Biomolecules

19 pages, 435 KiB

Open AccessEditor’s ChoiceReview

Mechanisms Controlling the Expression and Secretion of BDNF

by Juan Carlos Arévalo and Rubén Deogracias

Biomolecules 2023, 13(5), 789; https://doi.org/10.3390/biom13050789 - 2 May 2023

Cited by 46 | Viewed by 11830

Brain-derived nerve factor (BDNF), through TrkB receptor activation, is an important modulator for many different physiological and pathological functions in the nervous system. Among them, BDNF plays a crucial role in the development and correct maintenance of brain circuits and synaptic plasticity as [...] Read more.

Brain-derived nerve factor (BDNF), through TrkB receptor activation, is an important modulator for many different physiological and pathological functions in the nervous system. Among them, BDNF plays a crucial role in the development and correct maintenance of brain circuits and synaptic plasticity as well as in neurodegenerative diseases. The proper functioning of the central nervous system depends on the available BDNF concentrations, which are tightly regulated at transcriptional and translational levels but also by its regulated secretion. In this review we summarize the new advances regarding the molecular players involved in BDNF release. In addition, we will address how changes of their levels or function in these proteins have a great impact in those functions modulated by BDNF under physiological and pathological conditions. Full article

(This article belongs to the Special Issue Brain-Derived Neurotrophic Factor in Health and Diseases)

23 pages, 6079 KiB

Open AccessEditor’s ChoiceReview

Relaxin-like Gonad-Stimulating Peptides in Asteroidea

by Masatoshi Mita

Biomolecules 2023, 13(5), 781; https://doi.org/10.3390/biom13050781 - 30 Apr 2023

Cited by 8 | Viewed by 5115

Abstract

Starfish relaxin-like gonad-stimulating peptide (RGP) is the first identified peptide hormone with gonadotropin-like activity in invertebrates. RGP is a heterodimeric peptide, comprising A and B chains with disulfide cross-linkages. Although RGP had been named a gonad-stimulating substance (GSS), the purified peptide is a [...] Read more.

Starfish relaxin-like gonad-stimulating peptide (RGP) is the first identified peptide hormone with gonadotropin-like activity in invertebrates. RGP is a heterodimeric peptide, comprising A and B chains with disulfide cross-linkages. Although RGP had been named a gonad-stimulating substance (GSS), the purified peptide is a member of relaxin-type peptide family. Thus, GSS was renamed as RGP. The cDNA of RGP encodes not only the A and B chains, but also signal and C-peptides. After the rgp gene is translated as a precursor, mature RGP is produced by eliminating the signal and C-peptides. Hitherto, twenty-four RGP orthologs have been identified or predicted from starfish in the orders Valvatida, Forcipulatida, Paxillosida, Spinulosida, and Velatida. The molecular evolution of the RGP family is in good accordance with the phylogenetic taxonomy in Asteroidea. Recently, another relaxin-like peptide with gonadotropin-like activity, RLP2, was found in starfish. RGP is mainly present in the radial nerve cords and circumoral nerve rings, but also in the arm tips, the gonoducts, and the coelomocytes. RGP acts on ovarian follicle cells and testicular interstitial cells to induce the production of 1-methyladenine (1-MeAde), a starfish maturation-inducing hormone. RGP-induced 1-MeAde production is accompanied by an increase in intracellular cyclic AMP levels. This suggests that the receptor for RGP (RGPR) is a G protein-coupled receptor (GPCR). Two types of GPCRs, RGPR1 and RGPR2, have been postulated as candidates. Furthermore, 1-MeAde produced by RGP not only induces oocyte maturation, but also induces gamete shedding, possibly by stimulating the secretion of acetylcholine in the ovaries and testes. Thus, RGP plays an important role in starfish reproduction, but its secretion mechanism is still unknown. It has also been revealed that RGP is found in the peripheral adhesive papillae of the brachiolaria arms. However, gonads are not developed in the larvae before metamorphosis. It may be possible to discover new physiological functions of RGP other than gonadotropin-like activity. Full article

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

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8 pages, 2403 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Cornea: No Difference in the Wound Healing Response to Injury Related to Whether, or Not, There’s a Bowman’s Layer

by Steven E. Wilson

Biomolecules 2023, 13(5), 771; https://doi.org/10.3390/biom13050771 - 29 Apr 2023

Cited by 14 | Viewed by 4385

Abstract

Bowman’s layer is an acellular layer in the anterior stroma found in the corneas of humans, most other primates, chickens, and some other species. Many other species, however, including the rabbit, dog, wolf, cat, tiger, and lion, do not have a Bowman’s layer. [...] Read more.

Bowman’s layer is an acellular layer in the anterior stroma found in the corneas of humans, most other primates, chickens, and some other species. Many other species, however, including the rabbit, dog, wolf, cat, tiger, and lion, do not have a Bowman’s layer. Millions of humans who have had photorefractive keratectomy over the past thirty plus years have had Bowman’s layer removed by excimer laser ablation over their central cornea without apparent sequelae. A prior study showed that Bowman’s layer does not contribute significantly to mechanical stability within the cornea. Bowman’s layer does not have a barrier function, as many cytokines and growth factors, as well as other molecules, such as EBM component perlecan, pass bidirectionally through Bowman’s layer in normal corneal functions, and during the response to epithelial scrape injury. We hypothesized that Bowman’s layer represents a visible indicator of ongoing cytokine and growth factor-mediated interactions that occur between corneal epithelial cells (and corneal endothelial cells) and stromal keratocytes that maintain the normal corneal tissue organization via negative chemotactic and apoptotic effects of modulators produced by the epithelium on stromal keratocytes. Interleukin-1 alpha, produced constitutively by corneal epithelial cells and endothelial cells, is thought to be one of these cytokines. Bowman’s layer is destroyed in corneas with advanced Fuchs’ dystrophy or pseudophakic bullous keratopathy when the epithelium becomes edematous and dysfunctional, and fibrovascular tissue commonly develops beneath and/or within the epithelium in these corneas. Bowman’s-like layers have been noted to develop surrounding epithelial plugs within the stromal incisions years after radial keratotomy. Although there are species-related differences in corneal wound healing, and even between strains within a species, these differences are not related to the presence or absence of Bowman’s layer. Full article

(This article belongs to the Special Issue Ocular Damage and Wound Healing: From Mechanisms Exploration to Treatment)

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14 pages, 2601 KiB

Open AccessEditor’s ChoiceReview

Cardiac Imaging Biomarkers in Chronic Kidney Disease

by Silvia C. Valbuena-López, Giovanni Camastra, Luca Cacciotti, Eike Nagel, Valentina O. Puntmann and Luca Arcari

Biomolecules 2023, 13(5), 773; https://doi.org/10.3390/biom13050773 - 29 Apr 2023

Cited by 8 | Viewed by 3920

Abstract

Uremic cardiomyopathy (UC), the peculiar cardiac remodeling secondary to the systemic effects of renal dysfunction, is characterized by left ventricular (LV) diffuse fibrosis with hypertrophy (LVH) and stiffness and the development of heart failure and increased rates of cardiovascular mortality. Several imaging modalities [...] Read more.

Uremic cardiomyopathy (UC), the peculiar cardiac remodeling secondary to the systemic effects of renal dysfunction, is characterized by left ventricular (LV) diffuse fibrosis with hypertrophy (LVH) and stiffness and the development of heart failure and increased rates of cardiovascular mortality. Several imaging modalities can be used to obtain a non-invasive assessment of UC by different imaging biomarkers, which is the focus of the present review. Echocardiography has been largely employed in recent decades, especially for the determination of LVH by 2-dimensional imaging and diastolic dysfunction by pulsed-wave and tissue Doppler, where it retains a robust prognostic value; more recent techniques include parametric assessment of cardiac deformation by speckle tracking echocardiography and the use of 3D-imaging. Cardiac magnetic resonance (CMR) imaging allows a more accurate assessment of cardiac dimensions, including the right heart, and deformation by feature-tracking imaging; however, the most evident added value of CMR remains tissue characterization. T1 mapping demonstrated diffuse fibrosis in CKD patients, increasing with the worsening of renal disease and evident even in early stages of the disease, with few, but emerging, prognostic data. Some studies using T2 mapping highlighted the presence of subtle, diffuse myocardial edema. Finally, computed tomography, though rarely used to specifically assess UC, might provide incidental findings carrying prognostic relevance, including information on cardiac and vascular calcification. In summary, non-invasive cardiovascular imaging provides a wealth of imaging biomarkers for the characterization and risk-stratification of UC; integrating results from different imaging techniques can aid a better understanding of the physiopathology of UC and improve the clinical management of patients with CKD. Full article

(This article belongs to the Special Issue Novel Biomarkers of Kidney Diseases)

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13 pages, 1831 KiB

Open AccessEditor’s ChoiceArticle

Glucose Transporter Glut1-Dependent Metabolic Reprogramming Regulates Lipopolysaccharide-Induced Inflammation in RAW264.7 Macrophages

by Alex Cornwell, Hubert Ziółkowski and Alireza Badiei

Biomolecules 2023, 13(5), 770; https://doi.org/10.3390/biom13050770 - 29 Apr 2023

Cited by 17 | Viewed by 4340

Abstract

This study investigated the critical role of Glut1-mediated glucose metabolism in the inflammatory response of macrophages, which are energy-intensive cells within the innate immune system. Inflammation leads to increased Glut1 expression, ensuring sufficient glucose uptake to support macrophage functions. We demonstrated that using [...] Read more.

This study investigated the critical role of Glut1-mediated glucose metabolism in the inflammatory response of macrophages, which are energy-intensive cells within the innate immune system. Inflammation leads to increased Glut1 expression, ensuring sufficient glucose uptake to support macrophage functions. We demonstrated that using siRNA to knock down Glut1 reduces the expression of various pro-inflammatory cytokines and markers, such as IL-6, iNOS, MHC II/CD40, reactive oxygen species, and the hydrogen sulfide (H₂S)-producing enzyme cystathionine γ-lyase (CSE). Glut1 activates a pro-inflammatory profile through a nuclear factor (NF)-κB, while silencing Glut1 can prevent lipopolysaccharide (LPS)-induced IκB degradation, blocking NF-κB activation. Glut1’s role in autophagy, an essential process for macrophage functions such as antigen presentation, phagocytosis, and cytokine secretion, was also measured. The findings show that LPS stimulation decreases autophagosome formation, but Glut1 knockdown reverses this effect, increasing autophagy beyond control levels. The study highlights Glut1’s importance in macrophage immune responses and its regulation of apoptosis during LPS stimulation. Knocking down Glut1 negatively impacts cell viability and mitochondrial intrinsic pathway signaling. These findings collectively suggest that targeting macrophage glucose metabolism through Glut1 could potentially serve as a target for controlling inflammation. Full article

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21 pages, 3287 KiB

Open AccessEditor’s ChoiceArticle

Mice Mutated in the Third Fibronectin Domain of L1 Show Enhanced Hippocampal Neuronal Cell Death, Astrogliosis and Alterations in Behavior

by Ludovica Congiu, Viviana Granato, Igor Jakovcevski, Ralf Kleene, Luciana Fernandes, Sandra Freitag, Matthias Kneussel, Melitta Schachner and Gabriele Loers

Biomolecules 2023, 13(5), 776; https://doi.org/10.3390/biom13050776 - 29 Apr 2023

Cited by 2 | Viewed by 2412

Abstract

Adhesion molecules play major roles in cell proliferation, migration, survival, neurite outgrowth and synapse formation during nervous system development and in adulthood. The neural cell adhesion molecule L1 contributes to these functions during development and in synapse formation and synaptic plasticity after trauma [...] Read more.

Adhesion molecules play major roles in cell proliferation, migration, survival, neurite outgrowth and synapse formation during nervous system development and in adulthood. The neural cell adhesion molecule L1 contributes to these functions during development and in synapse formation and synaptic plasticity after trauma in adulthood. Mutations of L1 in humans result in L1 syndrome, which is associated with mild-to-severe brain malformations and mental disabilities. Furthermore, mutations in the extracellular domain were shown to cause a severe phenotype more often than mutations in the intracellular domain. To explore the outcome of a mutation in the extracellular domain, we generated mice with disruption of the dibasic sequences RK and KR that localize to position ₈₅₈RKHSKR₈₆₃ in the third fibronectin type III domain of murine L1. These mice exhibit alterations in exploratory behavior and enhanced marble burying activity. Mutant mice display higher numbers of caspase 3-positive neurons, a reduced number of principle neurons in the hippocampus, and an enhanced number of glial cells. Experiments suggest that disruption of the dibasic sequence in L1 results in subtle impairments in brain structure and functions leading to obsessive-like behavior in males and reduced anxiety in females. Full article

(This article belongs to the Special Issue More than Just Adhesion: Recognition Molecules, a Theme Issue Honoring Professor Melitta Schachner)

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17 pages, 5074 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Physico-Chemical Changes Induced by Gamma Irradiation on Some Structural Protein Extracts

by Maria Stanca, Carmen Gaidau, Traian Zaharescu, George-Alin Balan, Iulia Matei, Aurica Precupas, Anca Ruxandra Leonties and Gabriela Ionita

Biomolecules 2023, 13(5), 774; https://doi.org/10.3390/biom13050774 - 29 Apr 2023

Cited by 14 | Viewed by 2818

Abstract

In this study, the effect of gamma irradiation (10 kGy) on proteins extracted from animal hide, scales, and wool was evidenced by calorimetric (μDSC) and spectroscopic (IR, circular dichroism, and EPR) methods. Keratin was obtained from sheep wool, collagen and bovine gelatin from [...] Read more.

In this study, the effect of gamma irradiation (10 kGy) on proteins extracted from animal hide, scales, and wool was evidenced by calorimetric (μDSC) and spectroscopic (IR, circular dichroism, and EPR) methods. Keratin was obtained from sheep wool, collagen and bovine gelatin from bovine hide, and fish gelatin from fish scales. The μDSC experiments evidenced that gamma irradiation influences the thermal stability of these proteins differently. The thermal stability of keratin decreases, while a resistance to thermal denaturation was noticed for collagen and gelatins after gamma irradiation. The analysis of the IR spectra demonstrated that gamma irradiation determines changes in the vibrational modes of the amide groups that are associated with protein denaturation, most meaningfully in the case of keratin. As evidenced by circular dichroism for all proteins considered, exposure to gamma radiation produces changes in the secondary structure that are more significant than those produced by UV irradiation. Riboflavin has different effects on the secondary structure of the investigated proteins, a stabilizing effect for keratin and fish gelatin and a destabilizing effect for bovine gelatin, observed in both irradiated and non-irradiated samples. The EPR spectroscopy evidences the presence, in the gamma-irradiated samples, of free radicals centered on oxygen, and the increase in their EPR signals over time due to the presence of riboflavin. Full article

(This article belongs to the Special Issue Biomarkers of Oxidative and Radical Stress)

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17 pages, 6737 KiB

Open AccessEditor’s ChoiceArticle

Unexpected Distribution of Chitin and Chitin Synthase across Soft-Bodied Cnidarians

by Lauren E. Vandepas, Michael G. Tassia, Kenneth M. Halanych and Chris T. Amemiya

Biomolecules 2023, 13(5), 777; https://doi.org/10.3390/biom13050777 - 29 Apr 2023

Cited by 5 | Viewed by 3355

Abstract

Cnidarians are commonly recognized as sea jellies, corals, or complex colonies such as the Portuguese man-of-war. While some cnidarians possess rigid internal calcareous skeletons (e.g., corals), many are soft-bodied. Intriguingly, genes coding for the chitin-biosynthetic enzyme, chitin synthase (CHS), were recently identified [...] Read more.

Cnidarians are commonly recognized as sea jellies, corals, or complex colonies such as the Portuguese man-of-war. While some cnidarians possess rigid internal calcareous skeletons (e.g., corals), many are soft-bodied. Intriguingly, genes coding for the chitin-biosynthetic enzyme, chitin synthase (CHS), were recently identified in the model anemone Nematostella vectensis, a species lacking hard structures. Here we report the prevalence and diversity of CHS across Cnidaria and show that cnidarian chitin synthase genes display diverse protein domain organizations. We found that CHS is expressed in cnidarian species and/or developmental stages with no reported chitinous or rigid morphological structures. Chitin affinity histochemistry indicates that chitin is present in soft tissues of some scyphozoan and hydrozoan medusae. To further elucidate the biology of chitin in cnidarian soft tissues, we focused on CHS expression in N. vectensis. Spatial expression data show that three CHS orthologs are differentially expressed in Nematostella embryos and larvae during development, suggesting that chitin has an integral role in the biology of this species. Understanding how a non-bilaterian lineage such as Cnidaria employs chitin may provide new insight into hitherto unknown functions of polysaccharides in animals, as well as their role in the evolution of biological novelty. Full article

(This article belongs to the Collection Feature Papers in Biochemistry)

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34 pages, 6792 KiB

Open AccessFeature PaperEditor’s ChoiceReview

A New Generation of IMiDs as Treatments for Neuroinflammatory and Neurodegenerative Disorders

by Katherine O. Kopp, Margaret E. Greer, Elliot J. Glotfelty, Shih-Chang Hsueh, David Tweedie, Dong Seok Kim, Marcella Reale, Neil Vargesson and Nigel H. Greig

Biomolecules 2023, 13(5), 747; https://doi.org/10.3390/biom13050747 - 26 Apr 2023

Cited by 14 | Viewed by 5922

Abstract

The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, [...] Read more.

The immunomodulatory imide drug (IMiD) class, which includes the founding drug member thalidomide and later generation drugs, lenalidomide and pomalidomide, has dramatically improved the clinical treatment of specific cancers, such as multiple myeloma, and it combines potent anticancer and anti-inflammatory actions. These actions, in large part, are mediated by IMiD binding to the human protein cereblon that forms a critical component of the E3 ubiquitin ligase complex. This complex ubiquitinates and thereby regulates the levels of multiple endogenous proteins. However, IMiD-cereblon binding modifies cereblon’s normal targeted protein degradation towards a new set of neosubstrates that underlies the favorable pharmacological action of classical IMiDs, but also their adverse actions—in particular, their teratogenicity. The ability of classical IMiDs to reduce the synthesis of key proinflammatory cytokines, especially TNF-α levels, makes them potentially valuable to reposition as drugs to mitigate inflammatory-associated conditions and, particularly, neurological disorders driven by an excessive neuroinflammatory element, as occurs in traumatic brain injury, Alzheimer’s and Parkinson’s diseases, and ischemic stroke. The teratogenic and anticancer actions of classical IMiDs are substantial liabilities for effective drugs in these disorders and can theoretically be dialed out of the drug class. We review a select series of novel IMiDs designed to avoid binding with human cereblon and/or evade degradation of downstream neosubstrates considered to underpin the adverse actions of thalidomide-like drugs. These novel non-classical IMiDs hold potential as new medications for erythema nodosum leprosum (ENL), a painful inflammatory skin condition associated with Hansen’s disease for which thalidomide remains widely used, and, in particular, as a new treatment strategy for neurodegenerative disorders in which neuroinflammation is a key component. Full article

(This article belongs to the Section Molecular Medicine)

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18 pages, 1065 KiB

Open AccessEditor’s ChoiceReview

Update on Diabetic Kidney Disease (DKD): Focus on Non-Albuminuric DKD and Cardiovascular Risk

by Sabrina Scilletta, Maurizio Di Marco, Nicoletta Miano, Agnese Filippello, Stefania Di Mauro, Alessandra Scamporrino, Marco Musmeci, Giuseppe Coppolino, Francesco Di Giacomo Barbagallo, Giosiana Bosco, Roberto Scicali, Salvatore Piro, Francesco Purrello and Antonino Di Pino

Biomolecules 2023, 13(5), 752; https://doi.org/10.3390/biom13050752 - 26 Apr 2023

Cited by 46 | Viewed by 11612

Abstract

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD [...] Read more.

The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m², absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD. Full article

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

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15 pages, 3389 KiB

Open AccessEditor’s ChoiceArticle

Liposomal DQ in Combination with Copper Inhibits ARID1A Mutant Ovarian Cancer Growth

by Xuejia Kang, Qi Wang, Siqi Wu, Chuanyu Wang, Manjusha Annaji, Chung-Hui Huang, Jianzhong Shen, Pengyu Chen and R. Jayachandra Babu

Biomolecules 2023, 13(5), 744; https://doi.org/10.3390/biom13050744 - 25 Apr 2023

Cited by 4 | Viewed by 2798

Abstract

Therapeutic strategies for ARID1A-mutant ovarian cancers are limited. Higher basal reactive oxygen species (ROS) and lower basal glutathione (GSH) empower the aggressive proliferation ability and strong metastatic property of OCCCs, indicated by the increased marker of epithelial-mesenchymal transition (EMT) and serving the immunosuppressive [...] Read more.

Therapeutic strategies for ARID1A-mutant ovarian cancers are limited. Higher basal reactive oxygen species (ROS) and lower basal glutathione (GSH) empower the aggressive proliferation ability and strong metastatic property of OCCCs, indicated by the increased marker of epithelial-mesenchymal transition (EMT) and serving the immunosuppressive microenvironment. However, the aberrant redox homeostasis also empowers the sensitivity of DQ-Lipo/Cu in a mutant cell line. DQ, a carbamodithioic acid derivative, generates dithiocarbamate (DDC) in response to ROS, and the chelation of Cu and DDC further generates ROS and provides a ROS cascade. Besides, quinone methide (QM) released by DQ targets the vulnerability of GSH; this effect, plus the increase of ROS, destroys the redox homeostasis and causes cancer cell death. Also importantly, the formed Cu(DDC)₂ is a potent cytotoxic anti-cancer drug that successfully induces immunogenic cell death (ICD). The synergistic effect of EMT regulation and ICD will contribute to managing cancer metastasis and possible drug resistance. In summary, our DQ-Lipo/Cu shows promising inhibitory effects in cancer proliferation, EMT markers, and “heat” the immune response. Full article

(This article belongs to the Section Molecular Medicine)

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17 pages, 2389 KiB

Open AccessEditor’s ChoiceArticle

Plasmalogens: Free Radical Reactivity and Identification of Trans Isomers Relevant to Biological Membranes

by Carla Ferreri, Alessandra Ferocino, Gessica Batani, Chryssostomos Chatgilialoglu, Vanda Randi, Maria Vittoria Riontino, Fabrizio Vetica and Anna Sansone

Biomolecules 2023, 13(5), 730; https://doi.org/10.3390/biom13050730 - 24 Apr 2023

Cited by 11 | Viewed by 4229

Abstract

Plasmalogens are membrane phospholipids with two fatty acid hydrocarbon chains linked to L-glycerol, one containing a characteristic cis-vinyl ether function and the other one being a polyunsaturated fatty acid (PUFA) residue linked through an acyl function. All double bonds in these structures display [...] Read more.

Plasmalogens are membrane phospholipids with two fatty acid hydrocarbon chains linked to L-glycerol, one containing a characteristic cis-vinyl ether function and the other one being a polyunsaturated fatty acid (PUFA) residue linked through an acyl function. All double bonds in these structures display the cis geometrical configuration due to desaturase enzymatic activity and they are known to be involved in the peroxidation process, whereas the reactivity through cis-trans double bond isomerization has not yet been identified. Using 1-(1Z-octadecenyl)-2-arachidonoyl-sn-glycero-3-phosphocholine (C18 plasm-20:4 PC) as a representative molecule, we showed that the cis-trans isomerization can occur at both plasmalogen unsaturated moieties, and the product has characteristic analytical signatures useful for omics applications. Using plasmalogen-containing liposomes and red blood cell (RBC) ghosts under biomimetic Fenton-like conditions, in the presence or absence of thiols, peroxidation, and isomerization processes were found to occur with different reaction outcomes due to the particular liposome compositions. These results allow gaining a full scenario of plasmalogen reactivity under free radical conditions. Moreover, clarification of the plasmalogen reactivity under acidic and alkaline conditions was carried out, identifying the best protocol for RBC membrane fatty acid analysis due to their plasmalogen content of 15–20%. These results are important for lipidomic applications and for achieving a full scenario of radical stress in living organisms. Full article

(This article belongs to the Special Issue Biomarkers of Oxidative and Radical Stress)

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29 pages, 4603 KiB

Open AccessEditor’s ChoiceArticle

Structural and Biochemical Characterization of Mycobacterium tuberculosis Zinc SufU-SufS Complex

by Ingie Elchennawi, Philippe Carpentier, Christelle Caux, Marine Ponge and Sandrine Ollagnier de Choudens

Biomolecules 2023, 13(5), 732; https://doi.org/10.3390/biom13050732 - 24 Apr 2023

Cited by 12 | Viewed by 4799

Abstract

Iron-sulfur (Fe-S) clusters are inorganic prosthetic groups in proteins composed exclusively of iron and inorganic sulfide. These cofactors are required in a wide range of critical cellular pathways. Iron-sulfur clusters do not form spontaneously in vivo; several proteins are required to mobilize sulfur [...] Read more.

Iron-sulfur (Fe-S) clusters are inorganic prosthetic groups in proteins composed exclusively of iron and inorganic sulfide. These cofactors are required in a wide range of critical cellular pathways. Iron-sulfur clusters do not form spontaneously in vivo; several proteins are required to mobilize sulfur and iron, assemble and traffic-nascent clusters. Bacteria have developed several Fe-S assembly systems, such as the ISC, NIF, and SUF systems. Interestingly, in Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), the SUF machinery is the primary Fe-S biogenesis system. This operon is essential for the viability of Mtb under normal growth conditions, and the genes it contains are known to be vulnerable, revealing the Mtb SUF system as an interesting target in the fight against tuberculosis. In the present study, two proteins of the Mtb SUF system were characterized for the first time: Rv1464(sufS) and Rv1465(sufU). The results presented reveal how these two proteins work together and thus provide insights into Fe-S biogenesis/metabolism by this pathogen. Combining biochemistry and structural approaches, we showed that Rv1464 is a type II cysteine-desulfurase enzyme and that Rv1465 is a zinc-dependent protein interacting with Rv1464. Endowed with a sulfurtransferase activity, Rv1465 significantly enhances the cysteine-desulfurase activity of Rv1464 by transferring the sulfur atom from persulfide on Rv1464 to its conserved Cys40 residue. The zinc ion is important for the sulfur transfer reaction between SufS and SufU, and His354 in SufS plays an essential role in this reaction. Finally, we showed that Mtb SufS-SufU is more resistant to oxidative stress than E. coli SufS-SufE and that the presence of zinc in SufU is likely responsible for this improved resistance. This study on Rv1464 and Rv1465 will help guide the design of future anti-tuberculosis agents. Full article

(This article belongs to the Special Issue Biomolecule-Metal Ion Interaction)

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25 pages, 9999 KiB

Open AccessEditor’s ChoiceReview

Bio-Based Valorization of Lignin-Derived Phenolic Compounds: A Review

by Ludmila Martínková, Michal Grulich, Miroslav Pátek, Barbora Křístková and Margit Winkler

Biomolecules 2023, 13(5), 717; https://doi.org/10.3390/biom13050717 - 22 Apr 2023

Cited by 42 | Viewed by 6396

Abstract

Lignins are the most abundant biopolymers that consist of aromatic units. Lignins are obtained by fractionation of lignocellulose in the form of “technical lignins”. The depolymerization (conversion) of lignin and the treatment of depolymerized lignin are challenging processes due to the complexity and [...] Read more.

Lignins are the most abundant biopolymers that consist of aromatic units. Lignins are obtained by fractionation of lignocellulose in the form of “technical lignins”. The depolymerization (conversion) of lignin and the treatment of depolymerized lignin are challenging processes due to the complexity and resistance of lignins. Progress toward mild work-up of lignins has been discussed in numerous reviews. The next step in the valorization of lignin is the conversion of lignin-based monomers, which are limited in number, into a wider range of bulk and fine chemicals. These reactions may need chemicals, catalysts, solvents, or energy from fossil resources. This is counterintuitive to green, sustainable chemistry. Therefore, in this review, we focus on biocatalyzed reactions of lignin monomers, e.g., vanillin, vanillic acid, syringaldehyde, guaiacols, (iso)eugenol, ferulic acid, p-coumaric acid, and alkylphenols. For each monomer, its production from lignin or lignocellulose is summarized, and, mainly, its biotransformations that provide useful chemicals are discussed. The technological maturity of these processes is characterized based on, e.g., scale, volumetric productivities, or isolated yields. The biocatalyzed reactions are compared with their chemically catalyzed counterparts if the latter are available. Full article

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

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16 pages, 3638 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Peptidoglycan Synthesis and Regulation in Bacteria

by Anne Galinier, Clémentine Delan-Forino, Elodie Foulquier, Hakima Lakhal and Frédérique Pompeo

Biomolecules 2023, 13(5), 720; https://doi.org/10.3390/biom13050720 - 22 Apr 2023

Cited by 29 | Viewed by 8458

Abstract

Bacteria must synthesize their cell wall and membrane during their cell cycle, with peptidoglycan being the primary component of the cell wall in most bacteria. Peptidoglycan is a three-dimensional polymer that enables bacteria to resist cytoplasmic osmotic pressure, maintain their cell shape and [...] Read more.

Bacteria must synthesize their cell wall and membrane during their cell cycle, with peptidoglycan being the primary component of the cell wall in most bacteria. Peptidoglycan is a three-dimensional polymer that enables bacteria to resist cytoplasmic osmotic pressure, maintain their cell shape and protect themselves from environmental threats. Numerous antibiotics that are currently used target enzymes involved in the synthesis of the cell wall, particularly peptidoglycan synthases. In this review, we highlight recent progress in our understanding of peptidoglycan synthesis, remodeling, repair, and regulation in two model bacteria: the Gram-negative Escherichia coli and the Gram-positive Bacillus subtilis. By summarizing the latest findings in this field, we hope to provide a comprehensive overview of peptidoglycan biology, which is critical for our understanding of bacterial adaptation and antibiotic resistance. Full article

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

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14 pages, 977 KiB

Open AccessEditor’s ChoiceReview

An Integrated View of Stressors as Causative Agents in OA Pathogenesis

by Joseph S. Floramo, Vladimir Molchanov, Huadie Liu, Ye Liu, Sonya E. L. Craig and Tao Yang

Biomolecules 2023, 13(5), 721; https://doi.org/10.3390/biom13050721 - 22 Apr 2023

Cited by 4 | Viewed by 4325

Abstract

Cells in the body are exposed to dynamic external and internal environments, many of which cause cell damage. The cell’s response to this damage, broadly called the stress response, is meant to promote survival and repair or remove damage. However, not all damage [...] Read more.

Cells in the body are exposed to dynamic external and internal environments, many of which cause cell damage. The cell’s response to this damage, broadly called the stress response, is meant to promote survival and repair or remove damage. However, not all damage can be repaired, and sometimes, even worse, the stress response can overtax the system itself, further aggravating homeostasis and leading to its loss. Aging phenotypes are considered a manifestation of accumulated cellular damage and defective repair. This is particularly apparent in the primary cell type of the articular joint, the articular chondrocytes. Articular chondrocytes are constantly facing the challenge of stressors, including mechanical overloading, oxidation, DNA damage, proteostatic stress, and metabolic imbalance. The consequence of the accumulation of stress on articular chondrocytes is aberrant mitogenesis and differentiation, defective extracellular matrix production and turnover, cellular senescence, and cell death. The most severe form of stress-induced chondrocyte dysfunction in the joints is osteoarthritis (OA). Here, we summarize studies on the cellular effects of stressors on articular chondrocytes and demonstrate that the molecular effectors of the stress pathways connect to amplify articular joint dysfunction and OA development. Full article

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

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21 pages, 4159 KiB

Open AccessEditor’s ChoiceArticle

A Soluble Platelet-Derived Growth Factor Receptor-β Originates via Pre-mRNA Splicing in the Healthy Brain and Is Upregulated during Hypoxia and Aging

by Laura Beth Payne, Hanaa Abdelazim, Maruf Hoque, Audra Barnes, Zuzana Mironovova, Caroline E. Willi, Jordan Darden, Clifton Houk, Meghan W. Sedovy, Scott R. Johnstone and John C. Chappell

Biomolecules 2023, 13(4), 711; https://doi.org/10.3390/biom13040711 - 21 Apr 2023

Cited by 5 | Viewed by 4411

Abstract

The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRβ) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity [...] Read more.

The platelet-derived growth factor-BB (PDGF-BB) pathway provides critical regulation of cerebrovascular pericytes, orchestrating their investment and retention within the brain microcirculation. Dysregulated PDGF Receptor-beta (PDGFRβ) signaling can lead to pericyte defects that compromise blood-brain barrier (BBB) integrity and cerebral perfusion, impairing neuronal activity and viability, which fuels cognitive and memory deficits. Receptor tyrosine kinases such as PDGF-BB and vascular endothelial growth factor-A (VEGF-A) are often modulated by soluble isoforms of cognate receptors that establish signaling activity within a physiological range. Soluble PDGFRβ (sPDGFRβ) isoforms have been reported to form by enzymatic cleavage from cerebrovascular mural cells, and pericytes in particular, largely under pathological conditions. However, pre-mRNA alternative splicing has not been widely explored as a possible mechanism for generating sPDGFRβ variants, and specifically during tissue homeostasis. Here, we found sPDGFRβ protein in the murine brain and other tissues under normal, physiological conditions. Utilizing brain samples for follow-on analysis, we identified mRNA sequences corresponding to sPDGFRβ isoforms, which facilitated construction of predicted protein structures and related amino acid sequences. Human cell lines yielded comparable sequences and protein model predictions. Retention of ligand binding capacity was confirmed for sPDGFRβ by co-immunoprecipitation. Visualizing fluorescently labeled sPDGFRβ transcripts revealed a spatial distribution corresponding to murine brain pericytes alongside cerebrovascular endothelium. Soluble PDGFRβ protein was detected throughout the brain parenchyma in distinct regions, such as along the lateral ventricles, with signals also found more broadly adjacent to cerebral microvessels consistent with pericyte labeling. To better understand how sPDGFRβ variants might be regulated, we found elevated transcript and protein levels in the murine brain with age, and acute hypoxia increased sPDGFRβ variant transcripts in a cell-based model of intact vessels. Our findings indicate that soluble isoforms of PDGFRβ likely arise from pre-mRNA alternative splicing, in addition to enzymatic cleavage mechanisms, and these variants exist under normal physiological conditions. Follow-on studies will be needed to establish potential roles for sPDGFRβ in regulating PDGF-BB signaling to maintain pericyte quiescence, BBB integrity, and cerebral perfusion—critical processes underlying neuronal health and function, and in turn, memory and cognition. Full article

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

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20 pages, 847 KiB

Open AccessEditor’s ChoiceReview

Vitamin D and Autoimmune Rheumatic Diseases

by Lambros Athanassiou, Ifigenia Kostoglou-Athanassiou, Michael Koutsilieris and Yehuda Shoenfeld

Biomolecules 2023, 13(4), 709; https://doi.org/10.3390/biom13040709 - 21 Apr 2023

Cited by 52 | Viewed by 20320

Abstract

Vitamin D is a steroid hormone with potent immune-modulating properties. It has been shown to stimulate innate immunity and induce immune tolerance. Extensive research efforts have shown that vitamin D deficiency may be related to the development of autoimmune diseases. Vitamin D deficiency [...] Read more.

Vitamin D is a steroid hormone with potent immune-modulating properties. It has been shown to stimulate innate immunity and induce immune tolerance. Extensive research efforts have shown that vitamin D deficiency may be related to the development of autoimmune diseases. Vitamin D deficiency has been observed in patients with rheumatoid arthritis (RA) and has been shown to be inversely related to disease activity. Moreover, vitamin D deficiency may be implicated in the pathogenesis of the disease. Vitamin D deficiency has also been observed in patients with systemic lupus erythematosus (SLE). It has been found to be inversely related to disease activity and renal involvement. In addition, vitamin D receptor polymorphisms have been studied in SLE. Vitamin D levels have been studied in patients with Sjogren’s syndrome, and vitamin D deficiency may be related to neuropathy and the development of lymphoma in the context of Sjogren’s syndrome. Vitamin D deficiency has been observed in ankylosing spondylitis, psoriatic arthritis (PsA), and idiopathic inflammatory myopathies. Vitamin D deficiency has also been observed in systemic sclerosis. Vitamin D deficiency may be implicated in the pathogenesis of autoimmunity, and it may be administered to prevent autoimmune disease and reduce pain in the context of autoimmune rheumatic disorders. Full article

(This article belongs to the Section Molecular Medicine)

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15 pages, 1638 KiB

Open AccessEditor’s ChoiceArticle

Adenosine A_2A Receptors Shut Down Adenosine A₁ Receptor-Mediated Presynaptic Inhibition to Promote Implementation of Hippocampal Long-Term Potentiation

by Cátia R. Lopes, Francisco Q. Gonçalves, Simão Olaio, Angelo R. Tomé, Rodrigo A. Cunha and João Pedro Lopes

Biomolecules 2023, 13(4), 715; https://doi.org/10.3390/biom13040715 - 21 Apr 2023

Cited by 9 | Viewed by 2776

Abstract

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A₁ and A_2A receptors (A₁R, A_2AR), respectively. Supramaximal activation of A₁R can block hippocampal synaptic transmission, and the tonic engagement of [...] Read more.

Adenosine operates a modulation system fine-tuning the efficiency of synaptic transmission and plasticity through A₁ and A_2A receptors (A₁R, A_2AR), respectively. Supramaximal activation of A₁R can block hippocampal synaptic transmission, and the tonic engagement of A₁R-mediated inhibition is increased with increased frequency of nerve stimulation. This is compatible with an activity-dependent increase in extracellular adenosine in hippocampal excitatory synapses, which can reach levels sufficient to block synaptic transmission. We now report that A_2AR activation decreases A₁R-medated inhibition of synaptic transmission, with particular relevance during high-frequency-induced long-term potentiation (LTP). Thus, whereas the A₁R antagonist DPCPX (50 nM) was devoid of effects on LTP magnitude, the addition of an A_2AR antagonist SCH58261 (50 nM) allowed a facilitatory effect of DPCPX on LTP to be revealed. Additionally, the activation of A_2AR with CGS21680 (30 nM) decreased the potency of the A₁R agonist CPA (6–60 nM) to inhibit hippocampal synaptic transmission in a manner prevented by SCH58261. These observations show that A_2AR play a key role in dampening A₁R during high-frequency induction of hippocampal LTP. This provides a new framework for understanding how the powerful adenosine A₁R-mediated inhibition of excitatory transmission can be controlled to allow the implementation of hippocampal LTP. Full article

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

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20 pages, 3079 KiB

Open AccessEditor’s ChoiceReview

Protective Effect of Olive Oil Microconstituents in Atherosclerosis: Emphasis on PAF Implicated Atherosclerosis Theory

by Smaragdi Antonopoulou and Constantinos A. Demopoulos

Biomolecules 2023, 13(4), 700; https://doi.org/10.3390/biom13040700 - 20 Apr 2023

Cited by 25 | Viewed by 3111

Abstract

Atherosclerosis is a progressive vascular multifactorial process. The mechanisms underlining the initiating event of atheromatous plaque formation are inflammation and oxidation. Among the modifiable risk factors for cardiovascular diseases, diet and especially the Mediterranean diet (MedDiet), has been widely recognized as one of [...] Read more.

Atherosclerosis is a progressive vascular multifactorial process. The mechanisms underlining the initiating event of atheromatous plaque formation are inflammation and oxidation. Among the modifiable risk factors for cardiovascular diseases, diet and especially the Mediterranean diet (MedDiet), has been widely recognized as one of the healthiest dietary patterns. Olive oil (OO), the main source of the fatty components of the MedDiet is superior to the other “Mono-unsaturated fatty acids containing oils” due to the existence of specific microconstituents. In this review, the effects of OO microconstituents in atherosclerosis, based on data from in vitro and in vivo studies with special attention on their inhibitory activity against PAF (Platelet-Activating Factor) actions, are presented and critically discussed. In conclusion, we propose that the anti-atherogenic effect of OO is attributed to the synergistic action of its microconstituents, mainly polar lipids that act as PAF inhibitors, specific polyphenols and α-tocopherol that also exert anti-PAF activity. This beneficial effect, also mediated through anti-PAF action, can occur from microconstituents extracted from olive pomace, a toxic by-product of the OO production process that constitutes a significant ecological problem. Daily intake of moderate amounts of OO consumed in the context of a balanced diet is significant for healthy adults. Full article

(This article belongs to the Section Cellular Biochemistry)

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33 pages, 7619 KiB

Open AccessEditor’s ChoiceReview

Multiomics Analysis Reveals Novel Genetic Determinants for Lens Differentiation, Structure, and Transparency

by Joshua Disatham, Lisa Brennan, Ales Cvekl and Marc Kantorow

Biomolecules 2023, 13(4), 693; https://doi.org/10.3390/biom13040693 - 19 Apr 2023

Cited by 4 | Viewed by 3994

Abstract

Recent advances in next-generation sequencing and data analysis have provided new gateways for identification of novel genome-wide genetic determinants governing tissue development and disease. These advances have revolutionized our understanding of cellular differentiation, homeostasis, and specialized function in multiple tissues. Bioinformatic and functional [...] Read more.

Recent advances in next-generation sequencing and data analysis have provided new gateways for identification of novel genome-wide genetic determinants governing tissue development and disease. These advances have revolutionized our understanding of cellular differentiation, homeostasis, and specialized function in multiple tissues. Bioinformatic and functional analysis of these genetic determinants and the pathways they regulate have provided a novel basis for the design of functional experiments to answer a wide range of long-sought biological questions. A well-characterized model for the application of these emerging technologies is the development and differentiation of the ocular lens and how individual pathways regulate lens morphogenesis, gene expression, transparency, and refraction. Recent applications of next-generation sequencing analysis on well-characterized chicken and mouse lens differentiation models using a variety of omics techniques including RNA-seq, ATAC-seq, whole-genome bisulfite sequencing (WGBS), chip-seq, and CUT&RUN have revealed a wide range of essential biological pathways and chromatin features governing lens structure and function. Multiomics integration of these data has established new gene functions and cellular processes essential for lens formation, homeostasis, and transparency including the identification of novel transcription control pathways, autophagy remodeling pathways, and signal transduction pathways, among others. This review summarizes recent omics technologies applied to the lens, methods for integrating multiomics data, and how these recent technologies have advanced our understanding ocular biology and function. The approach and analysis are relevant to identifying the features and functional requirements of more complex tissues and disease states. Full article

(This article belongs to the Special Issue The Genomics Era: From Reference Genomes to Pan-Genomic Graphs)

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30 pages, 2180 KiB

Open AccessEditor’s ChoiceReview

Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities

by Prashanta Silwal, Allison M. Nguyen-Thai, Haneef Ahamed Mohammad, Yanshan Wang, Paul D. Robbins, Joon Y. Lee and Nam V. Vo

Biomolecules 2023, 13(4), 686; https://doi.org/10.3390/biom13040686 - 18 Apr 2023

Cited by 98 | Viewed by 8204

Abstract

Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors [...] Read more.

Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due to accumulated unrepaired cellular damage and irreversible cell cycle arrest. Senescent cells are characterized by their senescence-associated secretory phenotype that overproduces inflammatory and catabolic factors that hamper normal tissue homeostasis. Chronic accumulation of senescent cells is thought to be associated with intervertebral disc degeneration (IDD) in an aging population. This IDD is one of the largest age-dependent chronic disorders, often associated with neurological dysfunctions such as, low back pain, radiculopathy, and myelopathy. Senescent cells (SnCs) increase in number in the aged, degenerated discs, and have a causative role in driving age-related IDD. This review summarizes current evidence supporting the role of CS on onset and progression of age-related IDD. The discussion includes molecular pathways involved in CS such as p53-p21^CIP1, p16^INK4a, NF-κB, and MAPK, and the potential therapeutic value of targeting these pathways. We propose several mechanisms of CS in IDD including mechanical stress, oxidative stress, genotoxic stress, nutritional deprivation, and inflammatory stress. There are still large knowledge gaps in disc CS research, an understanding of which will provide opportunities to develop therapeutic interventions to treat age-related IDD. Full article

(This article belongs to the Special Issue Cell Senescence in Musculoskeletal Pathology and Associated Pain)

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17 pages, 1129 KiB

Open AccessEditor’s ChoiceReview

The Multifaceted Role of Glutathione S-Transferases in Health and Disease

by Aslam M. A. Mazari, Leilei Zhang, Zhi-Wei Ye, Jie Zhang, Kenneth D. Tew and Danyelle M. Townsend

Biomolecules 2023, 13(4), 688; https://doi.org/10.3390/biom13040688 - 18 Apr 2023

Cited by 128 | Viewed by 15705

Abstract

In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable structural similarity with some overlapping functionalities. As a primary function, GSTs play a putative role in Phase II metabolism by [...] Read more.

In humans, the cytosolic glutathione S-transferase (GST) family of proteins is encoded by 16 genes presented in seven different classes. GSTs exhibit remarkable structural similarity with some overlapping functionalities. As a primary function, GSTs play a putative role in Phase II metabolism by protecting living cells against a wide variety of toxic molecules by conjugating them with the tripeptide glutathione. This conjugation reaction is extended to forming redox sensitive post-translational modifications on proteins: S-glutathionylation. Apart from these catalytic functions, specific GSTs are involved in the regulation of stress-induced signaling pathways that govern cell proliferation and apoptosis. Recently, studies on the effects of GST genetic polymorphisms on COVID-19 disease development revealed that the individuals with higher numbers of risk-associated genotypes showed higher risk of COVID-19 prevalence and severity. Furthermore, overexpression of GSTs in many tumors is frequently associated with drug resistance phenotypes. These functional properties make these proteins promising targets for therapeutics, and a number of GST inhibitors have progressed in clinical trials for the treatment of cancer and other diseases. Full article

(This article belongs to the Special Issue Versatility of Glutathione Transferase Proteins)

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19 pages, 3900 KiB

Open AccessEditor’s ChoiceReview

Circular RNA Expression Profiling by Microarray—A Technical and Practical Perspective

by Yanggu Shi and Jindong Shang

Biomolecules 2023, 13(4), 679; https://doi.org/10.3390/biom13040679 - 17 Apr 2023

Cited by 11 | Viewed by 3041

Abstract

Circular RNAs, as covalently circularized RNA loops, have many unique biochemical properties. Many circRNA biological functions and clinical indications are being continually discovered. Increasingly, circRNAs are being used as a new class of biomarkers, which are potentially superior to linear RNAs due to [...] Read more.

Circular RNAs, as covalently circularized RNA loops, have many unique biochemical properties. Many circRNA biological functions and clinical indications are being continually discovered. Increasingly, circRNAs are being used as a new class of biomarkers, which are potentially superior to linear RNAs due to the unusual cell/tissue/disease specificities and the exonuclease-resistant stabilized circular form in the biofluids. Profiling circRNA expression has been a common step in circRNA research to provide much needed insight into circRNA biology and to facilitate rapid advances in the circRNA field. We will review circRNA microarrays as a practical and effective circRNA profiling technology for regularly equipped biological or clinical research labs, share valuable experiences, and highlight the significant findings from the profiling studies. Full article

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

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15 pages, 2396 KiB

Open AccessEditor’s ChoiceReview

Phytochemical Interactions with Calmodulin and Critical Calmodulin Binding Proteins Involved in Amyloidogenesis in Alzheimer’s Disease

by Danton H. O'Day

Biomolecules 2023, 13(4), 678; https://doi.org/10.3390/biom13040678 - 15 Apr 2023

Cited by 5 | Viewed by 2958

Abstract

An increasing number of plant-based herbal treatments, dietary supplements, medical foods and nutraceuticals and their component phytochemicals are used as alternative treatments to prevent or slow the onset and progression of Alzheimer’s disease. Their appeal stems from the fact that no current pharmaceutical [...] Read more.

An increasing number of plant-based herbal treatments, dietary supplements, medical foods and nutraceuticals and their component phytochemicals are used as alternative treatments to prevent or slow the onset and progression of Alzheimer’s disease. Their appeal stems from the fact that no current pharmaceutical or medical treatment can accomplish this. While a handful of pharmaceuticals are approved to treat Alzheimer’s, none has been shown to prevent, significantly slow or stop the disease. As a result, many see the appeal of alternative plant-based treatments as an option. Here, we show that many phytochemicals proposed or used as Alzheimer’s treatments share a common theme: they work via a calmodulin-mediated mode of action. Some phytochemicals bind to and inhibit calmodulin directly while others bind to and regulate calmodulin-binding proteins, including Aβ monomers and BACE1. Phytochemical binding to Aβ monomers can prevent the formation of Aβ oligomers. A limited number of phytochemicals are also known to stimulate calmodulin gene expression. The significance of these interactions to amyloidogenesis in Alzheimer’s disease is reviewed. Full article

(This article belongs to the Special Issue Role of Amyloid Protein in Neurological Diseases)

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12 pages, 927 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Roles of sPLA₂s in Skin Homeostasis and Disease

by Kei Yamamoto, Haruka Hakoi, Saki Nomura and Makoto Murakami

Biomolecules 2023, 13(4), 668; https://doi.org/10.3390/biom13040668 - 12 Apr 2023

Cited by 5 | Viewed by 2859

Abstract

Among the phospholipase A₂ (PLA₂) family, the secreted PLA₂ (sPLA₂) family in mammals contains 11 members that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using knockout and/or transgenic mice for a nearly full [...] Read more.

Among the phospholipase A₂ (PLA₂) family, the secreted PLA₂ (sPLA₂) family in mammals contains 11 members that exhibit unique tissue or cellular distributions and enzymatic properties. Current studies using knockout and/or transgenic mice for a nearly full set of sPLA₂s, in combination with comprehensive lipidomics, have revealed the diverse pathophysiological roles of sPLA₂s in various biological events. Individual sPLA₂s exert specific functions within tissue microenvironments, likely through the hydrolysis of extracellular phospholipids. Lipids are an essential biological component for skin homeostasis, and disturbance of lipid metabolism by deletion or overexpression of lipid-metabolizing enzymes or lipid-sensing receptors often leads to skin abnormalities that are easily visible on the outside. Over the past decades, our studies using knockout and transgenic mice for various sPLA₂s have uncovered several new aspects of these enzymes as modulators of skin homeostasis and disease. This article summarizes the roles of several sPLA₂s in skin pathophysiology, providing additional insight into the research fields of sPLA₂s, lipids, and skin biology. Full article

(This article belongs to the Collection Bioactive Lipids in Inflammation, Diabetes and Cancer)

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14 pages, 1040 KiB

Open AccessEditor’s ChoiceReview

The Emerging Role of IL-9 in the Anticancer Effects of Anti-PD-1 Therapy

by Daria Vinokurova and Lionel Apetoh

Biomolecules 2023, 13(4), 670; https://doi.org/10.3390/biom13040670 - 12 Apr 2023

Cited by 11 | Viewed by 3598

Abstract

PD-1 blockade rescues failing anticancer immune responses, resulting in durable remissions in some cancer patients. Cytokines such as IFNγ and IL-2 contribute to the anti-tumor effect of PD-1 blockade. IL-9 was identified over the last decade as a cytokine demonstrating a potent ability [...] Read more.

PD-1 blockade rescues failing anticancer immune responses, resulting in durable remissions in some cancer patients. Cytokines such as IFNγ and IL-2 contribute to the anti-tumor effect of PD-1 blockade. IL-9 was identified over the last decade as a cytokine demonstrating a potent ability to harness the anticancer functions of innate and adaptive immune cells in mice. Recent translational investigations suggest that the anticancer activity of IL-9 also extends to some human cancers. Increased T cell-derived IL-9 was proposed to predict the response to anti-PD-1 therapy. Preclinical investigations accordingly revealed that IL-9 could synergize with anti-PD-1 therapy in eliciting anticancer responses. Here, we review the findings suggesting an important contribution of IL-9 in the efficacy of anti-PD-1 therapy and discuss their clinical relevance. We will also discuss the role of host factors like the microbiota and TGFβ in the tumor microenvironment (TME) in the regulation of IL-9 secretion and anti-PD-1 treatment efficacy. Full article

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15 pages, 1785 KiB

Open AccessEditor’s ChoiceReview

The Hop2-Mnd1 Complex and Its Regulation of Homologous Recombination

by Hideo Tsubouchi

Biomolecules 2023, 13(4), 662; https://doi.org/10.3390/biom13040662 - 10 Apr 2023

Cited by 6 | Viewed by 4400

Abstract

Homologous recombination (HR) is essential for meiosis in most sexually reproducing organisms, where it is induced upon entry into meiotic prophase. Meiotic HR is conducted by the collaborative effort of proteins responsible for DNA double-strand break repair and those produced specifically during meiosis. [...] Read more.

Homologous recombination (HR) is essential for meiosis in most sexually reproducing organisms, where it is induced upon entry into meiotic prophase. Meiotic HR is conducted by the collaborative effort of proteins responsible for DNA double-strand break repair and those produced specifically during meiosis. The Hop2-Mnd1 complex was originally identified as a meiosis-specific factor that is indispensable for successful meiosis in budding yeast. Later, it was found that Hop2-Mnd1 is conserved from yeasts to humans, playing essential roles in meiosis. Accumulating evidence suggests that Hop2-Mnd1 promotes RecA-like recombinases towards homology search/strand exchange. This review summarizes studies on the mechanism of the Hop2-Mnd1 complex in promoting HR and beyond. Full article

(This article belongs to the Special Issue Yeast Models for Gene Regulation)

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24 pages, 4390 KiB

Open AccessEditor’s ChoiceReview

Myocardial Inflammation as a Manifestation of Genetic Cardiomyopathies: From Bedside to the Bench

by Giovanni Peretto, Elena Sommariva, Chiara Di Resta, Martina Rabino, Andrea Villatore, Davide Lazzeroni, Simone Sala, Giulio Pompilio and Leslie T. Cooper

Biomolecules 2023, 13(4), 646; https://doi.org/10.3390/biom13040646 - 4 Apr 2023

Cited by 19 | Viewed by 4720

Abstract

Over recent years, preclinical and clinical evidence has implicated myocardial inflammation (M-Infl) in the pathophysiology and phenotypes of traditionally genetic cardiomyopathies. M-Infl resembling myocarditis on imaging and histology occurs frequently as a clinical manifestation of classically genetic cardiac diseases, including dilated and arrhythmogenic [...] Read more.

Over recent years, preclinical and clinical evidence has implicated myocardial inflammation (M-Infl) in the pathophysiology and phenotypes of traditionally genetic cardiomyopathies. M-Infl resembling myocarditis on imaging and histology occurs frequently as a clinical manifestation of classically genetic cardiac diseases, including dilated and arrhythmogenic cardiomyopathy. The emerging role of M-Infl in disease pathophysiology is leading to the identification of druggable targets for molecular treatment of the inflammatory process and a new paradigm in the field of cardiomyopathies. Cardiomyopathies constitute a leading cause of heart failure and arrhythmic sudden death in the young population. The aim of this review is to present, from bedside to bench, the current state of the art about the genetic basis of M-Infl in nonischemic cardiomyopathies of the dilated and arrhythmogenic spectrum in order to prompt future research towards the identification of novel mechanisms and treatment targets, with the ultimate goal of lowering disease morbidity and mortality. Full article

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

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21 pages, 5694 KiB

Open AccessEditor’s ChoiceArticle

Tyrosinase Magnetic Cross-Linked Enzyme Aggregates: Biocatalytic Study in Deep Eutectic Solvent Aqueous Solutions

by Myrto G. Bellou, Michaela Patila, Renia Fotiadou, Konstantinos Spyrou, Feng Yan, Petra Rudolf, Dimitrios P. Gournis and Haralambos Stamatis

Biomolecules 2023, 13(4), 643; https://doi.org/10.3390/biom13040643 - 3 Apr 2023

Cited by 9 | Viewed by 11044

Abstract

In the field of biocatalysis, the implementation of sustainable processes such as enzyme immobilization or employment of environmentally friendly solvents, like Deep Eutectic Solvents (DESs) are of paramount importance. In this work, tyrosinase was extracted from fresh mushrooms and used in a carrier-free [...] Read more.

In the field of biocatalysis, the implementation of sustainable processes such as enzyme immobilization or employment of environmentally friendly solvents, like Deep Eutectic Solvents (DESs) are of paramount importance. In this work, tyrosinase was extracted from fresh mushrooms and used in a carrier-free immobilization towards the preparation of both non-magnetic and magnetic cross-linked enzyme aggregates (CLEAs). The prepared biocatalyst was characterized and the biocatalytic and structural traits of free tyrosinase and tyrosinase magnetic CLEAs (mCLEAs) were evaluated in numerous DES aqueous solutions. The results showed that the nature and the concentration of the DESs used as co-solvents significantly affected the catalytic activity and stability of tyrosinase, while the immobilization enhanced the activity of the enzyme in comparison with the non-immobilized enzyme up to 3.6-fold. The biocatalyst retained the 100% of its initial activity after storage at −20 °C for 1 year and the 90% of its activity after 5 repeated cycles. Tyrosinase mCLEAs were further applied in the homogeneous modification of chitosan with caffeic acid in the presence of DES. The biocatalyst demonstrated great ability in the functionalization of chitosan with caffeic acid in the presence of 10% v/v DES [Bet:Gly (1:3)], enhancing the antioxidant activity of the films. Full article

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10 pages, 2839 KiB

Open AccessEditor’s ChoiceArticle

CRISPR/Cas9 Mediated Fluorescent Tagging of Caenorhabditis elegans SPE-38 Reveals a Complete Localization Pattern in Live Spermatozoa

by Yamei Zuo, Xue Mei and Andrew Singson

Biomolecules 2023, 13(4), 623; https://doi.org/10.3390/biom13040623 - 30 Mar 2023

Cited by 3 | Viewed by 2542

Abstract

The Caenorhabditis elegans spe-38 gene encodes a four-pass transmembrane molecule that is required in sperm for fertilization. In previous work, the localization of the SPE-38 protein was examined using polyclonal antibodies on spermatids and mature amoeboid spermatozoa. SPE-38 is localized to unfused membranous organelles [...] Read more.

The Caenorhabditis elegans spe-38 gene encodes a four-pass transmembrane molecule that is required in sperm for fertilization. In previous work, the localization of the SPE-38 protein was examined using polyclonal antibodies on spermatids and mature amoeboid spermatozoa. SPE-38 is localized to unfused membranous organelles (MOs) in nonmotile spermatids. Different fixation conditions revealed that SPE-38 either localized to fused MOs and the cell body plasma membrane or the pseudopod plasma membrane of mature sperm. To address this localization paradox in mature sperm, CRISPR/Cas9 genome editing was used to tag endogenous SPE-38 with fluorescent wrmScarlet-I. Homozygous male and hermaphrodite worms encoding SPE-38::wrmScarlet-I were fertile indicating the fluorescent tag does not interfere with SPE-38 function during sperm activation or fertilization. We found that SPE-38::wrmScarlet-I localized to MOs in spermatids consistent with previous antibody localization. In mature and motile spermatozoa we found SPE-38::wrmScarlet-I in fused MOs, the cell body plasma membrane, and the pseudopod plasma membrane. We conclude that the localization pattern observed with SPE-38::wrmScarlet-I represents the complete distribution of SPE-38 in mature spermatozoa and this localization pattern is consistent with a hypothesized role of SPE-38 directly in sperm-egg binding and/or fusion. Full article

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

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18 pages, 1251 KiB

Open AccessEditor’s ChoiceReview

Microtubule Regulation in Plants: From Morphological Development to Stress Adaptation

by An-Shan Hsiao and Ji-Ying Huang

Biomolecules 2023, 13(4), 627; https://doi.org/10.3390/biom13040627 - 30 Mar 2023

Cited by 13 | Viewed by 8532

Abstract

Microtubules (MTs) are essential elements of the eukaryotic cytoskeleton and are critical for various cell functions. During cell division, plant MTs form highly ordered structures, and cortical MTs guide the cell wall cellulose patterns and thus control cell size and shape. Both are [...] Read more.

Microtubules (MTs) are essential elements of the eukaryotic cytoskeleton and are critical for various cell functions. During cell division, plant MTs form highly ordered structures, and cortical MTs guide the cell wall cellulose patterns and thus control cell size and shape. Both are important for morphological development and for adjusting plant growth and plasticity under environmental challenges for stress adaptation. Various MT regulators control the dynamics and organization of MTs in diverse cellular processes and response to developmental and environmental cues. This article summarizes the recent progress in plant MT studies from morphological development to stress responses, discusses the latest techniques applied, and encourages more research into plant MT regulation. Full article

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

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14 pages, 1901 KiB

Open AccessEditor’s ChoiceArticle

Blood–Brain Barrier Integrity Is Perturbed in a Mecp2-Null Mouse Model of Rett Syndrome

by Giuseppe Pepe, Salvatore Fioriniello, Federico Marracino, Luca Capocci, Vittorio Maglione, Maurizio D’Esposito, Alba Di Pardo and Floriana Della Ragione

Biomolecules 2023, 13(4), 606; https://doi.org/10.3390/biom13040606 - 28 Mar 2023

Cited by 9 | Viewed by 4177

Abstract

Rett syndrome (RTT, online MIM 312750) is a devastating neurodevelopmental disorder characterized by motor and cognitive disabilities. It is mainly caused by pathogenetic variants in the X-linked MECP2 gene, encoding an epigenetic factor crucial for brain functioning. Despite intensive studies, the RTT pathogenetic [...] Read more.

Rett syndrome (RTT, online MIM 312750) is a devastating neurodevelopmental disorder characterized by motor and cognitive disabilities. It is mainly caused by pathogenetic variants in the X-linked MECP2 gene, encoding an epigenetic factor crucial for brain functioning. Despite intensive studies, the RTT pathogenetic mechanism remains to be fully elucidated. Impaired vascular function has been previously reported in RTT mouse models; however, whether an altered brain vascular homeostasis and the subsequent blood–brain barrier (BBB) breakdown occur in RTT and contribute to the disease-related cognitive impairment is still unknown. Interestingly, in symptomatic Mecp2-null (Mecp2^-/y, Mecp2^tm1.1Bird) mice, we found enhanced BBB permeability associated with an aberrant expression of the tight junction proteins Ocln and Cldn-5 in different brain areas, in terms of both transcript and protein levels. Additionally, Mecp2-null mice showed an altered expression of different genes encoding factors with a role in the BBB structure and function, such as Cldn3, Cldn12, Mpdz, Jam2, and Aqp4. With this study, we provide the first evidence of impaired BBB integrity in RTT and highlight a potential new molecular hallmark of the disease that might open new perspectives for the setting-up of novel therapeutic strategies. Full article

(This article belongs to the Special Issue Neurodevelopmental Disorders: Linking Genetics and Epigenetics to Disease-Related Pathways)

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15 pages, 2600 KiB

Open AccessEditor’s ChoiceArticle

Triphenyltin(IV) Carboxylates with Exceptionally High Cytotoxicity against Different Breast Cancer Cell Lines

by Ivana Predarska, Mohamad Saoud, Ibrahim Morgan, Peter Lönnecke, Goran N. Kaluđerović and Evamarie Hey-Hawkins

Biomolecules 2023, 13(4), 595; https://doi.org/10.3390/biom13040595 - 26 Mar 2023

Cited by 14 | Viewed by 2957

Abstract

Organotin(IV) carboxylates are a class of compounds explored as alternatives to platinum-containing chemotherapeutics due to propitious in vitro and in vivo results, and distinct mechanisms of action. In this study, triphenyltin(IV) derivatives of non-steroidal anti-inflammatory drugs (indomethacin (HIND) and flurbiprofen (HFBP)) are synthesized [...] Read more.

Organotin(IV) carboxylates are a class of compounds explored as alternatives to platinum-containing chemotherapeutics due to propitious in vitro and in vivo results, and distinct mechanisms of action. In this study, triphenyltin(IV) derivatives of non-steroidal anti-inflammatory drugs (indomethacin (HIND) and flurbiprofen (HFBP)) are synthesized and characterized, namely [Ph₃Sn(IND)] and [Ph₃Sn(FBP)]. The crystal structure of [Ph₃Sn(IND)] reveals penta-coordination of the central tin atom with almost perfect trigonal bipyramidal geometry with phenyl groups in the equatorial positions and two axially located oxygen atoms belonging to two distinct carboxylato (IND) ligands leading to formation of a coordination polymer with bridging carboxylato ligands. Employing MTT and CV probes, the antiproliferative effects of both organotin(IV) complexes, indomethacin, and flurbiprofen were evaluated on different breast carcinoma cells (BT-474, MDA-MB-468, MCF-7 and HCC1937). [Ph₃Sn(IND)] and [Ph₃Sn(FBP)], unlike the inactive ligand precursors, were found extremely active towards all examined cell lines, demonstrating IC₅₀ concentrations in the range of 0.076–0.200 µM. Flow cytometry was employed to examine the mode of action showing that neither apoptotic nor autophagic mechanisms were triggered within the first 48 h of treatment. However, both tin(IV) complexes inhibited cell proliferation potentially related to the dramatic reduction in NO production, resulting from downregulation of nitric oxide synthase (iNOS) enzyme expression. Full article

(This article belongs to the Special Issue Recent Advances in Anti-tumor Metal Complexes and Drug Delivery Systems)

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12 pages, 1255 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Regulation of the SUV39H Family Methyltransferases: Insights from Fission Yeast

by Rinko Nakamura and Jun-ichi Nakayama

Biomolecules 2023, 13(4), 593; https://doi.org/10.3390/biom13040593 - 25 Mar 2023

Cited by 2 | Viewed by 3649

Abstract

Histones, which make up nucleosomes, undergo various post-translational modifications, such as acetylation, methylation, phosphorylation, and ubiquitylation. In particular, histone methylation serves different cellular functions depending on the location of the amino acid residue undergoing modification, and is tightly regulated by the antagonistic action [...] Read more.

Histones, which make up nucleosomes, undergo various post-translational modifications, such as acetylation, methylation, phosphorylation, and ubiquitylation. In particular, histone methylation serves different cellular functions depending on the location of the amino acid residue undergoing modification, and is tightly regulated by the antagonistic action of histone methyltransferases and demethylases. The SUV39H family of histone methyltransferases (HMTases) are evolutionarily conserved from fission yeast to humans and play an important role in the formation of higher-order chromatin structures called heterochromatin. The SUV39H family HMTases catalyzes the methylation of histone H3 lysine 9 (H3K9), and this modification serves as a binding site for heterochromatin protein 1 (HP1) to form a higher-order chromatin structure. While the regulatory mechanism of this family of enzymes has been extensively studied in various model organisms, Clr4, a fission yeast homologue, has made an important contribution. In this review, we focus on the regulatory mechanisms of the SUV39H family of proteins, in particular, the molecular mechanisms revealed by the studies of the fission yeast Clr4, and discuss their generality in comparison to other HMTases. Full article

(This article belongs to the Special Issue Yeast Models for Gene Regulation)

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20 pages, 2777 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Bacteriophages of the Order Crassvirales: What Do We Currently Know about This Keystone Component of the Human Gut Virome?

by Linda Smith, Ekaterina Goldobina, Bianca Govi and Andrey N. Shkoporov

Biomolecules 2023, 13(4), 584; https://doi.org/10.3390/biom13040584 - 24 Mar 2023

Cited by 26 | Viewed by 4885

Abstract

The order Crassvirales comprises dsDNA bacteriophages infecting bacteria in the phylum Bacteroidetes that are found in a variety of environments but are especially prevalent in the mammalian gut. This review summarises available information on the genomics, diversity, taxonomy, and ecology of this largely [...] Read more.

The order Crassvirales comprises dsDNA bacteriophages infecting bacteria in the phylum Bacteroidetes that are found in a variety of environments but are especially prevalent in the mammalian gut. This review summarises available information on the genomics, diversity, taxonomy, and ecology of this largely uncultured viral taxon. With experimental data available from a handful of cultured representatives, the review highlights key properties of virion morphology, infection, gene expression and replication processes, and phage-host dynamics. Full article

(This article belongs to the Special Issue Virology 130 Years After Ivanovsky—A Theme Issue Commemorating the Discovery of Viruses by Dmitri Ivanovsky)

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28 pages, 6466 KiB

Open AccessEditor’s ChoiceArticle

Genome and Genetic Engineering of the House Cricket (Acheta domesticus): A Resource for Sustainable Agriculture

by Aaron T. Dossey, Brenda Oppert, Fu-Chyun Chu, Marcé D. Lorenzen, Brian Scheffler, Sheron Simpson, Sergey Koren, J. Spencer Johnston, Kosuke Kataoka and Keigo Ide

Biomolecules 2023, 13(4), 589; https://doi.org/10.3390/biom13040589 - 24 Mar 2023

Cited by 21 | Viewed by 11029

Abstract

Background: The house cricket, Acheta domesticus, is one of the most farmed insects worldwide and the foundation of an emerging industry using insects as a sustainable food source. Edible insects present a promising alternative for protein production amid a plethora of reports [...] Read more.

Background: The house cricket, Acheta domesticus, is one of the most farmed insects worldwide and the foundation of an emerging industry using insects as a sustainable food source. Edible insects present a promising alternative for protein production amid a plethora of reports on climate change and biodiversity loss largely driven by agriculture. As with other crops, genetic resources are needed to improve crickets for food and other applications. Methods: We present the first high quality annotated genome assembly of A. domesticus from long read data and scaffolded to chromosome level, providing information needed for genetic manipulation. Results: Gene groups related to immunity were annotated and will be useful for improving value to insect farmers. Metagenome scaffolds in the A. domesticus assembly, including Invertebrate Iridescent Virus 6 (IIV6), were submitted as host-associated sequences. We demonstrate both CRISPR/Cas9-mediated knock-in and knock-out of A. domesticus and discuss implications for the food, pharmaceutical, and other industries. RNAi was demonstrated to disrupt the function of the vermilion eye-color gene producing a useful white-eye biomarker phenotype. Conclusions: We are utilizing these data to develop technologies for downstream commercial applications, including more nutritious and disease-resistant crickets, as well as lines producing valuable bioproducts, such as vaccines and antibiotics. Full article

(This article belongs to the Special Issue The Genomics Era: From Reference Genomes to Pan-Genomic Graphs)

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13 pages, 782 KiB

Open AccessEditor’s ChoiceReview

Mechanical Properties and Functions of Elastin: An Overview

by Hanna Trębacz and Angelika Barzycka

Biomolecules 2023, 13(3), 574; https://doi.org/10.3390/biom13030574 - 22 Mar 2023

Cited by 67 | Viewed by 14629

Abstract

Human tissues must be elastic, much like other materials that work under continuous loads without losing functionality. The elasticity of tissues is provided by elastin, a unique protein of the extracellular matrix (ECM) of mammals. Its function is to endow soft tissues with [...] Read more.

Human tissues must be elastic, much like other materials that work under continuous loads without losing functionality. The elasticity of tissues is provided by elastin, a unique protein of the extracellular matrix (ECM) of mammals. Its function is to endow soft tissues with low stiffness, high and fully reversible extensibility, and efficient elastic–energy storage. Depending on the mechanical functions, the amount and distribution of elastin-rich elastic fibers vary between and within tissues and organs. The article presents a concise overview of the mechanical properties of elastin and its role in the elasticity of soft tissues. Both the occurrence of elastin and the relationship between its spatial arrangement and mechanical functions in a given tissue or organ are overviewed. As elastin in tissues occurs only in the form of elastic fibers, the current state of knowledge about their mechanical characteristics, as well as certain aspects of degradation of these fibers and their mechanical performance, is presented. The overview also outlines the latest understanding of the molecular basis of unique physical characteristics of elastin and, in particular, the origin of the driving force of elastic recoil after stretching. Full article

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

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15 pages, 1699 KiB

Open AccessEditor’s ChoiceReview

Heme Scavenging and Delivery: The Role of Human Serum Albumin

by Giovanna De Simone, Romualdo Varricchio, Tommaso Francesco Ruberto, Alessandra di Masi and Paolo Ascenzi

Biomolecules 2023, 13(3), 575; https://doi.org/10.3390/biom13030575 - 22 Mar 2023

Cited by 22 | Viewed by 7218

Abstract

Heme is the reactive center of several metal-based proteins that are involved in multiple biological processes. However, free heme, defined as the labile heme pool, has toxic properties that are derived from its hydrophobic nature and the Fe-atom. Therefore, the heme concentration must [...] Read more.

Heme is the reactive center of several metal-based proteins that are involved in multiple biological processes. However, free heme, defined as the labile heme pool, has toxic properties that are derived from its hydrophobic nature and the Fe-atom. Therefore, the heme concentration must be tightly controlled to maintain cellular homeostasis and to avoid pathological conditions. Therefore, different systems have been developed to scavenge either Hb (i.e., haptoglobin (Hp)) or the free heme (i.e., high-density lipoproteins (HDL), low-density lipoproteins (LDL), hemopexin (Hx), and human serum albumin (HSA)). In the first seconds after heme appearance in the plasma, more than 80% of the heme binds to HDL and LDL, and only the remaining 20% binds to Hx and HSA. Then, HSA slowly removes most of the heme from HDL and LDL, and finally, heme transits to Hx, which releases it into hepatic parenchymal cells. The Hx:heme or HSA:heme complexes are internalized via endocytosis mediated by the CD91 and CD71 receptors, respectively. As heme constitutes a major iron source for pathogens, bacteria have evolved hemophores that can extract and uptake heme from host proteins, including HSA:heme. Here, the molecular mechanisms underlying heme scavenging and delivery from HSA are reviewed. Moreover, the relevance of HSA in disease states associated with increased heme plasma concentrations are discussed. Full article

(This article belongs to the Special Issue Hemoproteins and Proteolytic Enzymes: Variations on the Theme of Functional Modulation: A Themed Issue in Honor of Professor Massimo Coletta)

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14 pages, 1278 KiB

Open AccessEditor’s ChoiceReview

Alternative mRNA Splicing and Promising Therapies in Cancer

by James D. Fackenthal

Biomolecules 2023, 13(3), 561; https://doi.org/10.3390/biom13030561 - 20 Mar 2023

Cited by 10 | Viewed by 4407

Abstract

Cancer is among the leading causes of mortality worldwide. While considerable attention has been given to genetic and epigenetic sources of cancer-specific cellular activities, the role of alternative mRNA splicing has only recently received attention as a major contributor to cancer initiation and [...] Read more.

Cancer is among the leading causes of mortality worldwide. While considerable attention has been given to genetic and epigenetic sources of cancer-specific cellular activities, the role of alternative mRNA splicing has only recently received attention as a major contributor to cancer initiation and progression. The distribution of alternate mRNA splicing variants in cancer cells is different from their non-cancer counterparts, and cancer cells are more sensitive than non-cancer cells to drugs that target components of the splicing regulatory network. While many of the alternatively spliced mRNAs in cancer cells may represent “noise” from splicing dysregulation, certain recurring splicing variants have been shown to contribute to tumor progression. Some pathogenic splicing disruption events result from mutations in cis-acting splicing regulatory sequences in disease-associated genes, while others may result from shifts in balance among naturally occurring alternate splicing variants among mRNAs that participate in cell cycle progression and the regulation of apoptosis. This review provides examples of cancer-related alternate splicing events resulting from each step of mRNA processing and the promising therapies that may be used to address them. Full article

(This article belongs to the Special Issue The Functions and Mechanisms of Microenvironment in Cancer)

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14 pages, 828 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of the Transcription Factor Nrf2 in Alzheimer’s Disease: Therapeutic Opportunities

by Laura Maria De Plano, Giovanna Calabrese, Maria Giovanna Rizzo, Salvatore Oddo and Antonella Caccamo

Biomolecules 2023, 13(3), 549; https://doi.org/10.3390/biom13030549 - 17 Mar 2023

Cited by 33 | Viewed by 4849

Abstract

Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly. One of the key features of AD is the accumulation of reactive oxygen species (ROS), which leads to an overall increase in oxidative damage. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) [...] Read more.

Alzheimer’s disease (AD) is a common neurodegenerative disorder that affects the elderly. One of the key features of AD is the accumulation of reactive oxygen species (ROS), which leads to an overall increase in oxidative damage. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master regulator of the antioxidant response in cells. Under low ROS levels, Nrf2 is kept in the cytoplasm. However, an increase in ROS production leads to a translocation of Nrf2 into the nucleus, where it activates the transcription of several genes involved in the cells’ antioxidant response. Additionally, Nrf2 activation increases autophagy function. However, in AD, the accumulation of Aβ and tau reduces Nrf2 levels, decreasing the antioxidant response. The reduced Nrf2 levels contribute to the further accumulation of Aβ and tau by impairing their autophagy-mediated turnover. In this review, we discuss the overwhelming evidence indicating that genetic or pharmacological activation of Nrf2 is as a potential approach to mitigate AD pathology. Full article

(This article belongs to the Special Issue Role of Nrf2 in Disease: Novel Molecular Mechanisms and Therapeutic Approaches II)

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12 pages, 3894 KiB

Open AccessEditor’s ChoiceArticle

Kawain Inhibits Urinary Bladder Carcinogenesis through Epigenetic Inhibition of LSD1 and Upregulation of H3K4 Methylation

by Xia Xu, Xuejiao Tian, Liankun Song, Jun Xie, Joseph C. Liao, Joshua J. Meeks, Xue-Ru Wu, Greg E. Gin, Beverly Wang, Edward Uchio and Xiaolin Zi

Biomolecules 2023, 13(3), 521; https://doi.org/10.3390/biom13030521 - 13 Mar 2023

Cited by 2 | Viewed by 2595

Abstract

Epidemiological evidence suggests that kava (Piper methysticum Forst) drinks may reduce the risk of cancer in South Pacific Island smokers. However, little is known about the anti-carcinogenic effects of kava on tobacco smoking-related bladder cancer and its underlying mechanisms. Here we [...] Read more.

Epidemiological evidence suggests that kava (Piper methysticum Forst) drinks may reduce the risk of cancer in South Pacific Island smokers. However, little is known about the anti-carcinogenic effects of kava on tobacco smoking-related bladder cancer and its underlying mechanisms. Here we show that dietary feeding of kawain (a major active component in kava root extracts) to mice either before or after hydroxy butyl(butyl) nitrosamine (OH-BBN) carcinogen exposure slows down urinary bladder carcinogenesis and prolongs the survival of the OH-BBN-exposed mice. OH-BBN-induced bladder tumors exhibit significantly increased expression of lysine-specific demethylase 1 (LSD1), accompanied by decreased levels of H3K4 mono-methylation compared to normal bladder epithelium, whereas dietary kawain reverses the effects of OH-BBN on H3K4 mono-methylation. Human bladder cancer tumor tissues at different pathological grades also show significantly increased expression of LSD1 and decreased levels of H3K4 mono-methylation compared to normal urothelium. In addition, kava root extracts and the kavalactones kawain and methysticin all increase the levels of H3K4 mono- and di-methylation, leading to inhibitory effects on cell migration. Taken together, our results suggest that modification of histone lysine methylation may represent a new approach to bladder cancer prevention and treatment and that kavalactones may be promising agents for bladder cancer interception in both current and former smokers. Full article

(This article belongs to the Special Issue Dietary Phytochemicals - Mediated Cellular Signalling, Epigenetics/Epigenomics and Cancer Chemoprevention)

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15 pages, 1519 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Comparison of Biomolecular Condensate Localization and Protein Phase Separation Predictors

by Erich R. Kuechler, Alex Huang, Jennifer M. Bui, Thibault Mayor and Jörg Gsponer

Biomolecules 2023, 13(3), 527; https://doi.org/10.3390/biom13030527 - 13 Mar 2023

Cited by 6 | Viewed by 4003

Abstract

Research in the field of biochemistry and cellular biology has entered a new phase due to the discovery of phase separation driving the formation of biomolecular condensates, or membraneless organelles, in cells. The implications of this novel principle of cellular organization are vast [...] Read more.

Research in the field of biochemistry and cellular biology has entered a new phase due to the discovery of phase separation driving the formation of biomolecular condensates, or membraneless organelles, in cells. The implications of this novel principle of cellular organization are vast and can be applied at multiple scales, spawning exciting research questions in numerous directions. Of fundamental importance are the molecular mechanisms that underly biomolecular condensate formation within cells and whether insights gained into these mechanisms provide a gateway for accurate predictions of protein phase behavior. Within the last six years, a significant number of predictors for protein phase separation and condensate localization have emerged. Herein, we compare a collection of state-of-the-art predictors on different tasks related to protein phase behavior. We show that the tested methods achieve high AUCs in the identification of biomolecular condensate drivers and scaffolds, as well as in the identification of proteins able to phase separate in vitro. However, our benchmark tests reveal that their performance is poorer when used to predict protein segments that are involved in phase separation or to classify amino acid substitutions as phase-separation-promoting or -inhibiting mutations. Our results suggest that the phenomenological approach used by most predictors is insufficient to fully grasp the complexity of the phenomenon within biological contexts and make reliable predictions related to protein phase behavior at the residue level. Full article

(This article belongs to the Collection Feature Papers in Bioinformatics and Systems Biology Section)

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14 pages, 1975 KiB

Open AccessEditor’s ChoiceArticle

Dysregulation of AMPA Receptor Trafficking and Intracellular Vesicular Sorting in the Prefrontal Cortex of Dopamine Transporter Knock-Out Rats

by Giorgia Targa, Francesca Mottarlini, Beatrice Rizzi, Damiana Leo, Lucia Caffino and Fabio Fumagalli

Biomolecules 2023, 13(3), 516; https://doi.org/10.3390/biom13030516 - 11 Mar 2023

Cited by 5 | Viewed by 2796

Abstract

Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the [...] Read more.

Dopamine (DA) and glutamate interact, influencing neural excitability and promoting synaptic plasticity. However, little is known regarding the molecular mechanisms underlying this crosstalk. Since perturbation of DA-AMPA receptor interaction might sustain pathological conditions, the major aim of our work was to evaluate the effect of the hyperactive DA system on the AMPA subunit composition, trafficking, and membrane localization in the prefrontal cortex (PFC). Taking advantage of dopamine transporter knock-out (DAT^−/−) rats, we found that DA overactivity reduced the translation of cortical AMPA receptors and their localization at both synaptic and extra-synaptic sites through, at least in part, altered intracellular vesicular sorting. Moreover, the reduced expression of AMPA receptor-specific anchoring proteins and structural markers, such as Neuroligin-1 and nCadherin, likely indicate a pattern of synaptic instability. Overall, these data reveal that a condition of hyperdopaminergia markedly alters the homeostatic plasticity of AMPA receptors, suggesting a general destabilization and depotentiation of the AMPA-mediated glutamatergic neurotransmission in the PFC. This effect might be functionally relevant for disorders characterized by elevated dopaminergic activity. Full article

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

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23 pages, 1711 KiB

Open AccessEditor’s ChoiceReview

Actions and Consequences of Insulin in the Striatum

by Jyoti C. Patel, Kenneth D. Carr and Margaret E. Rice

Biomolecules 2023, 13(3), 518; https://doi.org/10.3390/biom13030518 - 11 Mar 2023

Cited by 12 | Viewed by 4107

Abstract

Insulin crosses the blood–brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which [...] Read more.

Insulin crosses the blood–brain barrier to enter the brain from the periphery. In the brain, insulin has well-established actions in the hypothalamus, as well as at the level of mesolimbic dopamine neurons in the midbrain. Notably, insulin also acts in the striatum, which shows abundant expression of insulin receptors (InsRs) throughout. These receptors are found on interneurons and striatal projections neurons, as well as on glial cells and dopamine axons. A striking functional consequence of insulin elevation in the striatum is promoting an increase in stimulated dopamine release. This boosting of dopamine release involves InsRs on cholinergic interneurons, and requires activation of nicotinic acetylcholine receptors on dopamine axons. Opposing this dopamine-enhancing effect, insulin also increases dopamine uptake through the action of insulin at InsRs on dopamine axons. Insulin acts on other striatal cells as well, including striatal projection neurons and astrocytes that also influence dopaminergic transmission and striatal function. Linking these cellular findings to behavior, striatal insulin signaling is required for the development of flavor–nutrient learning, implicating insulin as a reward signal in the brain. In this review, we discuss these and other actions of insulin in the striatum, including how they are influenced by diet and other physiological states. Full article

(This article belongs to the Special Issue 100th Anniversary of Insulin: Insulin Receptor Signaling in Health and Disease)

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23 pages, 2458 KiB

Open AccessEditor’s ChoiceArticle

How Clustered DNA Damage Can Change the Electronic Properties of ds-DNA—Differences between GAG, GA^OXOG, and ^OXOGA^OXOG

by Boleslaw Karwowski

Biomolecules 2023, 13(3), 517; https://doi.org/10.3390/biom13030517 - 11 Mar 2023

Cited by 6 | Viewed by 1953

Abstract

Every 24 h, roughly 3 × 10¹⁷ incidences of DNA damage are generated in the human body as a result of intra- or extra-cellular factors. The structure of the formed lesions is identical to that formed during radio- or chemotherapy. Increases in [...] Read more.

Every 24 h, roughly 3 × 10¹⁷ incidences of DNA damage are generated in the human body as a result of intra- or extra-cellular factors. The structure of the formed lesions is identical to that formed during radio- or chemotherapy. Increases in the clustered DNA damage (CDL) level during anticancer treatment have been observed compared to those found in untreated normal tissues. 7,8-dihydro-8-oxo-2′-deoxyguanosine (^OXOG) has been recognized as the most common lesion. In these studies, the influence of ^OXOG, as an isolated (oligo-^OG) or clustered DNA lesion (oligo-^OG^OG), on charge transfer has been analyzed in comparison to native oligo-G. DNA lesion repair depends on the damage recognition step, probably via charge transfer. Here the electronic properties of short ds-oligonucleotides were calculated and analyzed at the M062x/6-31++G** level of theory in a non-equilibrated and equilibrated solvent state. The rate constant of hole and electron transfer according to Marcus’ theory was also discussed. These studies elucidated that ^OXOG constitutes the sink for migrated radical cations. However, in the case of oligo-^OG^OG containing a 5′-^OXOGA^XOXG-3′ sequence, the 3′-End ^OXOG becomes predisposed to electron-hole accumulation contrary to the undamaged GAG fragment. Moreover, it was found that the 5′-End ^OXOG present in an ^OXOGA^OXOG fragment adopts a higher adiabatic ionization potential than the 2′-deoxyguanosine of an undamaged analog if both ds-oligos are present in a cationic form. Because increases in CDL formation have been observed during radio- or chemotherapy, understanding their role in the above processes can be crucial for the efficiency and safety of medical cancer treatment. Full article

(This article belongs to the Special Issue DNA Damage and DNA Repair in Cancer)

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14 pages, 901 KiB

Open AccessEditor’s ChoiceReview

Melatonin in Health and Disease: A Perspective for Livestock Production

by Zully E. Contreras-Correa, Riley D. Messman, Rebecca M. Swanson and Caleb O. Lemley

Biomolecules 2023, 13(3), 490; https://doi.org/10.3390/biom13030490 - 7 Mar 2023

Cited by 14 | Viewed by 6286

Abstract

Mounting evidence in the literature indicates an important role of endogenous and exogenous melatonin in driving physiological and molecular adaptations in livestock. Melatonin has been extensively studied in seasonally polyestrous animals whereby supplementation studies have been used to adjust circannual rhythms in herds [...] Read more.

Mounting evidence in the literature indicates an important role of endogenous and exogenous melatonin in driving physiological and molecular adaptations in livestock. Melatonin has been extensively studied in seasonally polyestrous animals whereby supplementation studies have been used to adjust circannual rhythms in herds of animals under abnormal photoperiodic conditions. Livestock undergo multiple metabolic and physiological adaptation processes throughout their production cycle which can result in decreased immune response leading to chronic illness, weight loss, or decreased production efficiency; however, melatonin’s antioxidant capacity and immunostimulatory properties could alleviate these effects. The cardiovascular system responds to melatonin and depending on receptor type and localization, melatonin can vasodilate or vasoconstrict several systemic arteries, thereby controlling whole animal nutrient partitioning via vascular resistance. Increased incidences of non-communicable diseases in populations exposed to circadian disruption have uncovered novel pathways of neurohormones, such as melatonin, influence health, and disease. Perturbations in immune function can negatively impact the growth and development of livestock which has been examined following melatonin supplementation. Specifically, melatonin can influence nutrient uptake, circulating nutrient profiles, and endocrine profiles controlling economically important livestock growth and development. This review focuses on the physiological, cellular, and molecular implications of melatonin on the health and disease of domesticated food animals. Full article

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

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11 pages, 681 KiB

Open AccessEditor’s ChoiceReview

Distinct Roles of SELENOF in Different Human Cancers

by Brenna Flowers, Oliwia Bochnacka, Allison Poles, Alan M. Diamond and Irida Kastrati

Biomolecules 2023, 13(3), 486; https://doi.org/10.3390/biom13030486 - 6 Mar 2023

Cited by 7 | Viewed by 3016

Abstract

SELENOF, previously known as SEP15, is a selenoprotein that contains selenium in the form of the amino acid selenocysteine. Like other selenoproteins, the role for SELENOF in carcinogenesis has been investigated due to its altered expression compared to the corresponding normal tissue, its [...] Read more.

SELENOF, previously known as SEP15, is a selenoprotein that contains selenium in the form of the amino acid selenocysteine. Like other selenoproteins, the role for SELENOF in carcinogenesis has been investigated due to its altered expression compared to the corresponding normal tissue, its molecular function, and the association of genetic variations in the SELENOF gene to cancer risk or outcome. This review summarizes SELENOF’s discovery, structure, cellular localization, and expression. SELENOF belongs to a new family of thioredoxin-like proteins. Published data summarized here indicate a likely role for SELENOF in redox protein quality control, and in the regulation of lipids, glucose, and energy metabolism. Current evidence indicates that loss of SELENOF contributes to the development of prostate and breast cancer, while its loss may be protective against colon cancer. Additional investigation into SELENOF’s molecular mechanisms and its impact on cancer is warranted. Full article

(This article belongs to the Special Issue Selenocysteine: Synthesis, Function, and Evolution of the 21st Amino Acid)

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21 pages, 968 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Caenorhabditis elegans as a Model System to Study Human Neurodegenerative Disorders

by Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis and Konstantinos Palikaras

Biomolecules 2023, 13(3), 478; https://doi.org/10.3390/biom13030478 - 5 Mar 2023

Cited by 41 | Viewed by 9754

Abstract

In recent years, advances in science and technology have improved our quality of life, enabling us to tackle diseases and increase human life expectancy. However, longevity is accompanied by an accretion in the frequency of age-related neurodegenerative diseases, creating a growing burden, with [...] Read more.

In recent years, advances in science and technology have improved our quality of life, enabling us to tackle diseases and increase human life expectancy. However, longevity is accompanied by an accretion in the frequency of age-related neurodegenerative diseases, creating a growing burden, with pervasive social impact for human societies. The cost of managing such chronic disorders and the lack of effective treatments highlight the need to decipher their molecular and genetic underpinnings, in order to discover new therapeutic targets. In this effort, the nematode Caenorhabditis elegans serves as a powerful tool to recapitulate several disease-related phenotypes and provides a highly malleable genetic model that allows the implementation of multidisciplinary approaches, in addition to large-scale genetic and pharmacological screens. Its anatomical transparency allows the use of co-expressed fluorescent proteins to track the progress of neurodegeneration. Moreover, the functional conservation of neuronal processes, along with the high homology between nematode and human genomes, render C. elegans extremely suitable for the study of human neurodegenerative disorders. This review describes nematode models used to study neurodegeneration and underscores their contribution in the effort to dissect the molecular basis of human diseases and identify novel gene targets with therapeutic potential. Full article

(This article belongs to the Special Issue Mitochondria and Central Nervous System Disorders II)

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15 pages, 2180 KiB

Open AccessEditor’s ChoiceArticle

Solid-State Preparation and Characterization of 2-Hydroxypropylcyclodextrins-Iodine Complexes as Stable Iodophors

by Sandro Dattilo, Fabiola Spitaleri, Danilo Aleo, Maria Grazia Saita and Angela Patti

Biomolecules 2023, 13(3), 474; https://doi.org/10.3390/biom13030474 - 3 Mar 2023

Cited by 13 | Viewed by 4419

Abstract

The use of iodine as antiseptic poses some issues related to its low water solubility and high volatility. Stable solid iodine-containing formulations are highly advisable and currently limited to the povidone-iodine complex. In this study, complexes of molecular iodine with 2-hydroxypropyl α-, β- [...] Read more.

The use of iodine as antiseptic poses some issues related to its low water solubility and high volatility. Stable solid iodine-containing formulations are highly advisable and currently limited to the povidone-iodine complex. In this study, complexes of molecular iodine with 2-hydroxypropyl α-, β- and γ-cyclodextrins were considered water-soluble iodophors and prepared in a solid state by using three different methods (liquid-assisted grinding, co-evaporation and sealed heating). The obtained solids were evaluated for their iodine content and stability over time in different conditions using a fully validated UV method. The assessment of the actual formation of an inclusion complex in a solid state was carried out by thermal analysis, and the presence of iodine was further confirmed by SEM/EDX and XPS analyses. High levels of iodine content (8.3–10.8%) were obtained with all the tested cyclodextrins, and some influence was exerted by the employed preparation method. Potential use as solid iodophors can be envisaged for these iodine complexes, among which those with 2-hydroxypropyl-α-cyclodextrin were found the most stable, regardless of the preparation technique. The three prepared cyclodextrin–iodine complexes proved effective as bactericides against S. epidermidis. Full article

(This article belongs to the Special Issue Cyclodextrin-Based Drug Release and Drug Delivery Systems)

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