Biomolecules

9 pages, 784 KiB

Open AccessEditor’s ChoiceArticle

IGFBP7 Concentration May Reflect Subclinical Myocardial Damage and Kidney Function in Patients with Stable Ischemic Heart Disease

by Anna Lisowska, Anna Szyszkowska, Małgorzata Knapp, Magda Łapińska, Marcin Kondraciuk, Inga Kamińska, Tomasz Hryszko, Katarzyna Ptaszyńska-Kopczyńska and Karol Kamiński

Biomolecules 2022, 12(2), 274; https://doi.org/10.3390/biom12020274 - 8 Feb 2022

Cited by 2 | Viewed by 1686

Abstract

The objective of this study was to determine the associations between insulin-like growth-factor-binding protein 7(IGFBP7) concentrations and concentrations of troponin T(TnT), N-terminal pro-B-type natriuretic peptide(NT-proBNP) and the parameters of kidney function in patients with stable ischemic heart disease(IHD). The IHD group consisted of [...] Read more.

The objective of this study was to determine the associations between insulin-like growth-factor-binding protein 7(IGFBP7) concentrations and concentrations of troponin T(TnT), N-terminal pro-B-type natriuretic peptide(NT-proBNP) and the parameters of kidney function in patients with stable ischemic heart disease(IHD). The IHD group consisted of 88 patients, and the population group comprised 66 subjects without a history of IHD. IGFBP7, TnT and NTproBNP concentrations were measured. The IGFBP7 value was considerably higher in the IHD group (1.76 ± 1 ng/mL vs. 1.43 ± 0.44 ng/mL, respectively, p = 0.019). Additionally, IHD subjects had a significantly higher concentration of TnT and NTproBNP. In both groups there was a significant correlation between IGFBP7 and serum parameters of kidney function (creatinine concentration: population gr. r = 0.45, p < 0.001, IHD gr. r = 0.86, p < 0.0001; urea concentration: population gr. r = 0.51, p < 0.0001, IHD gr. r = 0.71, p < 0.00001). No correlation between IGFBP7 and microalbuminuria or the albumin to creatinine ratio in urine was found. Moreover, there was a significant correlation between IGFBP7 concentration and markers of heart injury/overload-TnT and NT-BNP(r = 0.76, p < 0.001 and r = 0.72, p < 0.001, respectively). Multivariate regression analysis in joint both revealed that the IGFBP7 concentration is independently associated with urea, creatinine and TnT concentrations (R² for the model 0.76). IHD patients presented significantly higher IGFBP7 concentrations than the population group. Elevated IGFBP7 levels are associated predominantly with markers of kidney function and myocardial damage or overload. Full article

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22 pages, 3701 KiB

Open AccessEditor’s ChoiceArticle

APR-246—The Mutant TP53 Reactivator—Increases the Effectiveness of Berberine and Modified Berberines to Inhibit the Proliferation of Pancreatic Cancer Cells

by James Andrew McCubrey, Stephen L. Abrams, Linda S. Steelman, Lucio Cocco, Stefano Ratti, Alberto M. Martelli, Paolo Lombardi, Agnieszka Gizak and Przemysław Duda

Biomolecules 2022, 12(2), 276; https://doi.org/10.3390/biom12020276 - 8 Feb 2022

Cited by 6 | Viewed by 2391

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. In ~75% of PDAC, the tumor suppressor TP53 gene is mutated. Novel approaches to treat cancer involve compounds called mutant TP53 reactivators. They interact with mutant TP53 proteins and restore some [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. In ~75% of PDAC, the tumor suppressor TP53 gene is mutated. Novel approaches to treat cancer involve compounds called mutant TP53 reactivators. They interact with mutant TP53 proteins and restore some of their growth suppressive properties, but they may also interact with other proteins, e.g., TP63 and TP73. We examined the ability of the TP53 reactivator APR-246 to interact with eleven modified berberine compounds (NAX compounds) in the presence and absence of WT-TP53 in two PDAC cell lines: the MIA-PaCa-2, which has gain of function (GOF) TP53 mutations on both alleles, and PANC-28, which lacks expression of the WT TP53 protein. Our results indicate the TP53 reactivator-induced increase in therapeutic potential of many modified berberines. Full article

(This article belongs to the Special Issue Inflammatory Pathways in Neuro-Muscular Degeneration, Metabolic Syndromes, Cancer and Infection)

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17 pages, 12147 KiB

Open AccessEditor’s ChoiceArticle

Unlocking the Memory Component of Alzheimer’s Disease: Biological Processes and Pathways across Brain Regions

by Nikolas Dovrolis, Maria Nikou, Alexandra Gkrouzoudi, Nikolaos Dimitriadis and Ioanna Maroulakou

Biomolecules 2022, 12(2), 263; https://doi.org/10.3390/biom12020263 - 6 Feb 2022

Cited by 2 | Viewed by 2671

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and a general cognitive decline leading to dementia. AD is characterized by changes in the behavior of the genome and can be traced across multiple brain regions and cell [...] Read more.

Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by a progressive loss of memory and a general cognitive decline leading to dementia. AD is characterized by changes in the behavior of the genome and can be traced across multiple brain regions and cell types. It is mainly associated with β-amyloid deposits and tau protein misfolding, leading to neurofibrillary tangles. In recent years, however, research has shown that there is a high complexity of mechanisms involved in AD neurophysiology and functional decline enabling its diverse presentation and allowing more questions to arise. In this study, we present a computational approach to facilitate brain region-specific analysis of genes and biological processes involved in the memory process in AD. Utilizing current genetic knowledge we provide a gene set of 265 memory-associated genes in AD, combinations of which can be found co-expressed in 11 different brain regions along with their functional role. The identified genes participate in a spectrum of biological processes ranging from structural and neuronal communication to epigenetic alterations and immune system responses. These findings provide new insights into the molecular background of AD and can be used to bridge the genotype–phenotype gap and allow for new therapeutic hypotheses. Full article

(This article belongs to the Special Issue Core of Biomolecules Affecting Degenerative Disorders)

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12 pages, 2449 KiB

Open AccessEditor’s ChoiceArticle

Protein Binding of Benzofuran Derivatives: A CD Spectroscopic and In Silico Comparative Study of the Effects of 4-Nitrophenyl Functionalized Benzofurans and Benzodifurans on BSA Protein Structure

by Pasqualina Liana Scognamiglio, Caterina Vicidomini, Francesco Fontanella, Claudio De Stefano, Rosanna Palumbo and Giovanni N. Roviello

Biomolecules 2022, 12(2), 262; https://doi.org/10.3390/biom12020262 - 5 Feb 2022

Cited by 6 | Viewed by 2272

Abstract

Benzofuran derivatives are synthetic compounds that are finding an increasing interest in the scientific community not only as building blocks for the realization of new materials, but also as potential drugs thanks to their ability to interact with nucleic acids, interfere with the [...] Read more.

Benzofuran derivatives are synthetic compounds that are finding an increasing interest in the scientific community not only as building blocks for the realization of new materials, but also as potential drugs thanks to their ability to interact with nucleic acids, interfere with the amyloid peptide aggregation and cancer cell cycle. However, their ability to interact with proteins is a theme still in need of investigation for the therapeutic importance that benzofurans could have in the modulation of protein-driven processes and for the possibility of making use of serum albumins as benzofurans delivery systems. To this scope, we investigated the protein binding ability of two 4-nitrophenyl-functionalized benzofurans previously synthesized in our laboratory and herein indicated as BF1 and BDF1, which differed for the number of furan rings (a single moiety in BF1, two in BDF1), using bovine serum albumin (BSA) as a model protein. By circular dichroism (CD) spectroscopy we demonstrated the ability of the two heteroaromatic compounds to alter the secondary structure of the serum albumin leading to different consequences in terms of BSA thermal stability with respect to the unbound protein (ΔT_m > 3 °C for BF1, −0.8 °C for BDF1 with respect to unbound BSA, in PBS buffer, pH 7.5) as revealed in our CD melting studies. Moreover, a molecular docking study allowed us to compare the possible ligand binding modes of the mono and difuranic derivatives showing that while BF1 is preferentially housed in the interior of protein structure, BDF1 is predicted to bind the albumin surface with a lower affinity than BF1. Interestingly, the different affinity for the protein target predicted computationally was confirmed also experimentally by fluorescence spectroscopy (k_D = 142.4 ± 64.6 nM for BDF1 vs. 28.4 ± 10.1 nM for BF1). Overall, the above findings suggest the ability of benzofurans to bind serum albumins that could act as their carriers in drug delivery applications. Full article

(This article belongs to the Special Issue Experimental and Theoretical Approaches to Protein-Targeting Drug Discovery)

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15 pages, 2825 KiB

Open AccessEditor’s ChoiceArticle

Interaction with the Assembly Chaperone Ump1 Promotes Incorporation of the β7 Subunit into Half-Proteasome Precursor Complexes Driving Their Dimerization

by Jessica Zimmermann, Paula C. Ramos and R. Jürgen Dohmen

Biomolecules 2022, 12(2), 253; https://doi.org/10.3390/biom12020253 - 4 Feb 2022

Cited by 5 | Viewed by 2148

Abstract

Biogenesis of the eukaryotic 20S proteasome core particle (PC) is a complex process assisted by specific chaperones absent from the active complex. The first identified chaperone, Ump1, was found in a precursor complex (PC) called 15S PC. Yeast cells lacking Ump1 display strong [...] Read more.

Biogenesis of the eukaryotic 20S proteasome core particle (PC) is a complex process assisted by specific chaperones absent from the active complex. The first identified chaperone, Ump1, was found in a precursor complex (PC) called 15S PC. Yeast cells lacking Ump1 display strong defects in the autocatalytic processing of β subunits, and consequently have lower proteolytic activity. Here, we dissect an important interaction of Ump1 with the β7 subunit that is critical for proteasome biogenesis. Functional domains of Ump1 and the interacting proteasome subunit β7 were mapped, and the functional consequences of their deletion or mutation were analyzed. Cells in which the first sixteen Ump1 residues were deleted display growth phenotypes similar to ump1∆, but massively accumulate 15S PC and distinct proteasome intermediate complexes containing the truncated protein. The viability of these cells depends on the transcription factor Rpn4. Remarkably, β7 subunit overexpression re-established viability in the absence of Rpn4. We show that an N-terminal domain of Ump1 and the propeptide of β7 promote direct interaction of the two polypeptides in vitro. This interaction is of critical importance for the recruitment of β7 precursor during proteasome assembly, a step that drives dimerization of 15S PCs and the formation of 20S CPs. Full article

(This article belongs to the Special Issue The Assembly and Function of Proteasomes in Health and Disease)

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26 pages, 6801 KiB

Open AccessFeature PaperEditor’s ChoiceReview

PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New Target for Cancer Therapy

by Alberto Díaz-Talavera, Cristina Montero-Conde, Luis Javier Leandro-García and Mercedes Robledo

Biomolecules 2022, 12(2), 248; https://doi.org/10.3390/biom12020248 - 3 Feb 2022

Cited by 6 | Viewed by 4633

Abstract

DNA replication can encounter blocking obstacles, leading to replication stress and genome instability. There are several mechanisms for evading this blockade. One mechanism consists of repriming ahead of the obstacles, creating a new starting point; in humans, PrimPol is responsible for carrying out [...] Read more.

DNA replication can encounter blocking obstacles, leading to replication stress and genome instability. There are several mechanisms for evading this blockade. One mechanism consists of repriming ahead of the obstacles, creating a new starting point; in humans, PrimPol is responsible for carrying out this task. PrimPol is a primase that operates in both the nucleus and mitochondria. In contrast with conventional primases, PrimPol is a DNA primase able to initiate DNA synthesis de novo using deoxynucleotides, discriminating against ribonucleotides. In vitro, PrimPol can act as a DNA primase, elongating primers that PrimPol itself sythesizes, or as translesion synthesis (TLS) DNA polymerase, elongating pre-existing primers across lesions. However, the lack of evidence for PrimPol polymerase activity in vivo suggests that PrimPol only acts as a DNA primase. Here, we provide a comprehensive review of human PrimPol covering its biochemical properties and structure, in vivo function and regulation, and the processes that take place to fill the gap-containing lesion that PrimPol leaves behind. Finally, we explore the available data on human PrimPol expression in different tissues in physiological conditions and its role in cancer. Full article

(This article belongs to the Collection Feature Papers in Molecular Genetics)

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13 pages, 1961 KiB

Open AccessEditor’s ChoiceArticle

Identification of the Marine Alkaloid Lepadin A as Potential Inducer of Immunogenic Cell Death

by Genoveffa Nuzzo, Carmela Gallo, Fabio Crocetta, Lucia Romano, Giusi Barra, Giuseppina Senese, Mario dell’Isola, Dalila Carbone, Valentina Tanduo, Federica Albiani, Guido Villani, Giuliana d’Ippolito, Emiliano Manzo and Angelo Fontana

Biomolecules 2022, 12(2), 246; https://doi.org/10.3390/biom12020246 - 2 Feb 2022

Cited by 9 | Viewed by 2429

Abstract

Natural products and their synthetic analogs and derivatives are a traditional source of bioactive molecules with potential development as drug candidates. In this context, Marine Natural Products (MNPs) represent a rich reservoir of diverse molecular skeletons with potential pharmacological activity that, so far, [...] Read more.

Natural products and their synthetic analogs and derivatives are a traditional source of bioactive molecules with potential development as drug candidates. In this context, Marine Natural Products (MNPs) represent a rich reservoir of diverse molecular skeletons with potential pharmacological activity that, so far, has been mostly explored in cancer and infectious diseases. Starting from the development of a novel bioassay-guided screening platform for immunomodulatory compounds from an in-house MNPs library, we report the identification of the alkaloid lepadin A as a new model compound for immune-based anticancer activity with characteristics that suggest a possible mechanism as Immunogenic Cell Death inducer. The work describes the molecular-based bioprospecting in the Gulf of Naples together with the bioassay-guided fractionation, the chemical characterization of the alkaloid, and the biological activity in mouse dendritic cells (D1). Full article

(This article belongs to the Special Issue State-of-the-Art Isolation, Chemical and Biological Characterization, Synthesis and Formulation of Natural Products in Italy 2020–2021)

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14 pages, 968 KiB

Open AccessEditor’s ChoiceReview

Role of EPA in Inflammation: Mechanisms, Effects, and Clinical Relevance

by Rosalia Crupi and Salvatore Cuzzocrea

Biomolecules 2022, 12(2), 242; https://doi.org/10.3390/biom12020242 - 1 Feb 2022

Cited by 22 | Viewed by 4820

Abstract

Many chronic inflammatory processes are linked with the continuous release of inflammatory mediators and the activation of harmful signal-transduction pathways that are able to facilitate disease progression. In this context atherosclerosis represents the most common pathological substrate of coronary heart disease, and the [...] Read more.

Many chronic inflammatory processes are linked with the continuous release of inflammatory mediators and the activation of harmful signal-transduction pathways that are able to facilitate disease progression. In this context atherosclerosis represents the most common pathological substrate of coronary heart disease, and the characterization of the disease as a chronic low-grade inflammatory condition is now validated. The biomarkers of inflammation associated with clinical cardiovascular risk support the theory that targeted anti-inflammatory treatment appears to be a promising strategy in reducing residual cardiovascular risk. Several literature data highlight cardioprotective effects of the long-chain omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA). This PUFA lowers plasma triglyceride levels and has potential beneficial effects on atherosclerotic plaques. Preclinical studies reported that EPA reduces both pro-inflammatory cytokines and chemokines levels. Clinical studies in patients with coronary artery disease that receive pharmacological statin therapy suggest that EPA may decrease plaque vulnerability preventing plaque progression. This review aims to provide an overview of the links between inflammation and cardiovascular risk factors, importantly focusing on the role of diet, in particular examining the proposed role of EPA as well as the success or failure of standard pharmacological therapy for cardiovascular diseases. Full article

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

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14 pages, 2105 KiB

Open AccessEditor’s ChoiceArticle

Spexin Regulates Hypothalamic Leptin Action on Feeding Behavior

by Bora Jeong, Kwang-Kon Kim, Tae-Hwan Lee, Han-Rae Kim, Byong-Seo Park, Jeong-Woo Park, Jin-Kwon Jeong, Jae-Young Seong and Byung-Ju Lee

Biomolecules 2022, 12(2), 236; https://doi.org/10.3390/biom12020236 - 31 Jan 2022

Cited by 14 | Viewed by 3641

Abstract

Spexin (SPX) is a recently identified neuropeptide that is believed to play an important role in the regulation of energy homeostasis. Here, we describe a mediating function of SPX in hypothalamic leptin action. Intracerebroventricular (icv) SPX administration induced a decrease in food intake [...] Read more.

Spexin (SPX) is a recently identified neuropeptide that is believed to play an important role in the regulation of energy homeostasis. Here, we describe a mediating function of SPX in hypothalamic leptin action. Intracerebroventricular (icv) SPX administration induced a decrease in food intake and body weight gain. SPX was found to be expressed in cells expressing leptin receptor ObRb in the mouse hypothalamus. In line with this finding, icv leptin injection increased SPX mRNA in the ObRb-positive cells of the hypothalamus, which was blocked by treatment with a STAT3 inhibitor. Leptin also increased STAT3 binding to the SPX promoter, as measured by chromatin immunoprecipitation assays. In vivo blockade of hypothalamic SPX biosynthesis with an antisense oligodeoxynucleotide (AS ODN) resulted in a diminished leptin effect on food intake and body weight. AS ODN reversed leptin’s effect on the proopiomelanocortin (POMC) mRNA expression and, moreover, decreased leptin-induced STAT3 binding to the POMC promoter sequence. These results suggest that SPX is involved in leptin’s action on POMC gene expression in the hypothalamus and impacts the anorexigenic effects of leptin. Full article

(This article belongs to the Special Issue Novel Insights into the Physiological and Pathological Role of Leptin and Leptin Receptor)

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23 pages, 3578 KiB

Open AccessEditor’s ChoiceReview

Leukemia Inhibitory Factor: An Important Cytokine in Pathologies and Cancer

by Megan M. Jorgensen and Pilar de la Puente

Biomolecules 2022, 12(2), 217; https://doi.org/10.3390/biom12020217 - 27 Jan 2022

Cited by 21 | Viewed by 7336

Abstract

Leukemia Inhibitory Factor (LIF) is a member of the IL-6 cytokine family and is expressed in almost every tissue type within the body. Although LIF was named for its ability to induce differentiation of myeloid leukemia cells, studies of LIF in additional diseases [...] Read more.

Leukemia Inhibitory Factor (LIF) is a member of the IL-6 cytokine family and is expressed in almost every tissue type within the body. Although LIF was named for its ability to induce differentiation of myeloid leukemia cells, studies of LIF in additional diseases and solid tumor types have shown that it has the potential to contribute to many other pathologies. Exploring the roles of LIF in normal physiology and non-cancer pathologies can give important insights into how it may be dysregulated within cancers, and the possible effects of this dysregulation. Within various cancer types, LIF expression has been linked to hallmarks of cancer, such as proliferation, metastasis, and chemoresistance, as well as overall patient survival. The mechanisms behind these effects of LIF are not well understood and can differ between different tissue types. In fact, research has shown that while LIF may promote malignancy progression in some solid tumors, it can have anti-neoplastic effects in others. This review will summarize current knowledge of how LIF expression impacts cellular function and dysfunction to help reveal new adjuvant treatment options for cancer patients, while also revealing potential adverse effects of treatments targeting LIF signaling. Full article

(This article belongs to the Special Issue Biomolecules in Drug Resistance in Cancer and Metastatic Cancers)

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16 pages, 3569 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

A Stepwise Framework for the Systematic Development of Lipid Nanoparticles

by João Basso, Maria Mendes, Tânia Cova, João Sousa, Alberto Pais, Ana Fortuna, Rui Vitorino and Carla Vitorino

Biomolecules 2022, 12(2), 223; https://doi.org/10.3390/biom12020223 - 27 Jan 2022

Cited by 14 | Viewed by 7920

Abstract

A properly designed nanosystem aims to deliver an optimized concentration of the active pharmaceutical ingredient (API) at the site of action, resulting in a therapeutic response with reduced adverse effects. Due to the vast availability of lipids and surfactants, producing stable lipid dispersions [...] Read more.

A properly designed nanosystem aims to deliver an optimized concentration of the active pharmaceutical ingredient (API) at the site of action, resulting in a therapeutic response with reduced adverse effects. Due to the vast availability of lipids and surfactants, producing stable lipid dispersions is a double-edged sword: on the one hand, the versatility of composition allows for a refined design and tuning of properties; on the other hand, the complexity of the materials and their physical interactions often result in laborious and time-consuming pre-formulation studies. However, how can they be tailored, and which premises are required for a “right at first time” development? Here, a stepwise framework encompassing the sequential stages of nanoparticle production for disulfiram delivery is presented. Drug in lipid solubility analysis leads to the selection of the most suitable liquid lipids. As for the solid lipid, drug partitioning studies point out the lipids with increased capacity for solubilizing and entrapping disulfiram. The microscopical evaluation of the physical compatibility between liquid and solid lipids further indicates the most promising core compositions. The impact of the outer surfactant layer on the colloidal properties of the nanosystems is evaluated recurring to machine learning algorithms, in particular, hierarchical clustering, principal component analysis, and partial least squares regression. Overall, this work represents a comprehensive systematic approach to nanoparticle formulation studies that serves as a basis for selecting the most suitable excipients that comprise solid lipid nanoparticles and nanostructured lipid carriers. Full article

(This article belongs to the Special Issue Applications of Nanoparticles in Tumor Therapy)

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18 pages, 2129 KiB

Open AccessEditor’s ChoiceReview

Transgenic Mouse Overexpressing Spermine Oxidase in Cerebrocortical Neurons: Astrocyte Dysfunction and Susceptibility to Epileptic Seizures

by Manuela Marcoli, Chiara Cervetto, Sarah Amato, Cristian Fiorucci, Guido Maura, Paolo Mariottini and Manuela Cervelli

Biomolecules 2022, 12(2), 204; https://doi.org/10.3390/biom12020204 - 25 Jan 2022

Cited by 9 | Viewed by 3130

Abstract

Polyamines are organic polycations ubiquitously present in living cells. Polyamines are involved in many cellular processes, and their content in mammalian cells is tightly controlled. Among their function, these molecules modulate the activity of several ion channels. Spermine oxidase, specifically oxidized spermine, is [...] Read more.

Polyamines are organic polycations ubiquitously present in living cells. Polyamines are involved in many cellular processes, and their content in mammalian cells is tightly controlled. Among their function, these molecules modulate the activity of several ion channels. Spermine oxidase, specifically oxidized spermine, is a neuromodulator of several types of ion channel and ionotropic glutamate receptors, and its deregulated activity has been linked to several brain pathologies, including epilepsy. The Dach-SMOX mouse line was generated using a Cre/loxP-based recombination approach to study the complex and critical functions carried out by spermine oxidase and spermine in the mammalian brain. This mouse genetic model overexpresses spermine oxidase in the neocortex and is a chronic model of excitotoxic/oxidative injury and neuron vulnerability to oxidative stress and excitotoxic, since its phenotype revealed to be more susceptible to different acute oxidative insults. In this review, the molecular mechanisms underlined the Dach-SMOX phenotype, linked to reactive astrocytosis, neuron loss, chronic oxidative and excitotoxic stress, and susceptibility to seizures have been discussed in detail. The Dach-SMOX mouse model overexpressing SMOX may help in shedding lights on the susceptibility to epileptic seizures, possibly helping to understand the mechanisms underlying epileptogenesis in vulnerable individuals and contributing to provide new molecular mechanism targets to search for novel antiepileptic drugs. Full article

(This article belongs to the Section Molecular Genetics)

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13 pages, 2993 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Exogenous Gibberellin Treatment Enhances Melatonin Synthesis for Melatonin-Enriched Rice Production

by Ok Jin Hwang and Kyoungwhan Back

Biomolecules 2022, 12(2), 198; https://doi.org/10.3390/biom12020198 - 24 Jan 2022

Cited by 11 | Viewed by 3265

Abstract

Melatonin production is induced by many abiotic and biotic stressors; it modulates the levels of many plant hormones and their signaling pathways. This study investigated the effects of plant hormones on melatonin synthesis. Melatonin synthesis in rice seedlings was significantly induced upon exogenous [...] Read more.

Melatonin production is induced by many abiotic and biotic stressors; it modulates the levels of many plant hormones and their signaling pathways. This study investigated the effects of plant hormones on melatonin synthesis. Melatonin synthesis in rice seedlings was significantly induced upon exogenous gibberellin 3 (GA₃) treatment, while it was severely decreased by GA synthesis inhibitor paclobutrazol. In contrast, abscisic acid (ABA) strongly inhibited melatonin synthesis, whereas its inhibitor norflurazon (NF) induced melatonin synthesis. The observed GA-mediated increase in melatonin was closely associated with elevated expression levels of melatonin biosynthetic genes such as TDC3, T5H, and ASMT1; it was also associated with reduced expression levels of catabolic genes ASDAC and M2H. In a paddy field, the treatment of immature rice seeds with exogenous GA led to enhanced melatonin production in rice seeds; various transgenic rice plants downregulating a GA biosynthesis gene (GA3ox2) and a signaling gene (Gα) showed severely decreased melatonin levels, providing in vivo genetic evidence that GA has a positive effect on melatonin synthesis. This is the first study to report that GA is positively involved in melatonin synthesis in plants; GA treatment can be used to produce melatonin-rich seeds, vegetables, and fruits, which are beneficial for human health. Full article

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

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14 pages, 1286 KiB

Open AccessEditor’s ChoiceReview

Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles

by Yves Menezo, Kay Elder, Arthur Clement and Patrice Clement

Biomolecules 2022, 12(2), 197; https://doi.org/10.3390/biom12020197 - 24 Jan 2022

Cited by 49 | Viewed by 13821

Abstract

Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain [...] Read more.

Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain development and its maturation also depend on correct lipid methylation, and continued neuronal function depends on biogenic amines that require methylation for their synthesis. All methylation processes are carried out via a methyltransferase enzyme and its unique co-factor S-adenosylmethionine (SAM); the transfer of a methyl group to a target molecule results in the release of SAH (SA homocysteine), and then homocysteine (Hcy). Both of these molecules are toxic, inhibiting methylation in a variety of ways, and Hcy recycling to methionine is imperative; this is achieved via the one carbon cycle, supported by the folates cycle. Folate deficiency causes hyperhomocysteinaemia, with several associated diseases; during early pregnancy, deficiency interferes with closure of the neural tube at the fourth week of gestation, and nutraceutical supplementation has been routinely prescribed to prevent neural tube defects, mainly involving B vitamins, Zn and folates. The two metabolic pathways are subject to single nucleotide polymorphisms that alter their activity/capacity, often severely, impairing specific physiological functions including fertility, brain and cardiac function. The impact of three types of nutraceutical supplements, folic acid (FA), folinic acid (FLA) and 5 Methyl THF (MTHF), will be discussed here, with their positive effects alongside potentially hazardous secondary effects. The issue surrounding FA and its association with UMFA (unmetabolized folic acid) syndrome is now a matter of concern, as UMFA is currently found in the umbilical cord of the fetus, and even in infants’ blood. We will discuss its putative role in influencing the acquisition of epigenetic marks in the germline, acquired during embryogenesis, as well as the role of FA in the management of cancerous disease. Full article

(This article belongs to the Collection Feature Papers in Molecular Genetics)

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31 pages, 841 KiB

Open AccessEditor’s ChoiceReview

Targeted NMDA Receptor Interventions for Autism: Developmentally Determined Expression of GluN2B and GluN2A-Containing Receptors and Balanced Allosteric Modulatory Approaches

by Stephen I. Deutsch, Zachary N. M. Luyo and Jessica A. Burket

Biomolecules 2022, 12(2), 181; https://doi.org/10.3390/biom12020181 - 22 Jan 2022

Cited by 13 | Viewed by 4383

Abstract

Various ASD risk alleles have been associated with impairment of NMDA receptor activation (i.e., NMDA Receptor Hypofunction) and/or disturbance of the careful balance between activation mediated by GluN2B-subtype and GluN2A-subtype-containing NMDA receptors. Importantly, although these various risk alleles affect NMDA receptor activation through [...] Read more.

Various ASD risk alleles have been associated with impairment of NMDA receptor activation (i.e., NMDA Receptor Hypofunction) and/or disturbance of the careful balance between activation mediated by GluN2B-subtype and GluN2A-subtype-containing NMDA receptors. Importantly, although these various risk alleles affect NMDA receptor activation through different mechanisms, they share the pathogenic consequences of causing disturbance of highly regulated NMDA receptor activation. Disturbances of NMDA receptor activation due to sequence variants, protein termination variants and copy number variants are often cell-specific and regionally selective. Thus, translational therapeutic NMDA receptor agonist interventions, which may require chronic administration, must have specificity, selectivity and facilitate NMDA receptor activation in a manner that is physiologic (i.e., mimicking that of endogenously released glutamate and glycine/D-serine released in response to salient and relevant socio-cognitive provocations within discrete neural circuits). Importantly, knockout mice with absent expression and mice with haploinsufficient expression of the deleterious genes often serve as good models to test the potential efficacy of promising pharmacotherapeutic strategies. The Review considers diverse examples of “illness” genes, their pathogenic effects on NMDA receptor activation and, when available, results of studies of impaired sociability in mouse models, including “proof of principle/proof of concept” experiments exploring NMDA receptor agonist interventions and the development of promising positive allosteric modulators (PAMs), which serve as support and models for developing an inventory of PAMs and negative allosteric modulators (NAMs) for translational therapeutic intervention. Conceivably, selective PAMs and NAMs either alone or in combination will be administered to patients guided by their genotype in order to potentiate and/or restore disrupted balance between activation mediated by GluN2B-subtype and GluN2A-subtype containing NMDA receptors. Full article

(This article belongs to the Special Issue Clinical Phenotype of Autism Spectrum Disorder: Development and Delivery of Therapeutic Biomolecules to the CNS)

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13 pages, 3409 KiB

Open AccessEditor’s ChoiceArticle

CNS-Sparing Histamine H₃ Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms

by Arianna Carolina Rosa, Patrizia Nardini, Silvia Sgambellone, Maura Gurrieri, Simona Federica Spampinato, Alfonso Dell’Accio, Paul L Chazot, Ilona Obara, Wai L Liu and Alessandro Pini

Biomolecules 2022, 12(2), 184; https://doi.org/10.3390/biom12020184 - 22 Jan 2022

Cited by 5 | Viewed by 3183

Abstract

Among the histamine receptors, growing evidence points to the histamine H₃ receptor as a pharmacological candidate to counteract the autonomic neuropathy associated with diabetes. The study aimed to evaluate the effect of PF00868087 (also known as ZPL-868), a CNS-sparing histamine H₃ [...] Read more.

Among the histamine receptors, growing evidence points to the histamine H₃ receptor as a pharmacological candidate to counteract the autonomic neuropathy associated with diabetes. The study aimed to evaluate the effect of PF00868087 (also known as ZPL-868), a CNS-sparing histamine H₃ receptor antagonist, on the autonomic neuropathy of the intestinal tract associated with diabetes. Diabetes was induced in male BALB/c mice by a single high dose of streptozotocin (150 mg/kg). Colorectal specimens from control and diabetic mice, randomized to vehicle or PF0086087 (10, 30, 100 mg/kg/day by oral gavage for 14 days), were processed for morphological and immunohistochemical analysis. A significant overproduction of mucus in the intestinal mucosa of diabetic mice compared to the controls was observed. PF0086087 at the highest dose prevented mucin overproduction. The immunohistochemistry analysis demonstrated that diabetes causes a decrease in the inhibitory component of enteric motility, measured as the percentage of neuronal nitric oxide synthase-positive neurons (p < 0.05) and a parallel increase in the excitatory component evaluated as substance P-positive fibres (p < 0.01). PF0086087 dose-dependently prevented these pathophysiological events. In conclusion, PF0086087 may be an essential tool in preventing nitrergic dysfunction in the myenteric plexus of the distal colon and diabetes-induced gastrointestinal complications. Full article

(This article belongs to the Special Issue New Developments in Histamine Research)

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27 pages, 764 KiB

Open AccessEditor’s ChoiceReview

Dysregulated Epicardial Adipose Tissue as a Risk Factor and Potential Therapeutic Target of Heart Failure with Preserved Ejection Fraction in Diabetes

by Teresa Salvatore, Raffaele Galiero, Alfredo Caturano, Erica Vetrano, Luca Rinaldi, Francesca Coviello, Anna Di Martino, Gaetana Albanese, Sara Colantuoni, Giulia Medicamento, Raffaele Marfella, Celestino Sardu and Ferdinando Carlo Sasso

Biomolecules 2022, 12(2), 176; https://doi.org/10.3390/biom12020176 - 21 Jan 2022

Cited by 26 | Viewed by 5416

Abstract

Cardiovascular (CV) disease and heart failure (HF) are the leading cause of mortality in type 2 diabetes (T2DM), a metabolic disease which represents a fast-growing health challenge worldwide. Specifically, T2DM induces a cluster of systemic metabolic and non-metabolic signaling which may promote myocardium [...] Read more.

Cardiovascular (CV) disease and heart failure (HF) are the leading cause of mortality in type 2 diabetes (T2DM), a metabolic disease which represents a fast-growing health challenge worldwide. Specifically, T2DM induces a cluster of systemic metabolic and non-metabolic signaling which may promote myocardium derangements such as inflammation, fibrosis, and myocyte stiffness, which represent the hallmarks of heart failure with preserved ejection fraction (HFpEF). On the other hand, several observational studies have reported that patients with T2DM have an abnormally enlarged and biologically transformed epicardial adipose tissue (EAT) compared with non-diabetic controls. This expanded EAT not only causes a mechanical constriction of the diastolic filling but is also a source of pro-inflammatory mediators capable of causing inflammation, microcirculatory dysfunction and fibrosis of the underlying myocardium, thus impairing the relaxability of the left ventricle and increasing its filling pressure. In addition to representing a potential CV risk factor, emerging evidence shows that EAT may guide the therapeutic decision in diabetic patients as drugs such as metformin, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 inhibitors (SGLT2-Is), have been associated with attenuation of EAT enlargement. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

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26 pages, 2815 KiB

Open AccessEditor’s ChoiceArticle

Multi-Omics Analysis of Multiple Glucose-Sensing Receptor Systems in Yeast

by Shuang Li, Yuanyuan Li, Blake R. Rushing, Sarah E. Harris, Susan L. McRitchie, Daniel Dominguez, Susan J. Sumner and Henrik G. Dohlman

Biomolecules 2022, 12(2), 175; https://doi.org/10.3390/biom12020175 - 21 Jan 2022

Cited by 9 | Viewed by 3653

Abstract

The yeast Saccharomyces cerevisiae has long been used to produce alcohol from glucose and other sugars. While much is known about glucose metabolism, relatively little is known about the receptors and signaling pathways that indicate glucose availability. Here, we compare the two glucose [...] Read more.

The yeast Saccharomyces cerevisiae has long been used to produce alcohol from glucose and other sugars. While much is known about glucose metabolism, relatively little is known about the receptors and signaling pathways that indicate glucose availability. Here, we compare the two glucose receptor systems in S. cerevisiae. The first is a heterodimer of transporter-like proteins (transceptors), while the second is a seven-transmembrane receptor coupled to a large G protein (Gpa2) that acts in coordination with two small G proteins (Ras1 and Ras2). Through comprehensive measurements of glucose-dependent transcription and metabolism, we demonstrate that the two receptor systems have distinct roles in glucose signaling: the G-protein-coupled receptor directs carbohydrate and energy metabolism, while the transceptors regulate ancillary processes such as ribosome, amino acids, cofactor and vitamin metabolism. The large G-protein transmits the signal from its cognate receptor, while the small G-protein Ras2 (but not Ras1) integrates responses from both receptor pathways. Collectively, our analysis reveals the molecular basis for glucose detection and the earliest events of glucose-dependent signal transduction in yeast. Full article

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

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24 pages, 1808 KiB

Open AccessEditor’s ChoiceReview

Passive Immunization in Alpha-Synuclein Preclinical Animal Models

by Jonas Folke, Nelson Ferreira, Tomasz Brudek, Per Borghammer and Nathalie Van Den Berge

Biomolecules 2022, 12(2), 168; https://doi.org/10.3390/biom12020168 - 20 Jan 2022

Cited by 13 | Viewed by 4829

Abstract

Alpha-synucleinopathies include Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. These are all progressive neurodegenerative diseases that are characterized by pathological misfolding and accumulation of the protein alpha-synuclein (αsyn) in neurons, axons or glial cells in the brain, [...] Read more.

Alpha-synucleinopathies include Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. These are all progressive neurodegenerative diseases that are characterized by pathological misfolding and accumulation of the protein alpha-synuclein (αsyn) in neurons, axons or glial cells in the brain, but also in other organs. The abnormal accumulation and propagation of pathogenic αsyn across the autonomic connectome is associated with progressive loss of neurons in the brain and peripheral organs, resulting in motor and non-motor symptoms. To date, no cure is available for synucleinopathies, and therapy is limited to symptomatic treatment of motor and non-motor symptoms upon diagnosis. Recent advances using passive immunization that target different αsyn structures show great potential to block disease progression in rodent studies of synucleinopathies. However, passive immunotherapy in clinical trials has been proven safe but less effective than in preclinical conditions. Here we review current achievements of passive immunotherapy in animal models of synucleinopathies. Furthermore, we propose new research strategies to increase translational outcome in patient studies, (1) by using antibodies against immature conformations of pathogenic αsyn (monomers, post-translationally modified monomers, oligomers and protofibrils) and (2) by focusing treatment on body-first synucleinopathies where damage in the brain is still limited and effective immunization could potentially stop disease progression by blocking the spread of pathogenic αsyn from peripheral organs to the brain. Full article

(This article belongs to the Special Issue Protein Misfolding in Neurodegenerative Diseases: Recent Advances and Therapeutical Implications)

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19 pages, 2721 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Bcl-2 Family Members and the Mitochondrial Import Machineries: The Roads to Death

by Lisenn Lalier, François Vallette and Stéphen Manon

Biomolecules 2022, 12(2), 162; https://doi.org/10.3390/biom12020162 - 19 Jan 2022

Cited by 29 | Viewed by 3574

Abstract

The localization of Bcl-2 family members at the mitochondrial outer membrane (MOM) is a crucial step in the implementation of apoptosis. We review evidence showing the role of the components of the mitochondrial import machineries (translocase of the outer membrane (TOM) and the [...] Read more.

The localization of Bcl-2 family members at the mitochondrial outer membrane (MOM) is a crucial step in the implementation of apoptosis. We review evidence showing the role of the components of the mitochondrial import machineries (translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM)) in the mitochondrial localization of Bcl-2 family members and how these machineries regulate the function of pro- and anti-apoptotic proteins in resting cells and in cells committed into apoptosis. Full article

(This article belongs to the Special Issue State-of-the-Art Cell Death in France 2020-2021)

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27 pages, 2062 KiB

Open AccessEditor’s ChoiceReview

The Urokinase Plasminogen Activation System in Pancreatic Cancer: Prospective Diagnostic and Therapeutic Targets

by Ashna A. Kumar, Benjamin J. Buckley and Marie Ranson

Biomolecules 2022, 12(2), 152; https://doi.org/10.3390/biom12020152 - 18 Jan 2022

Cited by 19 | Viewed by 6246

Abstract

Pancreatic cancer is a highly aggressive malignancy that features high recurrence rates and the poorest prognosis of all solid cancers. The urokinase plasminogen activation system (uPAS) is strongly implicated in the pathophysiology and clinical outcomes of patients with pancreatic ductal adenocarcinoma (PDAC), which [...] Read more.

Pancreatic cancer is a highly aggressive malignancy that features high recurrence rates and the poorest prognosis of all solid cancers. The urokinase plasminogen activation system (uPAS) is strongly implicated in the pathophysiology and clinical outcomes of patients with pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic cancers. Overexpression of the urokinase-type plasminogen activator (uPA) or its cell surface receptor uPAR is a key step in the acquisition of a metastatic phenotype via multiple mechanisms, including the increased activation of cell surface localised plasminogen which generates the serine protease plasmin. This triggers multiple downstream processes that promote tumour cell migration and invasion. Increasing clinical evidence shows that the overexpression of uPA, uPAR, or of both is strongly associated with worse clinicopathological features and poor prognosis in PDAC patients. This review provides an overview of the current understanding of the uPAS in the pathogenesis and progression of pancreatic cancer, with a focus on PDAC, and summarises the substantial body of evidence that supports the role of uPAS components, including plasminogen receptors, in this disease. The review further outlines the clinical utility of uPAS components as prospective diagnostic and prognostic biomarkers for PDAC, as well as a rationale for the development of novel uPAS-targeted therapeutics. Full article

(This article belongs to the Special Issue Plasminogen, Plasminogen Receptors and Binding Mechanisms in Cancer)

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19 pages, 797 KiB

Open AccessEditor’s ChoiceReview

Adrenomedullin: Not Just Another Gastrointestinal Peptide

by Sonia Martínez-Herrero and Alfredo Martínez

Biomolecules 2022, 12(2), 156; https://doi.org/10.3390/biom12020156 - 18 Jan 2022

Cited by 9 | Viewed by 4114

Abstract

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two bioactive peptides derived from the same precursor with several biological functions including vasodilation, angiogenesis, or anti-inflammation, among others. AM and PAMP are widely expressed throughout the gastrointestinal (GI) tract where they behave as [...] Read more.

Adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) are two bioactive peptides derived from the same precursor with several biological functions including vasodilation, angiogenesis, or anti-inflammation, among others. AM and PAMP are widely expressed throughout the gastrointestinal (GI) tract where they behave as GI hormones, regulating numerous physiological processes such as gastric emptying, gastric acid release, insulin secretion, bowel movements, or intestinal barrier function. Furthermore, it has been recently demonstrated that AM/PAMP have an impact on gut microbiome composition, inhibiting the growth of bacteria related with disease and increasing the number of beneficial bacteria such as Lactobacillus or Bifidobacterium. Due to their wide functions in the GI tract, AM and PAMP are involved in several digestive pathologies such as peptic ulcer, diabetes, colon cancer, or inflammatory bowel disease (IBD). AM is a key protective factor in IBD onset and development, as it regulates cytokine production in the intestinal mucosa, improves vascular and lymphatic regeneration and function and mucosal epithelial repair, and promotes a beneficial gut microbiome composition. AM and PAMP are relevant GI hormones that can be targeted to develop novel therapeutic agents for IBD, other GI disorders, or microbiome-related pathologies. Full article

(This article belongs to the Special Issue Gastrointestinal Hormones)

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19 pages, 3310 KiB

Open AccessEditor’s ChoiceArticle

Potential Anticancer Agents against Melanoma Cells Based on an As-Synthesized Thiosemicarbazide Derivative

by Paweł Kozyra, Agnieszka Korga-Plewko, Zbigniew Karczmarzyk, Anna Hawrył, Waldemar Wysocki, Michał Człapski, Magdalena Iwan, Marta Ostrowska-Leśko, Emilia Fornal and Monika Pitucha

Biomolecules 2022, 12(2), 151; https://doi.org/10.3390/biom12020151 - 18 Jan 2022

Cited by 18 | Viewed by 2727

Abstract

In this paper, thiosemicarbazide derivatives were synthesized as potential anticancer agents. X-ray investigations for 1-(2,4-dichlorophenoxy)acetyl-4-(2-fluorophenyl) thiosemicarbazide, 1-(2,4-dichlorophenoxy)acetyl-4-(4-metylothiophenyl)thiosemicarbazide and 1-(2,4-di chlorophenoxy)acetyl-4-(4-iodophenyl)thiosemicarbazide were carried out in order to confirm the synthesis pathways, identify their tautomeric forms, analyze the conformational preferences of molecules, and identify intra- [...] Read more.

In this paper, thiosemicarbazide derivatives were synthesized as potential anticancer agents. X-ray investigations for 1-(2,4-dichlorophenoxy)acetyl-4-(2-fluorophenyl) thiosemicarbazide, 1-(2,4-dichlorophenoxy)acetyl-4-(4-metylothiophenyl)thiosemicarbazide and 1-(2,4-di chlorophenoxy)acetyl-4-(4-iodophenyl)thiosemicarbazide were carried out in order to confirm the synthesis pathways, identify their tautomeric forms, analyze the conformational preferences of molecules, and identify intra- and intermolecular interactions in the crystalline state. TLC and RP-HPLC analyses were used to determine lipophilicity. The lipophilicity analysis revealed that the 4-substituted halogen derivatives of thiosemicarbazides showed greater lipophilicity compared with 2-substituted derivatives. The optimal range of lipophilicity for biologically active compounds logkw is between 4.14 and 4.78. However, as the analysis showed, it is not a decisive parameter. The cytotoxicity of the new compounds was evaluated against both the G-361 and BJ cell lines. Cytotoxicity analyses and cell-cycle and cell apoptosis assays were performed. The MTT test demonstrated that three compounds were cytotoxic to melanoma cells and not toxic to normal fibroblasts in the concentration range used. The cell cycle analysis showed that the compounds had no significant effect on the cell cycle inhibition. An extensive gene expression analysis additionally revealed that all compounds tested downregulated the expression of dihydroorotate dehydrogenase (DHODH). DHODH is a mitochondrial enzyme involved in the de novo synthesis of pyrimidines. Due to the rapid rate of cancer cell proliferation and the increased demand for nucleotide synthesis, it has become a potential therapeutic target. Full article

(This article belongs to the Special Issue New Approaches for the Treatment of Civilization Diseases)

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16 pages, 959 KiB

Open AccessEditor’s ChoiceReview

Antioxidant Roles of SGLT2 Inhibitors in the Kidney

by Carmen Llorens-Cebrià, Mireia Molina-Van den Bosch, Ander Vergara, Conxita Jacobs-Cachá and Maria José Soler

Biomolecules 2022, 12(1), 143; https://doi.org/10.3390/biom12010143 - 16 Jan 2022

Cited by 20 | Viewed by 3546

Abstract

The reduction-oxidation (redox) system consists of the coupling and coordination of various electron gradients that are generated thanks to serial reduction-oxidation enzymatic reactions. These reactions happen in every cell and produce radical oxidants that can be mainly classified into reactive oxygen species (ROS) [...] Read more.

The reduction-oxidation (redox) system consists of the coupling and coordination of various electron gradients that are generated thanks to serial reduction-oxidation enzymatic reactions. These reactions happen in every cell and produce radical oxidants that can be mainly classified into reactive oxygen species (ROS) and reactive nitrogen species (RNS). ROS and RNS modulate cell-signaling pathways and cellular processes fundamental to normal cell function. However, overproduction of oxidative species can lead to oxidative stress (OS) that is pathological. Oxidative stress is a main contributor to diabetic kidney disease (DKD) onset. In the kidney, the proximal tubular cells require a high energy supply to reabsorb proteins, metabolites, ions, and water. In a diabetic milieu, glucose-induced toxicity promotes oxidative stress and mitochondrial dysfunction, impairing tubular function. Increased glucose level in urine and ROS enhance the activity of sodium/glucose co-transporter type 2 (SGLT2), which in turn exacerbates OS. SGLT2 inhibitors have demonstrated clear cardiovascular benefits in DKD which may be in part ascribed to the generation of a beneficial equilibrium between oxidant and antioxidant mechanisms. Full article

(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)

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20 pages, 1653 KiB

Open AccessEditor’s ChoiceReview

β-Synuclein: An Enigmatic Protein with Diverse Functionality

by Junna Hayashi and John A. Carver

Biomolecules 2022, 12(1), 142; https://doi.org/10.3390/biom12010142 - 16 Jan 2022

Cited by 15 | Viewed by 2878

Abstract

α-Synuclein (αS) is a small, unstructured, presynaptic protein expressed in the brain. Its aggregated form is a major component of Lewy bodies, the large proteinaceous deposits in Parkinson’s disease. The closely related protein, β-Synuclein (βS), is co-expressed with αS. In vitro, βS acts [...] Read more.

α-Synuclein (αS) is a small, unstructured, presynaptic protein expressed in the brain. Its aggregated form is a major component of Lewy bodies, the large proteinaceous deposits in Parkinson’s disease. The closely related protein, β-Synuclein (βS), is co-expressed with αS. In vitro, βS acts as a molecular chaperone to inhibit αS aggregation. As a result of this assignation, βS has been largely understudied in comparison to αS. However, recent reports suggest that βS promotes neurotoxicity, implying that βS is involved in other cellular pathways with functions independent of αS. Here, we review the current literature pertaining to human βS in order to understand better the role of βS in homeostasis and pathology. Firstly, the structure of βS is discussed. Secondly, the ability of βS to (i) act as a molecular chaperone; (ii) regulate synaptic function, lipid binding, and the nigrostriatal dopaminergic system; (iii) mediate apoptosis; (iv) participate in protein degradation pathways; (v) modulate intracellular metal levels; and (vi) promote cellular toxicity and protein aggregation is explored. Thirdly, the P123H and V70M mutations of βS, which are associated with dementia with Lewy bodies, are discussed. Finally, the importance of post-translational modifications on the structure and function of βS is reviewed. Overall, it is concluded that βS has both synergistic and antagonistic interactions with αS, but it may also possess important cellular functions independent of αS. Full article

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26 pages, 3482 KiB

Open AccessEditor’s ChoiceReview

Mass Spectrometry-Based Structural Proteomics for Metal Ion/Protein Binding Studies

by Yanchun Lin and Michael L. Gross

Biomolecules 2022, 12(1), 135; https://doi.org/10.3390/biom12010135 - 15 Jan 2022

Cited by 6 | Viewed by 3982

Abstract

Metal ions are critical for the biological and physiological functions of many proteins. Mass spectrometry (MS)-based structural proteomics is an ever-growing field that has been adopted to study protein and metal ion interactions. Native MS offers information on metal binding and its stoichiometry. [...] Read more.

Metal ions are critical for the biological and physiological functions of many proteins. Mass spectrometry (MS)-based structural proteomics is an ever-growing field that has been adopted to study protein and metal ion interactions. Native MS offers information on metal binding and its stoichiometry. Footprinting approaches coupled with MS, including hydrogen/deuterium exchange (HDX), “fast photochemical oxidation of proteins” (FPOP) and targeted amino-acid labeling, identify binding sites and regions undergoing conformational changes. MS-based titration methods, including “protein–ligand interactions by mass spectrometry, titration and HD exchange” (PLIMSTEX) and “ligand titration, fast photochemical oxidation of proteins and mass spectrometry” (LITPOMS), afford binding stoichiometry, binding affinity, and binding order. These MS-based structural proteomics approaches, their applications to answer questions regarding metal ion protein interactions, their limitations, and recent and potential improvements are discussed here. This review serves as a demonstration of the capabilities of these tools and as an introduction to wider applications to solve other questions. Full article

(This article belongs to the Collection Advances in Metal Binding Proteins)

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12 pages, 2764 KiB

Open AccessEditor’s ChoiceArticle

O-methylated N-glycans Distinguish Mosses from Vascular Plants

by David Stenitzer, Réka Mócsai, Harald Zechmeister, Ralf Reski, Eva L. Decker and Friedrich Altmann

Biomolecules 2022, 12(1), 136; https://doi.org/10.3390/biom12010136 - 15 Jan 2022

Cited by 6 | Viewed by 2420

Abstract

In the animal kingdom, a stunning variety of N-glycan structures have emerged with phylogenetic specificities of various kinds. In the plant kingdom, however, N-glycosylation appears to be strictly conservative and uniform. From mosses to all kinds of gymno- and angiosperms, land plants mainly [...] Read more.

In the animal kingdom, a stunning variety of N-glycan structures have emerged with phylogenetic specificities of various kinds. In the plant kingdom, however, N-glycosylation appears to be strictly conservative and uniform. From mosses to all kinds of gymno- and angiosperms, land plants mainly express structures with the common pentasaccharide core substituted with xylose, core α1,3-fucose, maybe terminal GlcNAc residues and Lewis A determinants. In contrast, green algae biosynthesise unique and unusual N-glycan structures with uncommon monosaccharides, a plethora of different structures and various kinds of O-methylation. Mosses, a group of plants that are separated by at least 400 million years of evolution from vascular plants, have hitherto been seen as harbouring an N-glycosylation machinery identical to that of vascular plants. To challenge this view, we analysed the N-glycomes of several moss species using MALDI-TOF/TOF, PGC-MS/MS and GC-MS. While all species contained the plant-typical heptasaccharide with no, one or two terminal GlcNAc residues (MMXF, MGnXF and GnGnXF, respectively), many species exhibited MS signals with 14.02 Da increments as characteristic for O-methylation. Throughout all analysed moss N-glycans, the level of methylation differed strongly even within the same family. In some species, methylated glycans dominated, while others had no methylation at all. GC-MS revealed the main glycan from Funaria hygrometrica to contain 2,6-O-methylated terminal mannose. Some mosses additionally presented very large, likewise methylated complex-type N-glycans. This first finding of the methylation of N-glycans in land plants mirrors the presumable phylogenetic relation of mosses to green algae, where the O-methylation of mannose and many other monosaccharides is a common trait. Full article

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

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10 pages, 1938 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

by Keiichi Asano, Anna Cantalupo, Lauriane Sedes and Francesco Ramirez

Biomolecules 2022, 12(1), 128; https://doi.org/10.3390/biom12010128 - 14 Jan 2022

Cited by 16 | Viewed by 4980

Abstract

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein [...] Read more.

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder. Full article

(This article belongs to the Special Issue Aortic Aneurysm and Dissection: Heterogeneity and Molecular Mechanisms)

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34 pages, 1491 KiB

Open AccessEditor’s ChoiceReview

Mechanistic Link between Vitamin B12 and Alzheimer’s Disease

by Anna Andrea Lauer, Heike Sabine Grimm, Birgit Apel, Nataliya Golobrodska, Lara Kruse, Elina Ratanski, Noemi Schulten, Laura Schwarze, Thomas Slawik, Saskia Sperlich, Antonia Vohla and Marcus Otto Walter Grimm

Biomolecules 2022, 12(1), 129; https://doi.org/10.3390/biom12010129 - 14 Jan 2022

Cited by 27 | Viewed by 14367

Abstract

Alzheimer’s disease (AD) is the most common form of dementia in the elderly population, affecting over 55 million people worldwide. Histopathological hallmarks of this multifactorial disease are an increased plaque burden and tangles in the brains of affected individuals. Several lines of evidence [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia in the elderly population, affecting over 55 million people worldwide. Histopathological hallmarks of this multifactorial disease are an increased plaque burden and tangles in the brains of affected individuals. Several lines of evidence indicate that B12 hypovitaminosis is linked to AD. In this review, the biochemical pathways involved in AD that are affected by vitamin B12, focusing on APP processing, Aβ fibrillization, Aβ-induced oxidative damage as well as tau hyperphosphorylation and tau aggregation, are summarized. Besides the mechanistic link, an overview of clinical studies utilizing vitamin B supplementation are given, and a potential link between diseases and medication resulting in a reduced vitamin B12 level and AD are discussed. Besides the disease-mediated B12 hypovitaminosis, the reduction in vitamin B12 levels caused by an increasing change in dietary preferences has been gaining in relevance. In particular, vegetarian and vegan diets are associated with vitamin B12 deficiency, and therefore might have potential implications for AD. In conclusion, our review emphasizes the important role of vitamin B12 in AD, which is particularly important, as even in industrialized countries a large proportion of the population might not be sufficiently supplied with vitamin B12. Full article

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9 pages, 1512 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of COA6 in the Mitochondrial Copper Delivery Pathway to Cytochrome c Oxidase

by Abhinav B. Swaminathan and Vishal M. Gohil

Biomolecules 2022, 12(1), 125; https://doi.org/10.3390/biom12010125 - 13 Jan 2022

Cited by 14 | Viewed by 3118

Abstract

Copper is essential for the stability and activity of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Copper is bound to COX1 and COX2, two core subunits of CcO, forming the Cu_B and Cu_A sites, respectively. Biogenesis [...] Read more.

Copper is essential for the stability and activity of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Copper is bound to COX1 and COX2, two core subunits of CcO, forming the Cu_B and Cu_A sites, respectively. Biogenesis of these two copper sites of CcO occurs separately and requires a number of evolutionarily conserved proteins that form the mitochondrial copper delivery pathway. Pathogenic mutations in some of the proteins of the copper delivery pathway, such as SCO1, SCO2, and COA6, have been shown to cause fatal infantile human disorders, highlighting the biomedical significance of understanding copper delivery mechanisms to CcO. While two decades of studies have provided a clearer picture regarding the biochemical roles of SCO1 and SCO2 proteins, some discrepancy exists regarding the function of COA6, the new member of this pathway. Initial genetic and biochemical studies have linked COA6 with copper delivery to COX2 and follow-up structural and functional studies have shown that it is specifically required for the biogenesis of the Cu_A site by acting as a disulfide reductase of SCO and COX2 proteins. Its role as a copper metallochaperone has also been proposed. Here, we critically review the recent literature regarding the molecular function of COA6 in Cu_A biogenesis. Full article

(This article belongs to the Special Issue Insights in the Structure and Functions of Mitochondrial Proteins and Metalloproteins)

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14 pages, 1494 KiB

Open AccessEditor’s ChoiceReview

The Builders of the Junction: Roles of Junctophilin1 and Junctophilin2 in the Assembly of the Sarcoplasmic Reticulum–Plasma Membrane Junctions in Striated Muscle

by Stefano Perni

Biomolecules 2022, 12(1), 109; https://doi.org/10.3390/biom12010109 - 10 Jan 2022

Cited by 8 | Viewed by 3045

Abstract

Contraction of striated muscle is triggered by a massive release of calcium from the sarcoplasmic reticulum (SR) into the cytoplasm. This intracellular calcium release is initiated by membrane depolarization, which is sensed by voltage-gated calcium channels Ca_V1.1 (in skeletal muscle) and [...] Read more.

Contraction of striated muscle is triggered by a massive release of calcium from the sarcoplasmic reticulum (SR) into the cytoplasm. This intracellular calcium release is initiated by membrane depolarization, which is sensed by voltage-gated calcium channels Ca_V1.1 (in skeletal muscle) and Ca_V1.2 (in cardiac muscle) in the plasma membrane (PM), which in turn activate the calcium-releasing channel ryanodine receptor (RyR) embedded in the SR membrane. This cross-communication between channels in the PM and in the SR happens at specialized regions, the SR-PM junctions, where these two compartments come in close proximity. Junctophilin1 and Junctophilin2 are responsible for the formation and stabilization of SR-PM junctions in striated muscle and actively participate in the recruitment of the two essential players in intracellular calcium release, Ca_V and RyR. This short review focuses on the roles of junctophilins1 and 2 in the formation and organization of SR-PM junctions in skeletal and cardiac muscle and on the functional consequences of the absence or malfunction of these proteins in striated muscle in light of recently published data and recent advancements in protein structure prediction. Full article

(This article belongs to the Special Issue State-of-the-Art of Myology in Italy 2020–2021)

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20 pages, 6389 KiB

Open AccessEditor’s ChoiceReview

Sex Hormone-Specific Neuroanatomy of Takotsubo Syndrome: Is the Insular Cortex a Moderator?

by Michiaki Nagai, Carola Yvette Förster and Keigo Dote

Biomolecules 2022, 12(1), 110; https://doi.org/10.3390/biom12010110 - 10 Jan 2022

Cited by 8 | Viewed by 3816

Abstract

Takotsubo syndrome (TTS), a transient form of dysfunction in the heart’s left ventricle, occurs predominantly in postmenopausal women who have emotional stress. Earlier studies support the concept that the human circulatory system is modulated by a cortical network (consisting of the anterior cingulate [...] Read more.

Takotsubo syndrome (TTS), a transient form of dysfunction in the heart’s left ventricle, occurs predominantly in postmenopausal women who have emotional stress. Earlier studies support the concept that the human circulatory system is modulated by a cortical network (consisting of the anterior cingulate gyrus, amygdala, and insular cortex (Ic)) that plays a pivotal role in the central autonomic nervous system in relation to emotional stressors. The Ic plays a crucial role in the sympathovagal balance, and decreased levels of female sex hormones have been speculated to change functional cerebral asymmetry, with a possible link to autonomic instability. In this review, we focus on the Ic as an important moderator of the human brain–heart axis in association with sex hormones. We also summarize the current knowledge regarding the sex-specific neuroanatomy in TTS. Full article

(This article belongs to the Special Issue Metabolic and Neurotrophic Pathways Driving the Brain-Heart-Axis)

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14 pages, 7816 KiB

Open AccessEditor’s ChoiceArticle

The Mucolipin TRPML2 Channel Enhances the Sensitivity of Multiple Myeloma Cell Lines to Ibrutinib and/or Bortezomib Treatment

by Giorgio Santoni, Consuelo Amantini, Federica Maggi, Oliviero Marinelli, Matteo Santoni and Maria Beatrice Morelli

Biomolecules 2022, 12(1), 107; https://doi.org/10.3390/biom12010107 - 9 Jan 2022

Cited by 4 | Viewed by 1932

Abstract

Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells and their accumulation in the bone marrow. The aim of the present study is the evaluation of biological effects of Ibrutinib in human MM cell lines alone [...] Read more.

Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells and their accumulation in the bone marrow. The aim of the present study is the evaluation of biological effects of Ibrutinib in human MM cell lines alone or in combination with different doses of Bortezomib. In addition, the relationship between the expression of TRPML2 channels and chemosensitivity of different MM cell lines to Ibrutinib administered alone or in combination with Bortezomib has been evaluated. By RT-PCR and Western blot analysis, we found that the Ibrutinib-resistant U266 cells showed lower TRPML2 expression, whereas higher TRPML2 mRNA and protein levels were evidenced in RPMI cells. Moreover, TRPML2 gene silencing in RPMI cells markedly reverted the effects induced by Ibrutinib alone or in combination with Bortezomib suggesting that the sensitivity to Ibrutinib is TRPML2 mediated. In conclusion, this study suggests that the expression of TRPML2 in MM cells increases the sensitivity to Ibrutinib treatment, suggesting for a potential stratification of Ibrutinib sensitivity of MM patients on the basis of the TRPML2 expression. Furthermore, studies in vitro and in vivo should still be necessary to completely address the molecular mechanisms and the potential role of TRPML2 channels in therapy and prognosis of MM patients. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels: Markers and Therapeutic Targets for Cancer?)

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15 pages, 1521 KiB

Open AccessEditor’s ChoiceReview

Multi-Organ Crosstalk with Endocrine Pancreas: A Focus on How Gut Microbiota Shapes Pancreatic Beta-Cells

by Elisa Fernández-Millán and Carlos Guillén

Biomolecules 2022, 12(1), 104; https://doi.org/10.3390/biom12010104 - 8 Jan 2022

Cited by 12 | Viewed by 5223

Abstract

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells [...] Read more.

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells communicate with metabolic and non-metabolic tissues provides a novel area for investigation and implicates the importance of inter-organ communication in the pathology of metabolic diseases such as T2D. In this review, we provide an overview of secreted factors from diverse organs and tissues that have been shown to impact beta-cell biology. Specifically, we discuss experimental and clinical evidence in support for a role of gut to beta-cell crosstalk, paying particular attention to bacteria-derived factors including short-chain fatty acids, lipopolysaccharide, and factors contained within extracellular vesicles that influence the function and/or the survival of beta cells under normal or diabetogenic conditions. Full article

(This article belongs to the Special Issue The Pancreatic Beta Cell)

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29 pages, 1962 KiB

Open AccessEditor’s ChoiceReview

Anti-Planktonic and Anti-Biofilm Properties of Pentacyclic Triterpenes—Asiatic Acid and Ursolic Acid as Promising Antibacterial Future Pharmaceuticals

by Zuzanna Sycz, Dorota Tichaczek-Goska and Dorota Wojnicz

Biomolecules 2022, 12(1), 98; https://doi.org/10.3390/biom12010098 - 7 Jan 2022

Cited by 32 | Viewed by 3116

Abstract

Due to the ever-increasing number of multidrug-resistant bacteria, research concerning plant-derived compounds with antimicrobial mechanisms of action has been conducted. Pentacyclic triterpenes, which have a broad spectrum of medicinal properties, are one of such groups. Asiatic acid (AA) and ursolic acid (UA), which [...] Read more.

Due to the ever-increasing number of multidrug-resistant bacteria, research concerning plant-derived compounds with antimicrobial mechanisms of action has been conducted. Pentacyclic triterpenes, which have a broad spectrum of medicinal properties, are one of such groups. Asiatic acid (AA) and ursolic acid (UA), which belong to this group, exhibit diverse biological activities that include antioxidant, anti-inflammatory, diuretic, and immunostimulatory. Some of these articles usually contain only a short section describing the antibacterial effects of AA or UA. Therefore, our review article aims to provide the reader with a broader understanding of the activity of these acids against pathogenic bacteria. The bacteria in the human body can live in the planktonic form and create a biofilm structure. Therefore, we found it valuable to present the action of AA and UA on both planktonic and biofilm cultures. The article also presents mechanisms of the biological activity of these substances against microorganisms. Full article

(This article belongs to the Collection Feature Papers in Synthetic Biology and Bioengineering)

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19 pages, 1191 KiB

Open AccessEditor’s ChoiceReview

The Role of miRNA in Regulating the Fate of Monocytes in Health and Cancer

by Anna Alwani, Aneta Andreasik, Rafał Szatanek, Maciej Siedlar and Monika Baj-Krzyworzeka

Biomolecules 2022, 12(1), 100; https://doi.org/10.3390/biom12010100 - 7 Jan 2022

Cited by 9 | Viewed by 2984

Abstract

Monocytes represent a heterogeneous population of blood cells that provide a link between innate and adaptive immunity. The unique potential of monocytes as both precursors (e.g., of macrophages) and effector cells (as phagocytes or cytotoxic cells) makes them an interesting research and therapeutic [...] Read more.

Monocytes represent a heterogeneous population of blood cells that provide a link between innate and adaptive immunity. The unique potential of monocytes as both precursors (e.g., of macrophages) and effector cells (as phagocytes or cytotoxic cells) makes them an interesting research and therapeutic target. At the site of a tumor, monocytes/macrophages constitute a major population of infiltrating leukocytes and, depending on the type of tumor, may play a dual role as either a bad or good indicator for cancer recovery. The functional activity of monocytes and macrophages derived from them is tightly regulated at the transcriptional and post-transcriptional level. This review summarizes the current understanding of the role of small regulatory miRNA in monocyte formation, maturation and function in health and cancer development. Additionally, signatures of miRNA-based monocyte subsets and the influence of exogenous miRNA generated in the tumor environment on the function of monocytes are discussed. Full article

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

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18 pages, 2669 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Role of Fibroblasts and Myofibroblasts on the Pathogenesis and Treatment of Pelvic Organ Prolapse

by Zeliha Guler and Jan Paul Roovers

Biomolecules 2022, 12(1), 94; https://doi.org/10.3390/biom12010094 - 6 Jan 2022

Cited by 29 | Viewed by 7461

Abstract

Pelvic organ prolapse (POP) is a multifactorial connective tissue disorder caused by damage to the supportive structures of the pelvic floor, leading to the descent of pelvic organs in the vagina. In women with POP, fibroblast function is disturbed or altered, which causes [...] Read more.

Pelvic organ prolapse (POP) is a multifactorial connective tissue disorder caused by damage to the supportive structures of the pelvic floor, leading to the descent of pelvic organs in the vagina. In women with POP, fibroblast function is disturbed or altered, which causes impaired collagen metabolism that affects the mechanical properties of the tissue. Ideal surgical repair, either native tissue repair or POP surgery using an implant, aims to create a functional pelvic floor that is load-bearing, activating fibroblasts to regulate collagen metabolism without creating fibrotic tissue. Fibroblast function plays a crucial role in the pathophysiology of POP by directly affecting the connective tissue quality. On the other hand, fibroblasts determine the success of the POP treatment, as the fibroblast-to-(myo)fibroblast transition is the key event during wound healing and tissue repair. In this review, we aim to resolve the question of “cause and result” for the fibroblasts in the development and treatment of POP. This review may contribute to preventing the development and progress of anatomical abnormalities involved in POP and to optimizing surgical outcomes. Full article

(This article belongs to the Special Issue Biology of Fibroblasts and Myofibroblasts)

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12 pages, 2324 KiB

Open AccessEditor’s ChoiceArticle

Characterization and Modification of Light-Sensitive Phosphodiesterases from Choanoflagellates

by Yuehui Tian, Shang Yang, Georg Nagel and Shiqiang Gao

Biomolecules 2022, 12(1), 88; https://doi.org/10.3390/biom12010088 - 6 Jan 2022

Cited by 3 | Viewed by 3220

Abstract

Enzyme rhodopsins, including cyclase opsins (Cyclops) and rhodopsin phosphodiesterases (RhoPDEs), were recently discovered in fungi, algae and protists. In contrast to the well-developed light-gated guanylyl/adenylyl cyclases as optogenetic tools, ideal light-regulated phosphodiesterases are still in demand. Here, we investigated and engineered the RhoPDEs [...] Read more.

Enzyme rhodopsins, including cyclase opsins (Cyclops) and rhodopsin phosphodiesterases (RhoPDEs), were recently discovered in fungi, algae and protists. In contrast to the well-developed light-gated guanylyl/adenylyl cyclases as optogenetic tools, ideal light-regulated phosphodiesterases are still in demand. Here, we investigated and engineered the RhoPDEs from Salpingoeca rosetta, Choanoeca flexa and three other protists. All the RhoPDEs (fused with a cytosolic N-terminal YFP tag) can be expressed in Xenopus oocytes, except the AsRhoPDE that lacks the retinal-binding lysine residue in the last (8th) transmembrane helix. An N296K mutation of YFP::AsRhoPDE enabled its expression in oocytes, but this mutant still has no cGMP hydrolysis activity. Among the RhoPDEs tested, SrRhoPDE, CfRhoPDE1, 4 and MrRhoPDE exhibited light-enhanced cGMP hydrolysis activity. Engineering SrRhoPDE, we obtained two single point mutants, L623F and E657Q, in the C-terminal catalytic domain, which showed ~40 times decreased cGMP hydrolysis activity without affecting the light activation ratio. The molecular characterization and modification will aid in developing ideal light-regulated phosphodiesterase tools in the future. Full article

(This article belongs to the Special Issue State-of-Art in Protein Engineering)

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17 pages, 2500 KiB

Open AccessEditor’s ChoiceReview

Breast Cancer Treatment: The Case of Gold(I)-Based Compounds as a Promising Class of Bioactive Molecules

by Rossana Galassi, Lorenzo Luciani, Junbiao Wang, Silvia Vincenzetti, Lishan Cui, Augusto Amici, Stefania Pucciarelli and Cristina Marchini

Biomolecules 2022, 12(1), 80; https://doi.org/10.3390/biom12010080 - 5 Jan 2022

Cited by 10 | Viewed by 2630

Abstract

Breast cancers (BCs) may present dramatic diagnoses, both for ineffective therapies and for the limited outcomes in terms of lifespan. For these types of tumors, the search for new drugs is a primary necessity. It is widely recognized that gold compounds are highly [...] Read more.

Breast cancers (BCs) may present dramatic diagnoses, both for ineffective therapies and for the limited outcomes in terms of lifespan. For these types of tumors, the search for new drugs is a primary necessity. It is widely recognized that gold compounds are highly active and extremely potent as anticancer agents against many cancer cell lines. The presence of the metal plays an essential role in the activation of the cytotoxicity of these coordination compounds, whose activity, if restricted to the ligands alone, would be non-existent. On the other hand, gold exhibits a complex biochemistry, substantially variable depending on the chemical environments around the central metal. In this review, the scientific findings of the last 6–7 years on two classes of gold(I) compounds, containing phosphane or carbene ligands, are reviewed. In addition to this class of Au(I) compounds, the recent developments in the application of Auranofin in regards to BCs are reported. Auranofin is a triethylphosphine-thiosugar compound that, being a drug approved by the FDA—therefore extensively studied—is an interesting lead gold compound and a good comparison to understand the activities of structurally related Au(I) compounds. Full article

(This article belongs to the Special Issue Bioactive Molecules: Structures, Functions, and Potential Uses for Cancer Prevention and Targeted Therapies)

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9 pages, 249 KiB

Open AccessEditor’s ChoiceArticle

Association between Soluble α-Klotho Protein and Metabolic Syndrome in the Adult Population

by Yung-Wen Cheng, Chun-Chi Hung, Wen-Hui Fang and Wei-Liang Chen

Biomolecules 2022, 12(1), 70; https://doi.org/10.3390/biom12010070 - 4 Jan 2022

Cited by 14 | Viewed by 2777

Abstract

Klotho protein is an anti-aging protein and plays multiple roles in ion-regulation, anti-oxidative stress, and energy metabolism through various pathways. Metabolic syndrome is a combination of multiple conditions that compose of multiple risk factors of cardiovascular disease and type 2 diabetes. Gene regulation [...] Read more.

Klotho protein is an anti-aging protein and plays multiple roles in ion-regulation, anti-oxidative stress, and energy metabolism through various pathways. Metabolic syndrome is a combination of multiple conditions that compose of multiple risk factors of cardiovascular disease and type 2 diabetes. Gene regulation and protein expression are discovered associated with metabolic syndrome. We aimed to figure out the correlation between Klotho protein and metabolic syndrome in generally healthy adults. A cross-sectional study of 9976 respondents ≥ 18 years old from the US National Health and Nutrition Examination Survey (2007–2012) by utilizing their soluble Klotho protein concentrations. Multivariate linear regression models were used to analyze the effect of soluble Klotho protein on the prevalence of metabolic syndrome. Soluble Klotho protein concentration was inversely correlated with the presence of metabolic syndromes (p = 0.013) and numbers of components that met the definition of metabolic syndrome (p < 0.05). The concentration of Soluble Klotho protein was negatively associated with abdominal obesity and high triglyceride (TG) in the adjusted model (p < 0.05). Soluble Klotho protein is correlated with changing metabolic syndrome components in adults, especially central obesity and high TG levels. Despite conventional function as co-factor with fibroblast growth factor-23 (FGF23) that regulates phosphate and vitamin D homeostasis, FGF23-independent soluble Klotho protein may act on multiple signal pathways in different organs and tissue in roles of anti-aging and protection from metabolic syndrome. Full article

10 pages, 2527 KiB

Open AccessEditor’s ChoiceArticle

Acetyltransferases GCN5 and PCAF Are Required for B Lymphocyte Maturation in Mice

by Valentyn Oksenych, Dan Su and Jeremy A. Daniel

Biomolecules 2022, 12(1), 61; https://doi.org/10.3390/biom12010061 - 31 Dec 2021

Cited by 4 | Viewed by 2773

Abstract

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region, and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for the successful maturation of [...] Read more.

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region, and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for the successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. CSR occurs outside of the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an open chromatin state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated a mouse model that lacked both GCN5 and PCAF in B cells. Double-deficient mice possessed low levels of mature B cells in the bone marrow and peripheral organs, an accumulation of pro-B cells in bone marrow, and reduced CSR levels. We concluded that both GCN5 and PCAF are required for B-cell development in vivo. Full article

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

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21 pages, 3531 KiB

Open AccessEditor’s ChoiceReview

Site-Specific Proteasome Inhibitors

by Alexei F. Kisselev

Biomolecules 2022, 12(1), 54; https://doi.org/10.3390/biom12010054 - 31 Dec 2021

Cited by 29 | Viewed by 3815

Abstract

Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, [...] Read more.

Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib are approved by the FDA for the treatment of multiple myeloma; another inhibitor, marizomib, is undergoing clinical trials. The proteolytic core of the proteasome has three pairs of active sites, β5, β2, and β1. All clinical inhibitors and inhibitors that are widely used as research tools (e.g., epoxomicin, MG-132) inhibit multiple active sites and have been extensively reviewed in the past. In the past decade, highly specific inhibitors of individual active sites and the distinct active sites of the lymphoid tissue-specific immunoproteasome have been developed. Here, we provide a comprehensive review of these site-specific inhibitors of mammalian proteasomes and describe their utilization in the studies of the biology of the active sites and their roles as drug targets for the treatment of different diseases. Full article

(This article belongs to the Special Issue Regulating Proteasome Activity)

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26 pages, 5586 KiB

Open AccessEditor’s ChoiceArticle

The Functional Differences between the GroEL Chaperonin of Escherichia coli and the HtpB Chaperonin of Legionella pneumophila Can Be Mapped to Specific Amino Acid Residues

by Karla N. Valenzuela-Valderas, Gabriel Moreno-Hagelsieb, John R. Rohde and Rafael A. Garduño

Biomolecules 2022, 12(1), 59; https://doi.org/10.3390/biom12010059 - 31 Dec 2021

Cited by 3 | Viewed by 2059

Abstract

Group I chaperonins are a highly conserved family of essential proteins that self-assemble into molecular nanoboxes that mediate the folding of cytoplasmic proteins in bacteria and organelles. GroEL, the chaperonin of Escherichia coli, is the archetype of the family. Protein folding-independent functions [...] Read more.

Group I chaperonins are a highly conserved family of essential proteins that self-assemble into molecular nanoboxes that mediate the folding of cytoplasmic proteins in bacteria and organelles. GroEL, the chaperonin of Escherichia coli, is the archetype of the family. Protein folding-independent functions have been described for numerous chaperonins, including HtpB, the chaperonin of the bacterial pathogen Legionella pneumophila. Several protein folding-independent functions attributed to HtpB are not shared by GroEL, suggesting that differences in the amino acid (aa) sequence between these two proteins could correlate with functional differences. GroEL and HtpB differ in 137 scattered aa positions. Using the Evolutionary Trace (ET) bioinformatics method, site-directed mutagenesis, and a functional reporter test based upon a yeast-two-hybrid interaction with the eukaryotic protein ECM29, it was determined that out of those 137 aa, ten (M68, M212, S236, K298, N507 and the cluster AEHKD in positions 471-475) were involved in the interaction of HtpB with ECM29. GroEL was completely unable to interact with ECM29, but when GroEL was modified at those 10 aa positions, to display the HtpB aa, it acquired a weak ability to interact with ECM29. This constitutes proof of concept that the unique functional abilities of HtpB can be mapped to specific aa positions. Full article

(This article belongs to the Special Issue Biomolecules of Legionella – Tiny Parts Building the Virulence Machinery)

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17 pages, 1305 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Adipose Triglyceride Lipase in Hepatic Physiology and Pathophysiology

by Tianjiao Li, Wei Guo and Zhanxiang Zhou

Biomolecules 2022, 12(1), 57; https://doi.org/10.3390/biom12010057 - 31 Dec 2021

Cited by 19 | Viewed by 4232

Abstract

The liver is extremely active in oxidizing triglycerides (TG) for energy production. An imbalance between TG synthesis and hydrolysis leads to metabolic disorders in the liver, including excessive lipid accumulation, oxidative stress, and ultimately liver damage. Adipose triglyceride lipase (ATGL) is the rate-limiting [...] Read more.

The liver is extremely active in oxidizing triglycerides (TG) for energy production. An imbalance between TG synthesis and hydrolysis leads to metabolic disorders in the liver, including excessive lipid accumulation, oxidative stress, and ultimately liver damage. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme that catalyzes the first step of TG breakdown to glycerol and fatty acids. Although its role in controlling lipid homeostasis has been relatively well-studied in the adipose tissue, heart, and skeletal muscle, it remains largely unknown how and to what extent ATGL is regulated in the liver, responds to stimuli and regulators, and mediates disease progression. Therefore, in this review, we describe the current understanding of the structure–function relationship of ATGL, the molecular mechanisms of ATGL regulation at translational and post-translational levels, and—most importantly—its role in lipid and glucose homeostasis in health and disease with a focus on the liver. Advances in understanding the molecular mechanisms underlying hepatic lipid accumulation are crucial to the development of targeted therapies for treating hepatic metabolic disorders. Full article

(This article belongs to the Special Issue Lipid and Glucose Metabolism in Liver Diseases)

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14 pages, 2437 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway

by Chen-Chi Liu, Hsin-Hsien Li, Jiun-Han Lin, Ming-Chen Chiang, Tien-Wei Hsu, Anna Fen-Yau Li, David Hung-Tsang Yen, Han-Shui Hsu and Shih-Chieh Hung

Biomolecules 2022, 12(1), 48; https://doi.org/10.3390/biom12010048 - 29 Dec 2021

Cited by 16 | Viewed by 3259

Abstract

Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we [...] Read more.

Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma. Full article

(This article belongs to the Special Issue Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem Cells)

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23 pages, 4457 KiB

Open AccessEditor’s ChoiceArticle

Secondary Metabolites Coordinately Protect Grapes from Excessive Light and Sunburn Damage during Development

by Joanna M. Gambetta, Valentina Romat, Leigh M. Schmidtke and Bruno P. Holzapfel

Biomolecules 2022, 12(1), 42; https://doi.org/10.3390/biom12010042 - 28 Dec 2021

Cited by 9 | Viewed by 2646

Abstract

Sunburn is a physiological disorder that reduces grape quality and vineyard yield. It is the result of excessive sunlight and high temperatures. As climate change continues to increase air temperatures, reports of sunburn damage in vineyards worldwide are becoming more frequent. Grapes produce [...] Read more.

Sunburn is a physiological disorder that reduces grape quality and vineyard yield. It is the result of excessive sunlight and high temperatures. As climate change continues to increase air temperatures, reports of sunburn damage in vineyards worldwide are becoming more frequent. Grapes produce secondary metabolites (carotenoids, polyphenols and aroma compounds) to counter photooxidative stress and acclimate to higher radiation environments. This study evaluated changes in these compounds in during ripening when grapes were exposed post-flowering (ED) and at véraison (LD), and compared them to a nondefoliated control (ND). ND contained more α-terpineol and violaxanthin, and the defoliated treatments contained more zeaxanthin, β-carotene, C₆ compounds and flavonoids. ED berries adapted better to higher-light environments, displayed larger changes in secondary metabolite concentrations and lower levels of sunburn damage than LD berries did. The composition of berries with increasing sunburn damage was evaluated for the first time. Berries with no damage had the lowest concentrations of flavonoids and oxidized glutathione, and the highest concentrations of chlorophyll and α-terpineol. As damage increased, destruction of photosynthetic pigments, increase in polyphenols and loss of aroma compounds were evidenced. A significant effect of temperature and developmental stage on grape composition was also observed. This study provides a holistic overview of changes in secondary metabolites experienced by grape berries when exposed to excessive light, how these vary along development and how they affect sunburn incidence. Full article

(This article belongs to the Special Issue Climate Change and Grape and Wine Biomolecules: Effect and Solutions)

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12 pages, 2806 KiB

Open AccessEditor’s ChoiceArticle

A Rapid Method for Postmortem Vitreous Chemistry—Deadside Analysis

by Brita Zilg, Kanar Alkass, Robert Kronstrand, Sören Berg and Henrik Druid

Biomolecules 2022, 12(1), 32; https://doi.org/10.3390/biom12010032 - 27 Dec 2021

Cited by 5 | Viewed by 3079

Abstract

Vitreous fluid is commonly collected for toxicological analysis during forensic postmortem investigations. Vitreous fluid is also often analyzed for potassium, sodium, chloride and glucose for estimation of time since death, and for the evaluation of electrolyte imbalances and hyperglycemia, respectively. Obtaining such results [...] Read more.

Vitreous fluid is commonly collected for toxicological analysis during forensic postmortem investigations. Vitreous fluid is also often analyzed for potassium, sodium, chloride and glucose for estimation of time since death, and for the evaluation of electrolyte imbalances and hyperglycemia, respectively. Obtaining such results in the early phase of a death investigation is desirable both in regard to assisting the police and in the decision-making prior to the autopsy. We analyzed vitreous fluid with blood gas instruments to evaluate/examine the possible impact of different sampling and pre-analytical treatment. We found that samples from the right and left eye, the center of the eye as well as whole vitreous samples gave similar results. We also found imprecision to be very low and that centrifugation and dilution were not necessary when analyzing vitreous samples with blood gas instruments. Similar results were obtained when analyzing the same samples with a regular multi-analysis instrument, but we found that such instruments could require dilution of samples with high viscosity, and that such dilution might impact measurement accuracy. In conclusion, using a blood gas instrument, the analysis of postmortem vitreous fluid for electrolytes and glucose without sample pretreatment produces rapid and reliable results. Full article

(This article belongs to the Special Issue Postmortem Biochemistry-When Death Matters)

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12 pages, 588 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Automatic Activity Arising in Cardiac Muscle Sleeves of the Pulmonary Vein

by Pierre Bredeloux, Come Pasqualin, Romain Bordy, Veronique Maupoil and Ian Findlay

Biomolecules 2022, 12(1), 23; https://doi.org/10.3390/biom12010023 - 24 Dec 2021

Cited by 7 | Viewed by 2833

Abstract

Ectopic activity in the pulmonary vein cardiac muscle sleeves can both induce and maintain human atrial fibrillation. A central issue in any study of the pulmonary veins is their difference from the left atrial cardiac muscle. Here, we attempt to summarize the physiological [...] Read more.

Ectopic activity in the pulmonary vein cardiac muscle sleeves can both induce and maintain human atrial fibrillation. A central issue in any study of the pulmonary veins is their difference from the left atrial cardiac muscle. Here, we attempt to summarize the physiological phenomena underlying the occurrence of ectopic electrical activity in animal pulmonary veins. We emphasize that the activation of multiple signaling pathways influencing not only myocyte electrophysiology but also the means of excitation–contraction coupling may be required for the initiation of triggered or automatic activity. We also gather information regarding not only the large-scale structure of cardiac muscle sleeves but also recent studies suggesting that cellular heterogeneity may contribute to the generation of arrythmogenic phenomena and to the distinction between pulmonary vein and left atrial heart muscle. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

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14 pages, 1909 KiB

Open AccessEditor’s ChoiceReview

Lipoprotein(a)—The Crossroads of Atherosclerosis, Atherothrombosis and Inflammation

by Sabina Ugovšek and Miran Šebeštjen

Biomolecules 2022, 12(1), 26; https://doi.org/10.3390/biom12010026 - 24 Dec 2021

Cited by 37 | Viewed by 5561

Abstract

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations [...] Read more.

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of chromosome 6, within region 6q2.6–2.7. Lp(a) levels increase cardiovascular risk through several unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipoprotein cholesterol, although it is even more prone to oxidation and penetration through endothelia to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the homology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70% homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms of Lp(a) is predominant in different groups of patients. Full article

(This article belongs to the Special Issue Emerging Circulating Biomarkers in Atherosclerosis: From Molecular Mechanisms to Therapeutic Strategies)

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Do Epstein–Barr Virus Mutations and Natural Genome Sequence Variations Contribute to Disease?

by Paul J. Farrell and Robert E. White

Biomolecules 2022, 12(1), 17; https://doi.org/10.3390/biom12010017 - 23 Dec 2021

Cited by 18 | Viewed by 4369

Abstract

Most of the world’s population is infected by the Epstein–Barr virus (EBV), but the incidence of the diseases associated with EBV infection differs greatly in different parts of the world. Many factors may determine those differences, but variation in the virus genome is [...] Read more.

Most of the world’s population is infected by the Epstein–Barr virus (EBV), but the incidence of the diseases associated with EBV infection differs greatly in different parts of the world. Many factors may determine those differences, but variation in the virus genome is likely to be a contributing factor for some of the diseases. Here, we describe the main forms of EBV genome sequence variation, and the mechanisms by which variations in the virus genome are likely to contribute to disease. EBV genome deletions or polymorphisms can also provide useful markers for monitoring disease. If some EBV strains prove to be more pathogenic than others, this suggests the possible value of immunising people against infection by those pathogenic strains. Full article

(This article belongs to the Special Issue Immunity and Pathogenesis of Epstein-Barr Virus Infection)

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