulmonary arterial vascular cells. BKCa channel is a possible therapeutic target, aimed to cause vasodilation in constricted or chronically stiffened vessels, as shown in various animal models. This review is a comprehensive collation of studies on BKCa channels in the pulmonary circulation under hypoxia (hypoxic pulmonary vasoconstriction; HPV), lung pathology, and fetal to neonatal transition, emphasising pharmacological interventions as viable therapeutic options. Full article

(This article belongs to the Special Issue Role of Ion Channels Signaling Pathways in the Development of Pulmonary Arterial Hypertension)

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17 pages, 1300 KiB

Open AccessEditor’s ChoiceReview

KCNQ1OT1: An Oncogenic Long Noncoding RNA

by Patrice Cagle, Qi Qi, Suryakant Niture and Deepak Kumar

Biomolecules 2021, 11(11), 1602; https://doi.org/10.3390/biom11111602 - 29 Oct 2021

Cited by 37 | Viewed by 4166

Abstract

Long noncoding RNAs (lncRNAs) are transcripts greater than 200 nucleotides that do not code for proteins but regulate gene expression. Recent studies indicate that lncRNAs are involved in the modulation of biological functions in human disease. KCNQ1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1) encodes [...] Read more.

Long noncoding RNAs (lncRNAs) are transcripts greater than 200 nucleotides that do not code for proteins but regulate gene expression. Recent studies indicate that lncRNAs are involved in the modulation of biological functions in human disease. KCNQ1 Opposite Strand/Antisense Transcript 1 (KCNQ1OT1) encodes a lncRNA from the opposite strand of KCNQ1 in the CDKN1C/KCNQ1OT1 cluster that is reported to play a vital role in the development and progression of cancer. KCNQ1OT1 regulates cancer cell proliferation, cell cycle, migration and invasion, metastasis, glucose metabolism, and immune evasion. The aberrant expression of KCNQ1OT1 in cancer patients is associated with poor prognosis and decreased survival. This review summarizes recent literature related to the biological functions and molecular mechanisms of KCNQ1OT1 in various human cancers, including colorectal, bladder, breast, oral, melanoma, osteosarcoma, lung, glioma, ovarian, liver, acute myeloid leukemia, prostate, and gastric. We also discuss the role of KCNQ1OT1 as a promising diagnostic biomarker and a novel therapeutic target in human cancers. Full article

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19 pages, 5233 KiB

Open AccessEditor’s ChoiceArticle

The Type III Effectome of the Symbiotic Bradyrhizobium vignae Strain ORS3257

by Nicolas Busset, Djamel Gully, Albin Teulet, Joël Fardoux, Alicia Camuel, David Cornu, Dany Severac, Eric Giraud and Peter Mergaert

Biomolecules 2021, 11(11), 1592; https://doi.org/10.3390/biom11111592 - 28 Oct 2021

Cited by 9 | Viewed by 3481

Abstract

Many Bradyrhizobium strains are able to establish a Nod factor-independent symbiosis with the leguminous plant Aeschynomene indica by the use of a type III secretion system (T3SS). Recently, an important advance in the understanding of the molecular factors supporting this symbiosis has been [...] Read more.

Many Bradyrhizobium strains are able to establish a Nod factor-independent symbiosis with the leguminous plant Aeschynomene indica by the use of a type III secretion system (T3SS). Recently, an important advance in the understanding of the molecular factors supporting this symbiosis has been achieved by the in silico identification and functional characterization of 27 putative T3SS effectors (T3Es) of Bradyrhizobium vignae ORS3257. In the present study, we experimentally extend this catalog of T3Es by using a multi-omics approach. Transcriptome analysis under non-inducing and inducing conditions in the ORS3257 wild-type strain and the ttsI mutant revealed that the expression of 18 out of the 27 putative effectors previously identified, is under the control of TtsI, the global transcriptional regulator of T3SS and T3Es. Quantitative shotgun proteome analysis of culture supernatant in the wild type and T3SS mutant strains confirmed that 15 of the previously determined candidate T3Es are secreted by the T3SS. Moreover, the combined approaches identified nine additional putative T3Es and one of them was experimentally validated as a novel effector. Our study underscores the power of combined proteome and transcriptome analyses to complement in silico predictions and produce nearly complete effector catalogs. The establishment of the ORS3257 effectome will form the basis for a full appraisal of the symbiotic properties of this strain during its interaction with various host legumes via different processes. 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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18 pages, 1045 KiB

Open AccessEditor’s ChoiceReview

Bioprinting Au Natural: The Biologics of Bioinks

by Kelsey Willson, Anthony Atala and James J. Yoo

Biomolecules 2021, 11(11), 1593; https://doi.org/10.3390/biom11111593 - 28 Oct 2021

Cited by 15 | Viewed by 2745

Abstract

The development of appropriate bioinks is a complex task, dependent on the mechanical and biochemical requirements of the final construct and the type of printer used for fabrication. The two most common tissue printers are micro-extrusion and digital light projection printers. Here we [...] Read more.

The development of appropriate bioinks is a complex task, dependent on the mechanical and biochemical requirements of the final construct and the type of printer used for fabrication. The two most common tissue printers are micro-extrusion and digital light projection printers. Here we briefly discuss the required characteristics of a bioink for each of these printing processes. However, physical printing is only a short window in the lifespan of a printed construct—the system must support and facilitate cellular development after it is printed. To that end, we provide a broad overview of some of the biological molecules currently used as bioinks. Each molecule has advantages for specific tissues/cells, and potential disadvantages are discussed, along with examples of their current use in the field. Notably, it is stressed that active researchers are trending towards the use of composite bioinks. Utilizing the strengths from multiple materials is highlighted as a key component of bioink development. Full article

(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)

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18 pages, 727 KiB

Open AccessEditor’s ChoiceReview

Self-Attention-Based Models for the Extraction of Molecular Interactions from Biological Texts

by Prashant Srivastava, Saptarshi Bej, Kristina Yordanova and Olaf Wolkenhauer

Biomolecules 2021, 11(11), 1591; https://doi.org/10.3390/biom11111591 - 27 Oct 2021

Cited by 11 | Viewed by 3192

Abstract

For any molecule, network, or process of interest, keeping up with new publications on these is becoming increasingly difficult. For many cellular processes, the amount molecules and their interactions that need to be considered can be very large. Automated mining of publications can [...] Read more.

For any molecule, network, or process of interest, keeping up with new publications on these is becoming increasingly difficult. For many cellular processes, the amount molecules and their interactions that need to be considered can be very large. Automated mining of publications can support large-scale molecular interaction maps and database curation. Text mining and Natural-Language-Processing (NLP)-based techniques are finding their applications in mining the biological literature, handling problems such as Named Entity Recognition (NER) and Relationship Extraction (RE). Both rule-based and Machine-Learning (ML)-based NLP approaches have been popular in this context, with multiple research and review articles examining the scope of such models in Biological Literature Mining (BLM). In this review article, we explore self-attention-based models, a special type of Neural-Network (NN)-based architecture that has recently revitalized the field of NLP, applied to biological texts. We cover self-attention models operating either at the sentence level or an abstract level, in the context of molecular interaction extraction, published from 2019 onwards. We conducted a comparative study of the models in terms of their architecture. Moreover, we also discuss some limitations in the field of BLM that identifies opportunities for the extraction of molecular interactions from biological text. Full article

(This article belongs to the Special Issue Computational Approaches for the Study of Biomolecular Networks)

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16 pages, 2882 KiB

Open AccessEditor’s ChoiceArticle

Glycan Epitopes and Potential Glycoside Antagonists of DC-SIGN Involved in COVID-19: In Silico Study

by Meina Gao, Hui Li, Chenghao Ye, Kaixian Chen, Hualiang Jiang and Kunqian Yu

Biomolecules 2021, 11(11), 1586; https://doi.org/10.3390/biom11111586 - 27 Oct 2021

Cited by 4 | Viewed by 3178

Abstract

Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 [...] Read more.

Glycosylation is an important post-translational modification that affects a wide variety of physiological functions. DC-SIGN (Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin) is a protein expressed in antigen-presenting cells that recognizes a variety of glycan epitopes. Until now, the binding of DC-SIGN to SARS-CoV-2 Spike glycoprotein has been reported in various articles and is regarded to be a factor in systemic infection and cytokine storm. The mechanism of DC-SIGN recognition offers an alternative method for discovering new medication for COVID-19 treatment. Here, we discovered three potential pockets that hold different glycan epitopes by performing molecular dynamics simulations of previously reported oligosaccharides. The “EPN” motif, “NDD” motif, and Glu354 form the most critical pocket, which is known as the Core site. We proposed that the type of glycan epitopes, rather than the precise amino acid sequence, determines the recognition. Furthermore, we deduced that oligosaccharides could occupy an additional site, which adds to their higher affinity than monosaccharides. Based on our findings and previously described glycoforms on the SARS-CoV-2 Spike, we predicted the potential glycan epitopes for DC-SIGN. It suggested that glycan epitopes could be recognized at multiple sites, not just Asn234, Asn149 and Asn343. Subsequently, we found that Saikosaponin A and Liquiritin, two plant glycosides, were promising DC-SIGN antagonists in silico. Full article

(This article belongs to the Topic Novel Biomolecules Modulating Innate Immune Responses against Virus Infection)

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15 pages, 5447 KiB

Open AccessEditor’s ChoiceArticle

Modeling Prostate Cancer Treatment Responses in the Organoid Era: 3D Environment Impacts Drug Testing

by Annelies Van Hemelryk, Lisanne Mout, Sigrun Erkens-Schulze, Pim J. French, Wytske M. van Weerden and Martin E. van Royen

Biomolecules 2021, 11(11), 1572; https://doi.org/10.3390/biom11111572 - 22 Oct 2021

Cited by 11 | Viewed by 3692

Abstract

Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental variability in organoid drug testing complicates reproducibility. For example, we observed PCa organoids to be less affected by cabazitaxel, abiraterone [...] Read more.

Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental variability in organoid drug testing complicates reproducibility. For example, we observed PCa organoids to be less affected by cabazitaxel, abiraterone and enzalutamide as compared to corresponding single cells prior to organoid assembly. We hypothesized that three-dimensional (3D) organoid organization and the use of various 3D scaffolds impact treatment efficacy. Live-cell imaging of androgen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilization was used to investigate the impact of 3D scaffolds, spatial organoid distribution and organoid size on treatment effect. Scaffolds delayed AR translocation and tubulin stabilization, with Matrigel causing a more pronounced delay than synthetic hydrogel as well as incomplete tubulin stabilization. Drug effect was further attenuated the more centrally organoids were located in the scaffold dome. Moreover, cells in the organoid core revealed a delayed treatment effect compared to cells in the organoid periphery, underscoring the impact of organoid size. These findings indicate that analysis of organoid drug responses needs careful interpretation and requires dedicated read-outs with consideration of underlying technical aspects. Full article

(This article belongs to the Special Issue Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine)

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15 pages, 2049 KiB

Open AccessEditor’s ChoiceArticle

Phytochemical Profile, α-Glucosidase, and α-Amylase Inhibition Potential and Toxicity Evaluation of Extracts from Citrus aurantium (L) Peel, a Valuable By-Product from Northeastern Morocco

by Ouijdane Benayad, Mohamed Bouhrim, Salima Tiji, Loubna Kharchoufa, Mohamed Addi, Samantha Drouet, Christophe Hano, Jose Manuel Lorenzo, Hasnae Bendaha, Mohamed Bnouham and Mostafa Mimouni

Biomolecules 2021, 11(11), 1555; https://doi.org/10.3390/biom11111555 - 20 Oct 2021

Cited by 37 | Viewed by 4408

Abstract

Due to the high volume of peel produced, Citrus by-product processing could be a significant source of phenolic compounds, in addition to essential oil. Citrus fruit residues, which are usually dumped as waste in the environment, could be used as a source of [...] Read more.

Due to the high volume of peel produced, Citrus by-product processing could be a significant source of phenolic compounds, in addition to essential oil. Citrus fruit residues, which are usually dumped as waste in the environment, could be used as a source of nutraceuticals. Citrus aurantium (L), also known as sour or bitter orange, is a member of the Rutaceae family and is the result of interspecific hybridization between Citrus reticulata and Citrus maxima. The purpose of this study is to chemically and biologically evaluate the peel of C. aurantium, which is considered a solid waste destined for abandonment. To achieve more complete extraction of the phytochemicals, we used a sequential extraction process with Soxhlet using the increasing polarity of solvents (i.e., cyclohexane, chloroform, ethyl acetate, acetone, and ethanol–water mixture). Essential oil (EO) from the Citrus peel, which was present at 1.12%, was also prepared by hydrodistillation for comparison. Various phytochemical assays were used to determine the qualitative chemical composition, which was subsequently characterized using GC-MS and HPLC-DAD. The inhibitory effects of C. aurantium peel extract on two enzymes, intestinal α-glucosidase and pancreatic α-amylase, were measured in vitro to determine their potential hypoglycemic and antidiabetic actions. Each extract had a significantly different phytochemical composition. According to GC-MS analyses, which allow the identification of 19 compounds, d-limonene is the most abundant compound in both EO and cyclohexane extract, at 35.17% and 36.15% (w/w). This comparison with hydrodistillation shows the value of the sequential process in extracting this valuable terpene in large quantities while also allowing for the subsequent extraction of other bioactive substances. On the contrary, linoleic acid is abundant (54.35% (w/w)) in ethyl acetate extract (EAE) with a lower amount of d-limonene. HPLC-DAD analysis allows the identification of 11 phytochemicals, with naringenin being the most abundant flavanone, detected in acetone extract (ACE) (23.94% (w/w)), ethanol–water extract mixture (EWE) (28.71% (w/w)), and chloroform extract (CFE) (30.20% (w/w)). Several extracts significantly inhibited α-amylase and/or α-glycosidase in vitro. At a dose of 332 g/mL, ACE, CFE, and EWE inhibited the two enzymes by approximately 98%. There were strong significant correlations between naringenin and α-glucosidase inhibition and between gallic acid and α-amylase inhibition. Molecular docking experiments further verified this. Finally, oral administration of C. aurantium extracts at a dose of 2000 mg/kg did not cause any effect on mice mortality or signs of acute toxicity, indicating that it is non-toxic at these doses. These findings suggest that C. aurantium peels could be a valuable by-product by providing a rich source of non-toxic phytoconstituents, particularly those with potential antidiabetic action that needs to be confirmed in vivo. Full article

(This article belongs to the Special Issue Phytochemical Omics in Medicinal Plants 2.0)

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18 pages, 1424 KiB

Open AccessEditor’s ChoiceReview

CB2 Receptor Involvement in the Treatment of Substance Use Disorders

by Francisco Navarrete, María S. García-Gutiérrez, Ani Gasparyan, Daniela Navarro and Jorge Manzanares

Biomolecules 2021, 11(11), 1556; https://doi.org/10.3390/biom11111556 - 20 Oct 2021

Cited by 14 | Viewed by 2766

Abstract

The pharmacological modulation of the cannabinoid receptor 2 (CB2r) has emerged as a promising potential therapeutic option in addiction. The purpose of this review was to determine the functional involvement of CB2r in the effects produced by drugs of abuse at the central [...] Read more.

The pharmacological modulation of the cannabinoid receptor 2 (CB2r) has emerged as a promising potential therapeutic option in addiction. The purpose of this review was to determine the functional involvement of CB2r in the effects produced by drugs of abuse at the central nervous system (CNS) level by assessing evidence from preclinical and clinical studies. In rodents, several reports suggest the functional involvement of CB2r in the effects produced by drugs of abuse such as alcohol, cocaine, or nicotine. In addition, the discovery of CB2r in brain areas that are part of the reward system supports the relevance of CB2r in the field of addiction. Interestingly, animal studies support that the CB2r regulates anxiety and depression behavioral traits. Due to its frequent comorbidity with neuropsychiatric disorders, these pharmacological actions may be of great interest in managing SUD. Preliminary clinical trials are focused on exploring the therapeutic potential of modulating CB2r in treating addictive disorders. These promising results support the development of new pharmacological tools regulating the CB2r that may help to increase the therapeutic success in the management of SUD. Full article

(This article belongs to the Special Issue Translational Biomarkers in Addictive Disorders)

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13 pages, 1622 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

New Insights to Regulation of Fructose-1,6-bisphosphatase during Anoxia in Red-Eared Slider, Trachemys scripta elegans

by Aakriti Gupta, Anchal Varma and Kenneth B. Storey

Biomolecules 2021, 11(10), 1548; https://doi.org/10.3390/biom11101548 - 19 Oct 2021

Cited by 7 | Viewed by 5902

Abstract

The red-eared slider (Trachemys scripta elegans) undergoes numerous changes to its physiological and metabolic processes to survive without oxygen. During anoxic conditions, its metabolic rate drops drastically to minimize energy requirements. The alterations in the central metabolic pathways are often accomplished [...] Read more.

The red-eared slider (Trachemys scripta elegans) undergoes numerous changes to its physiological and metabolic processes to survive without oxygen. During anoxic conditions, its metabolic rate drops drastically to minimize energy requirements. The alterations in the central metabolic pathways are often accomplished by the regulation of key enzymes. The regulation of one such enzyme, fructose-1,6-bisphosphatase (FBPase; EC 3.1.3.11), was characterized in the present study during anoxia in liver. FBPase is a crucial enzyme of gluconeogenesis. The FBPase was purified from liver tissue in both control and anoxic conditions and subsequently assayed to determine the kinetic parameters of the enzyme. The study revealed the relative degree of post-translational modifications in the FBPase from control and anoxic turtles. Further, this study demonstrated a significant decrease in the maximal activity in anoxic FBPase and decreased sensitivity to its substrate Fructose-1,6-bisphosphate (FBP) when compared to the control. Immunoblotting demonstrated increased threonine phosphorylation (~1.4-fold) in the anoxic FBPase. Taken together, these results suggest that the phosphorylation of liver FBPase is an important step in suppressing FBPase activity, ultimately leading to the inhibition of gluconeogenesis in the liver of the red-eared slider during anaerobic conditions. Full article

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15 pages, 31008 KiB

Open AccessEditor’s ChoiceArticle

Angiogenic Potential of VEGF Mimetic Peptides for the Biofunctionalization of Collagen/Hydroxyapatite Composites

by Suya Wang, Felix Umrath, Wanjing Cen, Siegmar Reinert and Dorothea Alexander

Biomolecules 2021, 11(10), 1538; https://doi.org/10.3390/biom11101538 - 19 Oct 2021

Cited by 16 | Viewed by 3715

Abstract

Currently, the focus on bioinspired concepts for the development of tissue engineering constructs is increasing. For this purpose, the combination of collagen (Coll) and hydroxyapatite (HA) comes closest to the natural composition of the bone. In order to confer angiogenic properties to the [...] Read more.

Currently, the focus on bioinspired concepts for the development of tissue engineering constructs is increasing. For this purpose, the combination of collagen (Coll) and hydroxyapatite (HA) comes closest to the natural composition of the bone. In order to confer angiogenic properties to the scaffold material, vascular endothelial growth factor (VEGF) is frequently used. In the present study, we used a VEGF mimetic peptide (QK) and a modified QK-peptide with a poly-glutamic acid tag (E7-QK) to enhance binding to HA, and analyzed in detail binding efficiency and angiogenic properties. We detected a significantly higher binding efficiency of E7-QK peptides to hydroxyapatite particles compared to the unmodified QK-peptide. Tube formation assays revealed similar angiogenic functions of E7-QK peptide (1µM) as induced by the entire VEGF protein. Analyses of gene expression of angiogenic factors and their receptors (FLT-1, KDR, HGF, MET, IL-8, HIF-1α, MMP-1, IGFBP-1, IGFBP-2, VCAM-1, and ANGPT-1) showed higher expression levels in HUVECs cultured in the presence of 1 µM E7-QK and VEGF compared to those detected in the negative control group without any angiogenic stimuli. In contrast, the expression of the anti-angiogenic gene TIMP-1 showed lower mRNA levels in HUVECs cultured with E7-QK and VEGF. Sprouting assays with HUVEC spheroids within Coll/HA/E7-QK scaffolds showed significantly longer sprouts compared to those induced within Coll/HA/QK or Coll/HA scaffolds. Our results demonstrate a significantly better functionality of the E7-QK peptide, electrostatically bound to hydroxyapatite particles compared to that of unmodified QK peptide. We conclude that the used E7-QK peptide represents an excellently suited biomolecule for the generation of collagen/hydroxyapatite composites with angiogenic properties. Full article

(This article belongs to the Special Issue Biomolecule-Based Composites, Hybrids and Nanostructures for Biomedical Applications)

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26 pages, 6249 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Cdc42-Specific GTPase-Activating Protein Rga1 Squelches Crosstalk between the High-Osmolarity Glycerol (HOG) and Mating Pheromone Response MAPK Pathways

by Jesse C. Patterson, Louise S. Goupil and Jeremy Thorner

Biomolecules 2021, 11(10), 1530; https://doi.org/10.3390/biom11101530 - 17 Oct 2021

Cited by 4 | Viewed by 3664

Abstract

Eukaryotes utilize distinct mitogen/messenger-activated protein kinase (MAPK) pathways to evoke appropriate responses when confronted with different stimuli. In yeast, hyperosmotic stress activates MAPK Hog1, whereas mating pheromones activate MAPK Fus3 (and MAPK Kss1). Because these pathways share several upstream components, including the small [...] Read more.

Eukaryotes utilize distinct mitogen/messenger-activated protein kinase (MAPK) pathways to evoke appropriate responses when confronted with different stimuli. In yeast, hyperosmotic stress activates MAPK Hog1, whereas mating pheromones activate MAPK Fus3 (and MAPK Kss1). Because these pathways share several upstream components, including the small guanosine-5'-triphosphate phosphohydrolase (GTPase) cell-division-cycle-42 (Cdc42), mechanisms must exist to prevent inadvertent cross-pathway activation. Hog1 activity is required to prevent crosstalk to Fus3 and Kss1. To identify other factors required to maintain signaling fidelity during hypertonic stress, we devised an unbiased genetic selection for mutants unable to prevent such crosstalk even when active Hog1 is present. We repeatedly isolated truncated alleles of RGA1, a Cdc42-specific GTPase-activating protein (GAP), each lacking its C-terminal catalytic domain, that permit activation of the mating MAPKs under hyperosmotic conditions despite Hog1 being present. We show that Rga1 down-regulates Cdc42 within the high-osmolarity glycerol (HOG) pathway, but not the mating pathway. Because induction of mating pathway output via crosstalk from the HOG pathway takes significantly longer than induction of HOG pathway output, our findings suggest that, under normal conditions, Rga1 contributes to signal insulation by limiting availability of the GTP-bound Cdc42 pool generated by hypertonic stress. Thus, Rga1 action contributes to squelching crosstalk by imposing a type of “kinetic proofreading”. Although Rga1 is a Hog1 substrate in vitro, we eliminated the possibility that its direct Hog1-mediated phosphorylation is necessary for its function in vivo. Instead, we found first that, like its paralog Rga2, Rga1 is subject to inhibitory phosphorylation by the S. cerevisiae cyclin-dependent protein kinase 1 (Cdk1) ortholog Cdc28 and that hyperosmotic shock stimulates its dephosphorylation and thus Rga1 activation. Second, we found that Hog1 promotes Rga1 activation by blocking its Cdk1-mediated phosphorylation, thereby allowing its phosphoprotein phosphatase 2A (PP2A)-mediated dephosphorylation. These findings shed light on why Hog1 activity is required to prevent crosstalk from the HOG pathway to the mating pheromone response pathway. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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16 pages, 999 KiB

Open AccessEditor’s ChoiceReview

MicroRNAs and Metabolism: Revisiting the Warburg Effect with Emphasis on Epigenetic Background and Clinical Applications

by Zsuzsanna Gaál

Biomolecules 2021, 11(10), 1531; https://doi.org/10.3390/biom11101531 - 17 Oct 2021

Cited by 5 | Viewed by 3895

Abstract

Since the well-known hallmarks of cancer were described by Hanahan and Weinberg, fundamental advances of molecular genomic technologies resulted in the discovery of novel puzzle pieces in the multistep pathogenesis of cancer. MicroRNAs are involved in the altered epigenetic pattern and metabolic phenotype [...] Read more.

Since the well-known hallmarks of cancer were described by Hanahan and Weinberg, fundamental advances of molecular genomic technologies resulted in the discovery of novel puzzle pieces in the multistep pathogenesis of cancer. MicroRNAs are involved in the altered epigenetic pattern and metabolic phenotype of malignantly transformed cells. They contribute to the initiation, progression and metastasis-formation of cancers, also interacting with oncogenes, tumor-suppressor genes and epigenetic modifiers. Metabolic reprogramming of cancer cells results from the dysregulation of a complex network, in which microRNAs are located at central hubs. MicroRNAs regulate the expression of several metabolic enzymes, including tumor-specific isoforms. Therefore, they have a direct impact on the levels of metabolites, also influencing epigenetic pattern due to the metabolite cofactors of chromatin modifiers. Targets of microRNAs include numerous epigenetic enzymes, such as sirtuins, which are key regulators of cellular metabolic homeostasis. A better understanding of reversible epigenetic and metabolic alterations opened up new horizons in the personalized treatment of cancer. MicroRNA expression levels can be utilized in differential diagnosis, prognosis stratification and prediction of chemoresistance. The therapeutic modulation of microRNA levels is an area of particular interest that provides a promising tool for restoring altered metabolism of cancer cells. Full article

(This article belongs to the Special Issue MicroRNAs - Small Molecules with Great Potential in Tumorigenesis)

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23 pages, 2779 KiB

Open AccessEditor’s ChoiceReview

Decoding Stem Cells: An Overview on Planarian Stem Cell Heterogeneity and Lineage Progression

by M. Dolores Molina and Francesc Cebrià

Biomolecules 2021, 11(10), 1532; https://doi.org/10.3390/biom11101532 - 17 Oct 2021

Cited by 14 | Viewed by 6936

Abstract

Planarians are flatworms capable of whole-body regeneration, able to regrow any missing body part after injury or amputation. The extraordinary regenerative capacity of planarians is based upon the presence in the adult of a large population of somatic pluripotent stem cells. These cells, [...] Read more.

Planarians are flatworms capable of whole-body regeneration, able to regrow any missing body part after injury or amputation. The extraordinary regenerative capacity of planarians is based upon the presence in the adult of a large population of somatic pluripotent stem cells. These cells, called neoblasts, offer a unique system to study the process of stem cell specification and differentiation in vivo. In recent years, FACS-based isolation of neoblasts, RNAi functional analyses as well as high-throughput approaches such as single-cell sequencing have allowed a rapid progress in our understanding of many different aspects of neoblast biology. Here, we summarize our current knowledge on the molecular signatures that define planarian neoblasts heterogeneity, which includes a percentage of truly pluripotent stem cells, and guide the commitment of pluripotent neoblasts into lineage-specific progenitor cells, as well as their differentiation into specific planarian cell types. Full article

(This article belongs to the Special Issue New Insights into Stem Cell Regulation)

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34 pages, 8749 KiB

Open AccessEditor’s ChoiceReview

Hyaluronic Acid: A Key Ingredient in the Therapy of Inflammation

by Andreia Marinho, Cláudia Nunes and Salette Reis

Biomolecules 2021, 11(10), 1518; https://doi.org/10.3390/biom11101518 - 15 Oct 2021

Cited by 153 | Viewed by 12747

Abstract

Hyaluronic acid (HA) is a natural polymer, produced endogenously by the human body, which has unique physicochemical and biological properties, exhibiting desirable biocompatibility and biodegradability. Therefore, it has been widely studied for possible applications in the area of inflammatory diseases. Although exogenous HA [...] Read more.

Hyaluronic acid (HA) is a natural polymer, produced endogenously by the human body, which has unique physicochemical and biological properties, exhibiting desirable biocompatibility and biodegradability. Therefore, it has been widely studied for possible applications in the area of inflammatory diseases. Although exogenous HA has been described as unable to restore or replace the properties and activities of endogenous HA, it can still provide satisfactory pain relief. This review aims to discuss the advances that have been achieved in the treatment of inflammatory diseases using hyaluronic acid as a key ingredient, essentially focusing on studies carried out between the years 2017 and 2021. Full article

(This article belongs to the Special Issue Hyaluronic Acid in Human Medicine)

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28 pages, 2663 KiB

Open AccessEditor’s ChoiceReview

Alternative Pre-mRNA Splicing of the Mu Opioid Receptor Gene, OPRM1: Insight into Complex Mu Opioid Actions

by Shan Liu, Wen-Jia Kang, Anna Abrimian, Jin Xu, Luca Cartegni, Susruta Majumdar, Patrick Hesketh, Alex Bekker and Ying-Xian Pan

Biomolecules 2021, 11(10), 1525; https://doi.org/10.3390/biom11101525 - 15 Oct 2021

Cited by 14 | Viewed by 3913

Abstract

Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, [...] Read more.

Most opioid analgesics used clinically, including morphine and fentanyl, as well as the recreational drug heroin, act primarily through the mu opioid receptor, a class A Rhodopsin-like G protein-coupled receptor (GPCR). The single-copy mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, creating multiple splice variants or isoforms via a variety of alternative splicing events. These OPRM1 splice variants can be categorized into three major types based on the receptor structure: (1) full-length 7 transmembrane (TM) C-terminal variants; (2) truncated 6TM variants; and (3) single TM variants. Increasing evidence suggests that these OPRM1 splice variants are pharmacologically important in mediating the distinct actions of various mu opioids. More importantly, the OPRM1 variants can be targeted for development of novel opioid analgesics that are potent against multiple types of pain, but devoid of many side-effects associated with traditional opiates. In this review, we provide an overview of OPRM1 alternative splicing and its functional relevance in opioid pharmacology. Full article

(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)

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11 pages, 932 KiB

Open AccessEditor’s ChoiceReview

Hyperbaric Oxygen Treatment—From Mechanisms to Cognitive Improvement

by Irit Gottfried, Nofar Schottlender and Uri Ashery

Biomolecules 2021, 11(10), 1520; https://doi.org/10.3390/biom11101520 - 15 Oct 2021

Cited by 52 | Viewed by 9566

Abstract

Hyperbaric oxygen treatment (HBOT)—the medical use of oxygen at environmental pressure greater than one atmosphere absolute—is a very effective therapy for several approved clinical situations, such as carbon monoxide intoxication, incurable diabetes or radiation-injury wounds, and smoke inhalation. In recent years, it has [...] Read more.

Hyperbaric oxygen treatment (HBOT)—the medical use of oxygen at environmental pressure greater than one atmosphere absolute—is a very effective therapy for several approved clinical situations, such as carbon monoxide intoxication, incurable diabetes or radiation-injury wounds, and smoke inhalation. In recent years, it has also been used to improve cognition, neuro-wellness, and quality of life following brain trauma and stroke. This opens new avenues for the elderly, including the treatment of neurological and neurodegenerative diseases and improvement of cognition and brain metabolism in cases of mild cognitive impairment. Alongside its integration into clinics, basic research studies have elucidated HBOT’s mechanisms of action and its effects on cellular processes, transcription factors, mitochondrial function, oxidative stress, and inflammation. Therefore, HBOT is becoming a major player in 21st century research and clinical treatments. The following review will discuss the basic mechanisms of HBOT, and its effects on cellular processes, cognition, and brain disorders. Full article

(This article belongs to the Special Issue Oxygen Therapy)

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15 pages, 4219 KiB

Open AccessEditor’s ChoiceArticle

A Promising Intracellular Protein-Degradation Strategy: TRIMbody-Away Technique Based on Nanobody Fragment

by Gang Chen, Yu Kong, You Li, Ailing Huang, Chunyu Wang, Shanshan Zhou, Zhenlin Yang, Yanling Wu, Jianke Ren and Tianlei Ying

Biomolecules 2021, 11(10), 1512; https://doi.org/10.3390/biom11101512 - 14 Oct 2021

Cited by 12 | Viewed by 4143

Abstract

Most recently, a technology termed TRIM-Away has allowed acute and rapid destruction of endogenous target proteins in cultured cells using specific antibodies and endogenous/exogenous tripartite motif 21 (TRIM21). However, the relatively large size of the full-size mAbs (150 kDa) results in correspondingly low [...] Read more.

Most recently, a technology termed TRIM-Away has allowed acute and rapid destruction of endogenous target proteins in cultured cells using specific antibodies and endogenous/exogenous tripartite motif 21 (TRIM21). However, the relatively large size of the full-size mAbs (150 kDa) results in correspondingly low tissue penetration and inaccessibility of some sterically hindered epitopes, which limits the target protein degradation. In addition, exogenous introduction of TRIM21 may cause side effects for treated cells. To tackle these limitations, we sought to replace full-size mAbs with the smaller format of antibodies, a nanobody (VHH, 15 kDa), and construct a new type of fusion protein named TRIMbody by fusing the nanobody and RBCC motif of TRIM21. Next, we introduced enhanced green fluorescent protein (EGFP) as a model substrate and generated αEGFP TRIMbody using a bispecific anti-EGFP (αEGFP) nanobody. Remarkably, inducible expression of αEGFP TRIMbody could specifically degrade intracellular EGFP in HEK293T cells in a time-dependent manner. By treating cells with inhibitors, we found that intracellular EGFP degradation by αEGFP TRIMbody relies on both ubiquitin–proteasome and autophagy–lysosome pathways. Taken together, these results suggested that TRIMbody-Away technology could be utilized to specifically degrade intracellular protein and could expand the potential applications of degrader technologies. Full article

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19 pages, 1784 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Dysfunction, Protein Misfolding and Neuroinflammation in Parkinson’s Disease: Roads to Biomarker Discovery

by Anna Picca, Flora Guerra, Riccardo Calvani, Roberta Romano, Hélio José Coelho-Júnior, Cecilia Bucci and Emanuele Marzetti

Biomolecules 2021, 11(10), 1508; https://doi.org/10.3390/biom11101508 - 13 Oct 2021

Cited by 70 | Viewed by 7870

Abstract

Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational [...] Read more.

Parkinson’s Disease (PD) is a highly prevalent neurodegenerative disease among older adults. PD neuropathology is marked by the progressive loss of the dopaminergic neurons of the substantia nigra pars compacta and the widespread accumulation of misfolded intracellular α-synuclein (α-syn). Genetic mutations and post-translational modifications, such as α-syn phosphorylation, have been identified among the multiple factors supporting α-syn accrual during PD. A decline in the clearance capacity of the ubiquitin-proteasome and the autophagy-lysosomal systems, together with mitochondrial dysfunction, have been indicated as major pathophysiological mechanisms of PD neurodegeneration. The accrual of misfolded α-syn aggregates into soluble oligomers, and the generation of insoluble fibrils composing the core of intraneuronal Lewy bodies and Lewy neurites observed during PD neurodegeneration, are ignited by the overproduction of reactive oxygen species (ROS). The ROS activate the α-syn aggregation cascade and, together with the Lewy bodies, promote neurodegeneration. However, the molecular pathways underlying the dynamic evolution of PD remain undeciphered. These gaps in knowledge, together with the clinical heterogeneity of PD, have hampered the identification of the biomarkers that may be used to assist in diagnosis, treatment monitoring, and prognostication. Herein, we illustrate the main pathways involved in PD pathogenesis and discuss their possible exploitation for biomarker discovery. Full article

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

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30 pages, 1439 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Genetic, Environmental and Lifestyle Determinants of Accelerated Telomere Attrition as Contributors to Risk and Severity of Multiple Sclerosis

by Michael Hecker, Jan Bühring, Brit Fitzner, Paulus Stefan Rommer and Uwe Klaus Zettl

Biomolecules 2021, 11(10), 1510; https://doi.org/10.3390/biom11101510 - 13 Oct 2021

Cited by 22 | Viewed by 6220

Abstract

Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative [...] Read more.

Telomeres are protective structures at the ends of linear chromosomes. Shortened telomere lengths (TL) are an indicator of premature biological aging and have been associated with a wide spectrum of disorders, including multiple sclerosis (MS). MS is a chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system. The exact cause of MS is still unclear. Here, we provide an overview of genetic, environmental and lifestyle factors that have been described to influence TL and to contribute to susceptibility to MS and possibly disease severity. We show that several early-life factors are linked to both reduced TL and higher risk of MS, e.g., adolescent obesity, lack of physical activity, smoking and vitamin D deficiency. This suggests that the mechanisms underlying the disease are connected to cellular aging and senescence promoted by increased inflammation and oxidative stress. Additional prospective research is needed to clearly define the extent to which lifestyle changes can slow down disease progression and prevent accelerated telomere loss in individual patients. It is also important to further elucidate the interactions between shared determinants of TL and MS. In future, cell type-specific studies and advanced TL measurement methods could help to better understand how telomeres may be causally involved in disease processes and to uncover novel opportunities for improved biomarkers and therapeutic interventions in MS. Full article

(This article belongs to the Special Issue The Molecular Mechanisms and Therapeutics in Multiple Sclerosis)

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13 pages, 4389 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Quantitative Super-Resolution Imaging for the Analysis of GPCR Oligomerization

by Megan D. Joseph, Elena Tomas Bort, Richard P. Grose, Peter J. McCormick and Sabrina Simoncelli

Biomolecules 2021, 11(10), 1503; https://doi.org/10.3390/biom11101503 - 12 Oct 2021

Cited by 10 | Viewed by 5433

Abstract

G-protein coupled receptors (GPCRs) are known to form homo- and hetero- oligomers which are considered critical to modulate their function. However, studying the existence and functional implication of these complexes is not straightforward as controversial results are obtained depending on the method of [...] Read more.

G-protein coupled receptors (GPCRs) are known to form homo- and hetero- oligomers which are considered critical to modulate their function. However, studying the existence and functional implication of these complexes is not straightforward as controversial results are obtained depending on the method of analysis employed. Here, we use a quantitative single molecule super-resolution imaging technique named qPAINT to quantify complex formation within an example GPCR. qPAINT, based upon DNA-PAINT, takes advantage of the binding kinetics between fluorescently labelled DNA imager strands to complementary DNA docking strands coupled to protein targeting antibodies to quantify the protein copy number in nanoscale dimensions. We demonstrate qPAINT analysis via a novel pipeline to study the oligomerization of the purinergic receptor Y2 (P2Y₂), a rhodopsin-like GPCR, highly expressed in the pancreatic cancer cell line AsPC-1, under control, agonistic and antagonistic conditions. Results reveal that whilst the density of P2Y₂ receptors remained unchanged, antagonistic conditions displayed reduced percentage of oligomers, and smaller numbers of receptors in complexes. Yet, the oligomeric state of the receptors was not affected by agonist treatment, in line with previous reports. Understanding P2Y₂ oligomerization under agonistic and antagonistic conditions will contribute to unravelling P2Y₂ mechanistic action and therapeutic targeting. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)

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12 pages, 1141 KiB

Open AccessEditor’s ChoiceReview

Osteogenesis Imperfecta: Current and Prospective Therapies

by Malwina Botor, Agnieszka Fus-Kujawa, Marta Uroczynska, Karolina L. Stepien, Anna Galicka, Katarzyna Gawron and Aleksander L. Sieron

Biomolecules 2021, 11(10), 1493; https://doi.org/10.3390/biom11101493 - 10 Oct 2021

Cited by 37 | Viewed by 11338

Abstract

Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a [...] Read more.

Osteogenesis Imperfecta (OI) is a group of connective tissue disorders with a broad range of phenotypes characterized primarily by bone fragility. The prevalence of OI ranges from about 1:15,000 to 1:20,000 births. Five types of the disease are commonly distinguished, ranging from a mild (type I) to a lethal one (type II). Types III and IV are severe forms allowing survival after the neonatal period, while type V is characterized by a mild to moderate phenotype with calcification of interosseous membranes. In most cases, there is a reduction in the production of normal type I collagen (col I) or the synthesis of abnormal collagen as a result of mutations in col I genes. Moreover, mutations in genes involved in col I synthesis and processing as well as in osteoblast differentiation have been reported. The currently available treatments try to prevent fractures, control symptoms and increase bone mass. Commonly used medications in OI treatment are bisphosphonates, Denosumab, synthetic parathyroid hormone and growth hormone for children therapy. The main disadvantages of these therapies are their relatively weak effectiveness, lack of effects in some patients or cytotoxic side effects. Experimental approaches, particularly those based on stem cell transplantation and genetic engineering, seem to be promising to improve the therapeutic effects of OI. Full article

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

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23 pages, 4315 KiB

Open AccessEditor’s ChoiceReview

DNA End Joining: G0-ing to the Core

by Richard L. Frock, Cheyenne Sadeghi, Jodie Meng and Jing L. Wang

Biomolecules 2021, 11(10), 1487; https://doi.org/10.3390/biom11101487 - 9 Oct 2021

Cited by 10 | Viewed by 4842

Abstract

Humans have evolved a series of DNA double-strand break (DSB) repair pathways to efficiently and accurately rejoin nascently formed pairs of double-stranded DNA ends (DSEs). In G0/G1-phase cells, non-homologous end joining (NHEJ) and alternative end joining (A-EJ) operate to support covalent rejoining of [...] Read more.

Humans have evolved a series of DNA double-strand break (DSB) repair pathways to efficiently and accurately rejoin nascently formed pairs of double-stranded DNA ends (DSEs). In G0/G1-phase cells, non-homologous end joining (NHEJ) and alternative end joining (A-EJ) operate to support covalent rejoining of DSEs. While NHEJ is predominantly utilized and collaborates extensively with the DNA damage response (DDR) to support pairing of DSEs, much less is known about A-EJ collaboration with DDR factors when NHEJ is absent. Non-cycling lymphocyte progenitor cells use NHEJ to complete V(D)J recombination of antigen receptor genes, initiated by the RAG1/2 endonuclease which holds its pair of targeted DSBs in a synapse until each specified pair of DSEs is handed off to the NHEJ DSB sensor complex, Ku. Similar to designer endonuclease DSBs, the absence of Ku allows for A-EJ to access RAG1/2 DSEs but with random pairing to complete their repair. Here, we describe recent insights into the major phases of DSB end joining, with an emphasis on synapsis and tethering mechanisms, and bring together new and old concepts of NHEJ vs. A-EJ and on RAG2-mediated repair pathway choice. Full article

(This article belongs to the Collection DNA Repair and Immune Response)

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19 pages, 5890 KiB

Open AccessEditor’s ChoiceArticle

Alcohol Metabolism Enriches Squamous Cell Carcinoma Cancer Stem Cells That Survive Oxidative Stress via Autophagy

by Masataka Shimonosono, Koji Tanaka, Samuel Flashner, Satoshi Takada, Norihiro Matsuura, Yasuto Tomita, Uma M. Sachdeva, Eishi Noguchi, Veena Sangwan, Lorenzo Ferri, Fatemeh Momen-Heravi, Angela J. Yoon, Andres J. Klein-Szanto, J. Alan Diehl and Hiroshi Nakagawa

Biomolecules 2021, 11(10), 1479; https://doi.org/10.3390/biom11101479 - 7 Oct 2021

Cited by 10 | Viewed by 4401

Abstract

Background: Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood. Methods: We utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how [...] Read more.

Background: Alcohol (ethanol) consumption is a major risk factor for head and neck and esophageal squamous cell carcinomas (SCCs). However, how ethanol (EtOH) affects SCC homeostasis is incompletely understood. Methods: We utilized three-dimensional (3D) organoids and xenograft tumor transplantation models to investigate how EtOH exposure influences intratumoral SCC cell populations including putative cancer stem cells defined by high CD44 expression (CD44H cells). Results: Using 3D organoids generated from SCC cell lines, patient-derived xenograft tumors, and patient biopsies, we found that EtOH is metabolized via alcohol dehydrogenases to induce oxidative stress associated with mitochondrial superoxide generation and mitochondrial depolarization, resulting in apoptosis of the majority of SCC cells within organoids. However, CD44H cells underwent autophagy to negate EtOH-induced mitochondrial dysfunction and apoptosis and were subsequently enriched in organoids and xenograft tumors when exposed to EtOH. Importantly, inhibition of autophagy increased EtOH-mediated apoptosis and reduced CD44H cell enrichment, xenograft tumor growth, and organoid formation rate. Conclusions: This study provides mechanistic insights into how EtOH may influence SCC cells and establishes autophagy as a potential therapeutic target for the treatment of EtOH-associated SCC. Full article

(This article belongs to the Special Issue Aldehyde Toxicity and Metabolism)

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20 pages, 915 KiB

Open AccessEditor’s ChoiceArticle

Antibacterial and Antifungal Properties of Silver Nanoparticles—Effect of a Surface-Stabilizing Agent

by Agnieszka Gibała, Paulina Żeliszewska, Tomasz Gosiewski, Agnieszka Krawczyk, Dorota Duraczyńska, Joanna Szaleniec, Maciej Szaleniec and Magdalena Oćwieja

Biomolecules 2021, 11(10), 1481; https://doi.org/10.3390/biom11101481 - 7 Oct 2021

Cited by 52 | Viewed by 3520

Abstract

The biocidal properties of silver nanoparticles (AgNPs) prepared with the use of biologically active compounds seem to be especially significant for biological and medical application. Therefore, the aim of this research was to determine and compare the antibacterial and fungicidal properties of fifteen [...] Read more.

The biocidal properties of silver nanoparticles (AgNPs) prepared with the use of biologically active compounds seem to be especially significant for biological and medical application. Therefore, the aim of this research was to determine and compare the antibacterial and fungicidal properties of fifteen types of AgNPs. The main hypothesis was that the biological activity of AgNPs characterized by comparable size distributions, shapes, and ion release profiles is dependent on the properties of stabilizing agent molecules adsorbed on their surfaces. Escherichia coli and Staphylococcus aureus were selected as models of two types of bacterial cells. Candida albicans was selected for the research as a representative type of eukaryotic microorganism. The conducted studies reveal that larger AgNPs can be more biocidal than smaller ones. It was found that positively charged arginine-stabilized AgNPs (ARGSBAgNPs) were the most biocidal among all studied nanoparticles. The strongest fungicidal properties were detected for negatively charged EGCGAgNPs obtained using (−)-epigallocatechin gallate (EGCG). It was concluded that, by applying a specific stabilizing agent, one can tune the selectivity of AgNP toxicity towards desired pathogens. It was established that E. coli was more sensitive to AgNP exposure than S. aureus regardless of AgNP size and surface properties. Full article

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35 pages, 2833 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Coordination of RNA Processing Regulation by Signal Transduction Pathways

by Veronica Ruta, Vittoria Pagliarini and Claudio Sette

Biomolecules 2021, 11(10), 1475; https://doi.org/10.3390/biom11101475 - 7 Oct 2021

Cited by 9 | Viewed by 3989

Abstract

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as [...] Read more.

Signal transduction pathways transmit the information received from external and internal cues and generate a response that allows the cell to adapt to changes in the surrounding environment. Signaling pathways trigger rapid responses by changing the activity or localization of existing molecules, as well as long-term responses that require the activation of gene expression programs. All steps involved in the regulation of gene expression, from transcription to processing and utilization of new transcripts, are modulated by multiple signal transduction pathways. This review provides a broad overview of the post-translational regulation of factors involved in RNA processing events by signal transduction pathways, with particular focus on the regulation of pre-mRNA splicing, cleavage and polyadenylation. The effects of several post-translational modifications (i.e., sumoylation, ubiquitination, methylation, acetylation and phosphorylation) on the expression, subcellular localization, stability and affinity for RNA and protein partners of many RNA-binding proteins are highlighted. Moreover, examples of how some of the most common signal transduction pathways can modulate biological processes through changes in RNA processing regulation are illustrated. Lastly, we discuss challenges and opportunities of therapeutic approaches that correct RNA processing defects and target signaling molecules. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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21 pages, 7014 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

An OpenCV-Based Approach for Automated Cardiac Rhythm Measurement in Zebrafish from Video Datasets

by Ali Farhan, Kevin Adi Kurnia, Ferry Saputra, Kelvin H.-C. Chen, Jong-Chin Huang, Marri Jmelou M. Roldan, Yu-Heng Lai and Chung-Der Hsiao

Biomolecules 2021, 11(10), 1476; https://doi.org/10.3390/biom11101476 - 7 Oct 2021

Cited by 11 | Viewed by 4609

Abstract

Cardiac arrhythmia has been defined as one of the abnormal heart rhythm symptoms, which is a common problem dealt with by cardiologists. Zebrafish were established as a powerful animal model with a transparent body that enables optical observation to analyze cardiac morphology and [...] Read more.

Cardiac arrhythmia has been defined as one of the abnormal heart rhythm symptoms, which is a common problem dealt with by cardiologists. Zebrafish were established as a powerful animal model with a transparent body that enables optical observation to analyze cardiac morphology and cardiac rhythm regularity. Currently, research has observed heart-related parameters in zebrafish, which used different approaches, such as starting from the use of fluorescent transgenic zebrafish, different software, and different observation methods. In this study, we developed an innovative approach by using the OpenCV library to measure zebrafish larvae heart rate and rhythm. The program is designed in Python, with the feature of multiprocessing for simultaneous region-of-interest (ROI) detection, covering both the atrium and ventricle regions in the video, and was designed to be simple and user-friendly, having utility even for users who are unfamiliar with Python. Results were validated with our previously published method using ImageJ, which observes pixel changes. In summary, the results showed good consistency in heart rate-related parameters. In addition, the established method in this study also can be widely applied to other invertebrates (like Daphnia) for cardiac rhythm measurement. Full article

(This article belongs to the Special Issue Fish as Simple Models for Human Disease and Drug Screen)

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15 pages, 3125 KiB

Open AccessEditor’s ChoiceArticle

Rosmarinic Acid Exhibits a Lipid-Lowering Effect by Modulating the Expression of Reverse Cholesterol Transporters and Lipid Metabolism in High-Fat Diet-Fed Mice

by Jean Baptiste Nyandwi, Young Shin Ko, Hana Jin, Seung Pil Yun, Sang Won Park and Hye Jung Kim

Biomolecules 2021, 11(10), 1470; https://doi.org/10.3390/biom11101470 - 6 Oct 2021

Cited by 17 | Viewed by 3953

Abstract

Hyperlipidemia is a potent risk factor for the development of cardiovascular diseases. The reverse cholesterol transport (RCT) process has been shown to alleviate hyperlipidemia and protect against cardiovascular diseases. Recently, rosmarinic acid was reported to exhibit lipid-lowering effects. However, the underlying mechanism is [...] Read more.

Hyperlipidemia is a potent risk factor for the development of cardiovascular diseases. The reverse cholesterol transport (RCT) process has been shown to alleviate hyperlipidemia and protect against cardiovascular diseases. Recently, rosmarinic acid was reported to exhibit lipid-lowering effects. However, the underlying mechanism is still unclear. This study aims to investigate whether rosmarinic acid lowers lipids by modulating the RCT process in high-fat diet (HFD)-induced hyperlipidemic C57BL/6J mice. Our results indicated that rosmarinic acid treatment significantly decreased body weight, blood glucose, and plasma total cholesterol and triglyceride levels in HFD-fed mice. Rosmarinic acid increased the expression levels of cholesterol uptake-associated receptors in liver tissues, including scavenger receptor B type 1 (SR-B1) and low-density lipoprotein receptor (LDL-R). Furthermore, rosmarinic acid treatment notably increased the expression of cholesterol excretion molecules, ATP-binding cassette G5 (ABCG5) and G8 (ABCG8) transporters, and cholesterol 7 alpha-hydroxylase A1 (CYP7A1) as well as markedly reduced cholesterol and triglyceride levels in liver tissues. In addition, rosmarinic acid facilitated fatty acid oxidation through AMP-activated protein kinase (AMPK)-mediated carnitine palmitoyltransferase 1A (CPT1A) induction. In conclusion, rosmarinic acid exhibited a lipid-lowering effect by modulating the expression of RCT-related proteins and lipid metabolism-associated molecules, confirming its potential for the prevention or treatment of hyperlipidemia-derived diseases. Full article

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17 pages, 2856 KiB

Open AccessEditor’s ChoiceArticle

AG-205 Upregulates Enzymes Involved in Cholesterol Biosynthesis and Steroidogenesis in Human Endometrial Cells Independently of PGRMC1 and Related MAPR Proteins

by Charlotte Thieffry, Marie Van Wynendaele, Asena Aynaci, Mauriane Maja, Caroline Dupuis, Axelle Loriot, Etienne Marbaix and Patrick Henriet

Biomolecules 2021, 11(10), 1472; https://doi.org/10.3390/biom11101472 - 6 Oct 2021

Cited by 11 | Viewed by 2942

Abstract

An inappropriate response to progestogens in the human endometrium can result in fertility issues and jeopardize progestin-based treatments against pathologies such as endometriosis. PGRMC1 can mediate progesterone response in the breast and ovaries but its endometrial functions remain unknown. AG-205 is an alleged [...] Read more.

An inappropriate response to progestogens in the human endometrium can result in fertility issues and jeopardize progestin-based treatments against pathologies such as endometriosis. PGRMC1 can mediate progesterone response in the breast and ovaries but its endometrial functions remain unknown. AG-205 is an alleged PGRMC1 inhibitor but its specificity was recently questioned. We added AG-205 in the cultures of two endometrial cell lines and performed a transcriptomic comparison. AG-205 significantly increased expression of genes coding enzymes of the cholesterol biosynthetic pathway or of steroidogenesis. However, these observations were not reproduced with cells transfected with siRNA against PGRMC1 or its related proteins (MAPRs). Furthermore, AG-205 retained its ability to increase expression of selected target genes even when expression of PGRMC1 or all MAPRs was concomitantly downregulated, indicating that neither PGRMC1 nor any MAPR is required to mediate AG-205 effect. In conclusion, although AG-205 has attractive effects encouraging its use to develop therapeutic strategies, for instance against breast cancer, our study delivers two important warning messages. First, AG-205 is not specific for PGRMC1 or other MAPRs and its mechanisms of action remain unclear. Second, due to its effects on genes involved in steroidogenesis, its use may increase the risk for endometrial pathologies resulting from imbalanced hormones concentrations. Full article

(This article belongs to the Section Molecular Biology)

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16 pages, 4104 KiB

Open AccessEditor’s ChoiceArticle

DJ-1 Acts as a Scavenger of α-Synuclein Oligomers and Restores Monomeric Glycated α-Synuclein

by Tamr B. Atieh, Jonathan Roth, Xue Yang, Cody L. Hoop and Jean Baum

Biomolecules 2021, 11(10), 1466; https://doi.org/10.3390/biom11101466 - 6 Oct 2021

Cited by 7 | Viewed by 3730

Abstract

Glycation of α-synuclein (αSyn), as occurs with aging, has been linked to the progression of Parkinson’s disease (PD) through the promotion of advanced glycation end-products and the formation of toxic oligomers that cannot be properly cleared from neurons. DJ-1, an antioxidative protein that [...] Read more.

Glycation of α-synuclein (αSyn), as occurs with aging, has been linked to the progression of Parkinson’s disease (PD) through the promotion of advanced glycation end-products and the formation of toxic oligomers that cannot be properly cleared from neurons. DJ-1, an antioxidative protein that plays a critical role in PD pathology, has been proposed to repair glycation in proteins, yet a mechanism has not been elucidated. In this study, we integrate solution nuclear magnetic resonance (NMR) spectroscopy and liquid atomic force microscopy (AFM) techniques to characterize glycated N-terminally acetylated-αSyn (glyc-ac-αSyn) and its interaction with DJ-1. Glycation of ac-αSyn by methylglyoxal increases oligomer formation, as visualized by AFM in solution, resulting in decreased dynamics of the monomer amide backbone around the Lys residues, as measured using NMR. Upon addition of DJ-1, this NMR signature of glyc-ac-αSyn monomers reverts to a native ac-αSyn-like character. This phenomenon is reversible upon removal of DJ-1 from the solution. Using relaxation-based NMR, we have identified the binding site on DJ-1 for glycated and native ac-αSyn as the catalytic pocket and established that the oxidation state of the catalytic cysteine is imperative for binding. Based on our results, we propose a novel mechanism by which DJ-1 scavenges glyc-ac-αSyn oligomers without chemical deglycation, suppresses glyc-ac-αSyn monomer–oligomer interactions, and releases free glyc-ac-αSyn monomers in solution. The interference of DJ-1 with ac-αSyn oligomers may promote free ac-αSyn monomer in solution and suppress the propagation of toxic oligomer and fibril species. These results expand the understanding of the role of DJ-1 in PD pathology by acting as a scavenger for aggregated αSyn. Full article

(This article belongs to the Special Issue The Amazing World of IDPs in Human Diseases II)

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17 pages, 1939 KiB

Open AccessEditor’s ChoiceReview

Natural Products Are a Promising Source for Anthelmintic Drug Discovery

by K. L. T. Dilrukshi Jayawardene, Enzo A. Palombo and Peter R. Boag

Biomolecules 2021, 11(10), 1457; https://doi.org/10.3390/biom11101457 - 4 Oct 2021

Cited by 37 | Viewed by 7613

Abstract

Parasitic nematodes infect almost all forms of life. In the human context, parasites are one of the major causative factors for physical and intellectual growth retardation in the developing world. In the agricultural setting, parasites have a great economic impact through a reduction [...] Read more.

Parasitic nematodes infect almost all forms of life. In the human context, parasites are one of the major causative factors for physical and intellectual growth retardation in the developing world. In the agricultural setting, parasites have a great economic impact through a reduction in livestock performance or control cost. The main method of controlling these devastating conditions is the use of anthelmintic drugs. Unfortunately, there are only a few anthelmintic drug classes available in the market and significant resistance has developed in most of the parasitic species of livestock. Therefore, development of new anthelmintics with different modes of action is critical for sustainable parasitic control in the future. The drug development pipeline is broadly limited to two types of molecules, namely synthetic compounds and natural plant products. Compared to synthetic compounds, natural products are highly diverse, and many have historically proven valuable in folk medicine to treat various gastrointestinal ailments. This review focus on the use of traditional knowledge-based plant extracts in the development of new therapeutic leads, the approaches used as screening techniques, and common bottlenecks and opportunities in plant-based anthelmintic drug discovery. Full article

(This article belongs to the Section Natural and Bio-derived Molecules)

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16 pages, 1023 KiB

Open AccessEditor’s ChoiceReview

Stress Relief Techniques: p38 MAPK Determines the Balance of Cell Cycle and Apoptosis Pathways

by Robert H. Whitaker and Jeanette Gowen Cook

Biomolecules 2021, 11(10), 1444; https://doi.org/10.3390/biom11101444 - 2 Oct 2021

Cited by 46 | Viewed by 6349

Abstract

Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via [...] Read more.

Protein signaling networks are formed from diverse and inter-connected cell signaling pathways converging into webs of function and regulation. These signaling pathways both receive and conduct molecular messages, often by a series of post-translation modifications such as phosphorylation or through protein–protein interactions via intrinsic motifs. The mitogen activated protein kinases (MAPKs) are components of kinase cascades that transmit signals through phosphorylation. There are several MAPK subfamilies, and one subfamily is the stress-activated protein kinases, which in mammals is the p38 family. The p38 enzymes mediate a variety of cellular outcomes including DNA repair, cell survival/cell fate decisions, and cell cycle arrest. The cell cycle is itself a signaling system that precisely controls DNA replication, chromosome segregation, and cellular division. Another indispensable cell function influenced by the p38 stress response is programmed cell death (apoptosis). As the regulators of cell survival, the BCL2 family of proteins and their dynamics are exquisitely sensitive to cell stress. The BCL2 family forms a protein–protein interaction network divided into anti-apoptotic and pro-apoptotic members, and the balance of binding between these two sides determines cell survival. Here, we discuss the intersections among the p38 MAPK, cell cycle, and apoptosis signaling pathways. Full article

(This article belongs to the Special Issue Transmembrane and Intracellular Signal Transduction Mechanisms: A Themed Issue in Honor of Professor Jeremy Thorner)

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17 pages, 1664 KiB

Open AccessEditor’s ChoiceArticle

Depside and Depsidone Synthesis in Lichenized Fungi Comes into Focus through a Genome-Wide Comparison of the Olivetoric Acid and Physodic Acid Chemotypes of Pseudevernia furfuracea

by Garima Singh, Daniele Armaleo, Francesco Dal Grande and Imke Schmitt

Biomolecules 2021, 11(10), 1445; https://doi.org/10.3390/biom11101445 - 2 Oct 2021

Cited by 26 | Viewed by 4228

Abstract

Primary biosynthetic enzymes involved in the synthesis of lichen polyphenolic compounds depsides and depsidones are non-reducing polyketide synthases (NR-PKSs), and cytochrome P450s. However, for most depsides and depsidones the corresponding PKSs are unknown. Additionally, in non-lichenized fungi specific fatty acid synthases (FASs) provide [...] Read more.

Primary biosynthetic enzymes involved in the synthesis of lichen polyphenolic compounds depsides and depsidones are non-reducing polyketide synthases (NR-PKSs), and cytochrome P450s. However, for most depsides and depsidones the corresponding PKSs are unknown. Additionally, in non-lichenized fungi specific fatty acid synthases (FASs) provide starters to the PKSs. Yet, the presence of such FASs in lichenized fungi remains to be investigated. Here we implement comparative genomics and metatranscriptomics to identify the most likely PKS and FASs for olivetoric acid and physodic acid biosynthesis, the primary depside and depsidone defining the two chemotypes of the lichen Pseudevernia furfuracea. We propose that the gene cluster PF33-1_006185, found in both chemotypes, is the most likely candidate for the olivetoric acid and physodic acid biosynthesis. This is the first study to identify the gene cluster and the FAS likely responsible for olivetoric acid and physodic acid biosynthesis in a lichenized fungus. Our findings suggest that gene regulation and other epigenetic factors determine whether the mycobiont produces the depside or the depsidone, providing the first direct indication that chemotype diversity in lichens can arise through regulatory and not only through genetic diversity. Combining these results and existing literature, we propose a detailed scheme for depside/depsidone synthesis. Full article

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14 pages, 722 KiB

Open AccessEditor’s ChoiceReview

Interactions of HMGB Proteins with the Genome and the Impact on Disease

by Calvin K. Voong, James A. Goodrich and Jennifer F. Kugel

Biomolecules 2021, 11(10), 1451; https://doi.org/10.3390/biom11101451 - 2 Oct 2021

Cited by 30 | Viewed by 4417

Abstract

High Mobility Group Box (HMGB) proteins are small architectural DNA binding proteins that regulate multiple genomic processes such as DNA damage repair, nucleosome sliding, telomere homeostasis, and transcription. In doing so they control both normal cellular functions and impact a myriad of disease [...] Read more.

High Mobility Group Box (HMGB) proteins are small architectural DNA binding proteins that regulate multiple genomic processes such as DNA damage repair, nucleosome sliding, telomere homeostasis, and transcription. In doing so they control both normal cellular functions and impact a myriad of disease states, including cancers and autoimmune diseases. HMGB proteins bind to DNA and nucleosomes to modulate the local chromatin environment, which facilitates the binding of regulatory protein factors to the genome and modulates higher order chromosomal organization. Numerous studies over the years have characterized the structure and function of interactions between HMGB proteins and DNA, both biochemically and inside cells, providing valuable mechanistic insight as well as evidence these interactions influence pathological processes. This review highlights recent studies supporting the roles of HMGB1 and HMGB2 in global organization of the genome, as well as roles in transcriptional regulation and telomere maintenance via interactions with G-quadruplex structures. Moreover, emerging models for how HMGB proteins function as RNA binding proteins are presented. Nuclear HMGB proteins have broad regulatory potential to impact numerous aspects of cellular metabolism in normal and disease states. Full article

(This article belongs to the Special Issue HMG Proteins from Molecules to Disease)

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