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Editor’s Choice Articles

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

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Review

15 pages, 1350 KiB  
Review
Metallothionein and Cadmium Toxicology—Historical Review and Commentary
by Monica Nordberg and Gunnar F. Nordberg
Biomolecules 2022, 12(3), 360; https://doi.org/10.3390/biom12030360 - 24 Feb 2022
Cited by 70 | Viewed by 5795
Abstract
More than one and a half centuries ago, adverse human health effects were reported after use of a cadmium-containing silver polishing agent. Long-term cadmium exposure gives rise to kidney or bone disease, reproductive toxicity and cancer in animals and humans. At present, high [...] Read more.
More than one and a half centuries ago, adverse human health effects were reported after use of a cadmium-containing silver polishing agent. Long-term cadmium exposure gives rise to kidney or bone disease, reproductive toxicity and cancer in animals and humans. At present, high human exposures to cadmium occur in small-scale mining, underlining the need for preventive measures. This is particularly urgent in view of the growing demand for minerals and metals in global climate change mitigation. This review deals with a specific part of cadmium toxicology that is important for understanding when toxic effects appear and, thus, is crucial for risk assessment. The discovery of the low-molecular-weight protein metallothionein (MT) in 1957 was an important milestone because, when this protein binds cadmium, it modifies cellular cadmium toxicity. The present authors contributed evidence in the 1970s concerning cadmium binding to MT and synthesis of the protein in tissues. We showed that binding of cadmium to metallothionein in tissues prevented some toxic effects, but that metallothionein can increase the transport of cadmium to the kidneys. Special studies showed the importance of the Cd/Zn ratio in MT for expression of toxicity in the kidneys. We also developed models of cadmium toxicokinetics based on our MT-related findings. This model combined with estimates of tissue levels giving rise to toxicity, made it possible to calculate expected risks in relation to exposure. Other scientists developed these models further and international organizations have successfully used these amended models in recent publications. Our contributions in recent decades included studies in humans of MT-related biomarkers showing the importance of MT gene expression in lymphocytes and MT autoantibodies for risks of Cd-related adverse effects in cadmium-exposed population groups. In a study of the impact of zinc status on the risk of kidney dysfunction in a cadmium-exposed group, the risks were low when zinc status was good and high when zinc status was poor. The present review summarizes this evidence in a risk assessment context and calls for its application in order to improve preventive measures against adverse effects of cadmium exposures in humans and animals. Full article
(This article belongs to the Special Issue Toxic and Essential Metals in Human Health and Disease 2021)
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12 pages, 901 KiB  
Review
Glucose- and Non-Glucose-Induced Mitochondrial Dysfunction in Diabetic Kidney Disease
by Marie Ito, Margaret Zvido Gurumani, Sandra Merscher and Alessia Fornoni
Biomolecules 2022, 12(3), 351; https://doi.org/10.3390/biom12030351 - 23 Feb 2022
Cited by 15 | Viewed by 3360
Abstract
Mitochondrial dysfunction plays an important role in the pathogenesis and progression of diabetic kidney disease (DKD). In this review, we will discuss mitochondrial dysfunction observed in preclinical models of DKD as well as in clinical DKD with a focus on oxidative phosphorylation (OXPHOS), [...] Read more.
Mitochondrial dysfunction plays an important role in the pathogenesis and progression of diabetic kidney disease (DKD). In this review, we will discuss mitochondrial dysfunction observed in preclinical models of DKD as well as in clinical DKD with a focus on oxidative phosphorylation (OXPHOS), mitochondrial reactive oxygen species (mtROS), biogenesis, fission and fusion, mitophagy and urinary mitochondrial biomarkers. Both glucose- and non-glucose-induced mitochondrial dysfunction will be discussed. In terms of glucose-induced mitochondrial dysfunction, the energetic shift from OXPHOS to aerobic glycolysis, called the Warburg effect, occurs and the resulting toxic intermediates of glucose metabolism contribute to DKD-induced injury. In terms of non-glucose-induced mitochondrial dysfunction, we will review the roles of lipotoxicity, hypoxia and vasoactive pathways, including endothelin-1 (Edn1)/Edn1 receptor type A signaling pathways. Although the relative contribution of each of these pathways to DKD remains unclear, the goal of this review is to highlight the complexity of mitochondrial dysfunction in DKD and to discuss how markers of mitochondrial dysfunction could help us stratify patients at risk for DKD. Full article
(This article belongs to the Special Issue Redox Imbalance and Mitochondrial Abnormalities in Kidney Disease)
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24 pages, 2687 KiB  
Review
Nutrient Regulation of Pancreatic Islet β-Cell Secretory Capacity and Insulin Production
by Kristen E. Rohli, Cierra K. Boyer, Sandra E. Blom and Samuel B. Stephens
Biomolecules 2022, 12(2), 335; https://doi.org/10.3390/biom12020335 - 20 Feb 2022
Cited by 16 | Viewed by 5037
Abstract
Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). [...] Read more.
Pancreatic islet β-cells exhibit tremendous plasticity for secretory adaptations that coordinate insulin production and release with nutritional demands. This essential feature of the β-cell can allow for compensatory changes that increase secretory output to overcome insulin resistance early in Type 2 diabetes (T2D). Nutrient-stimulated increases in proinsulin biosynthesis may initiate this β-cell adaptive compensation; however, the molecular regulators of secretory expansion that accommodate the increased biosynthetic burden of packaging and producing additional insulin granules, such as enhanced ER and Golgi functions, remain poorly defined. As these adaptive mechanisms fail and T2D progresses, the β-cell succumbs to metabolic defects resulting in alterations to glucose metabolism and a decline in nutrient-regulated secretory functions, including impaired proinsulin processing and a deficit in mature insulin-containing secretory granules. In this review, we will discuss how the adaptative plasticity of the pancreatic islet β-cell’s secretory program allows insulin production to be carefully matched with nutrient availability and peripheral cues for insulin signaling. Furthermore, we will highlight potential defects in the secretory pathway that limit or delay insulin granule biosynthesis, which may contribute to the decline in β-cell function during the pathogenesis of T2D. Full article
(This article belongs to the Special Issue The Pancreatic Beta Cell)
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16 pages, 1162 KiB  
Review
Targeting the Endocannabinoidome in Pancreatic Cancer
by Valerio Falasca and Marco Falasca
Biomolecules 2022, 12(2), 320; https://doi.org/10.3390/biom12020320 - 17 Feb 2022
Cited by 6 | Viewed by 4121
Abstract
Pancreatic Ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is an aggressive and lethal form of cancer with a very high mortality rate. High heterogeneity, asymptomatic initial stages and a lack of specific diagnostic markers result in an end-stage diagnosis when [...] Read more.
Pancreatic Ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, is an aggressive and lethal form of cancer with a very high mortality rate. High heterogeneity, asymptomatic initial stages and a lack of specific diagnostic markers result in an end-stage diagnosis when the tumour has locally advanced or metastasised. PDAC is resistant to most of the available chemotherapy and radiation therapy treatments, making surgery the most potent curative treatment. The desmoplastic tumour microenvironment contributes to determining PDAC pathophysiology, immune response and therapeutic efficacy. The existing therapeutic approaches such as FDA-approved chemotherapeutics, gemcitabine, abraxane and folfirinox, prolong survival marginally and are accompanied by adverse effects. Several studies suggest the role of cannabinoids as anti-cancer agents. Cannabinoid receptors are known to be expressed in pancreatic cells, with a higher expression reported in pancreatic cancer patients. Therefore, pharmacological targeting of the endocannabinoid system might offer therapeutic benefits in pancreatic cancer. In addition, emerging data suggest that cannabinoids in combination with chemotherapy can increase survival in transgenic pancreatic cancer murine models. This review provides an overview of the regulation of the expanded endocannabinoid system, or endocannabinoidome, in PDAC and will explore the potential of targeting this system for novel anticancer approaches. Full article
(This article belongs to the Collection Recent Advances in Pancreatic Cancer)
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19 pages, 7615 KiB  
Review
Cytoplasmic and Nuclear Functions of cIAP1
by Aymeric Zadoroznyj and Laurence Dubrez
Biomolecules 2022, 12(2), 322; https://doi.org/10.3390/biom12020322 - 17 Feb 2022
Cited by 9 | Viewed by 3363
Abstract
Cellular inhibitor of apoptosis 1 (cIAP1) is a cell signaling regulator of the IAP family. Through its E3-ubiquitine ligase activity, it has the ability to activate intracellular signaling pathways, modify signal transduction pathways by changing protein-protein interaction networks, and stop signal transduction by [...] Read more.
Cellular inhibitor of apoptosis 1 (cIAP1) is a cell signaling regulator of the IAP family. Through its E3-ubiquitine ligase activity, it has the ability to activate intracellular signaling pathways, modify signal transduction pathways by changing protein-protein interaction networks, and stop signal transduction by promoting the degradation of critical components of signaling pathways. Thus, cIAP1 appears to be a potent determinant of the response of cells, enabling their rapid adaptation to changing environmental conditions or intra- or extracellular stresses. It is expressed in almost all tissues, found in the cytoplasm, membrane and/or nucleus of cells. cIAP1 regulates innate immunity by controlling signaling pathways mediated by tumor necrosis factor receptor superfamily (TNFRs), some cytokine receptors and pattern recognition-receptors (PRRs). Although less documented, cIAP1 has also been involved in the regulation of cell migration and in the control of transcriptional programs. Full article
(This article belongs to the Special Issue State-of-the-Art Cell Death in France 2020-2021)
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42 pages, 1981 KiB  
Review
Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer
by Sarah Koushyar, Valerie S. Meniel, Toby J. Phesse and Helen B. Pearson
Biomolecules 2022, 12(2), 309; https://doi.org/10.3390/biom12020309 - 15 Feb 2022
Cited by 18 | Viewed by 5654
Abstract
Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence [...] Read more.
Aberrant activation of the Wnt pathway is emerging as a frequent event during prostate cancer that can facilitate tumor formation, progression, and therapeutic resistance. Recent discoveries indicate that targeting the Wnt pathway to treat prostate cancer may be efficacious. However, the functional consequence of activating the Wnt pathway during the different stages of prostate cancer progression remains unclear. Preclinical work investigating the efficacy of targeting Wnt signaling for the treatment of prostate cancer, both in primary and metastatic lesions, and improving our molecular understanding of treatment responses is crucial to identifying effective treatment strategies and biomarkers that help guide treatment decisions and improve patient care. In this review, we outline the type of genetic alterations that lead to activated Wnt signaling in prostate cancer, highlight the range of laboratory models used to study the role of Wnt genetic drivers in prostate cancer, and discuss new mechanistic insights into how the Wnt cascade facilitates prostate cancer growth, metastasis, and drug resistance. Full article
(This article belongs to the Special Issue Prostate Cancer: From Models to Molecular Mechanisms and Precision Medicine)
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19 pages, 1166 KiB  
Review
An Introduction to Bacterial Biofilms and Their Proteases, and Their Roles in Host Infection and Immune Evasion
by Juan Sebastián Ramírez-Larrota and Ulrich Eckhard
Biomolecules 2022, 12(2), 306; https://doi.org/10.3390/biom12020306 - 14 Feb 2022
Cited by 24 | Viewed by 5156
Abstract
Bacterial biofilms represent multicellular communities embedded in a matrix of extracellular polymeric substances, conveying increased resistance against environmental stress factors but also antibiotics. They are shaped by secreted enzymes such as proteases, which can aid pathogenicity by degrading host proteins of the connective [...] Read more.
Bacterial biofilms represent multicellular communities embedded in a matrix of extracellular polymeric substances, conveying increased resistance against environmental stress factors but also antibiotics. They are shaped by secreted enzymes such as proteases, which can aid pathogenicity by degrading host proteins of the connective tissue or the immune system. Importantly, both secreted proteases and the capability of biofilm formation are considered key virulence factors. In this review, we focus on the basic aspects of proteolysis and protein secretion, and highlight various secreted bacterial proteases involved in biofilm establishment and dispersal, and how they aid bacteria in immune evasion by degrading immunoglobulins and components of the complement system. Thus, secreted proteases represent not only prominent antimicrobial targets but also enzymes that can be used for dedicated applications in biotechnology and biomedicine, including their use as laundry detergents, in mass spectrometry for the glycoprofiling of antibodies, and the desensitization of donor organs intended for positive crossmatch patients. Full article
(This article belongs to the Special Issue New Insights into Proteases and Chaperones in Pathogenic Microorganisms)
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22 pages, 2330 KiB  
Review
Impact of Non-Coding RNAs on Chemotherapeutic Resistance in Oral Cancer
by Karen Yamaguchi, Tomofumi Yamamoto, Junichiro Chikuda, Tatsuo Shirota and Yusuke Yamamoto
Biomolecules 2022, 12(2), 284; https://doi.org/10.3390/biom12020284 - 9 Feb 2022
Cited by 9 | Viewed by 3215
Abstract
Drug resistance in oral cancer is one of the major problems in oral cancer therapy because therapeutic failure directly results in tumor recurrence and eventually in metastasis. Accumulating evidence has demonstrated the involvement of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long [...] Read more.
Drug resistance in oral cancer is one of the major problems in oral cancer therapy because therapeutic failure directly results in tumor recurrence and eventually in metastasis. Accumulating evidence has demonstrated the involvement of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), in processes related to the development of drug resistance. A number of studies have shown that ncRNAs modulate gene expression at the transcriptional or translational level and regulate biological processes, such as epithelial-to-mesenchymal transition, apoptosis, DNA repair and drug efflux, which are tightly associated with drug resistance acquisition in many types of cancer. Interestingly, these ncRNAs are commonly detected in extracellular vesicles (EVs) and are known to be delivered into surrounding cells. This intercellular communication via EVs is currently considered to be important for acquired drug resistance. Here, we review the recent advances in the study of drug resistance in oral cancer by mainly focusing on the function of ncRNAs, since an increasing number of studies have suggested that ncRNAs could be therapeutic targets as well as biomarkers for cancer diagnosis. Full article
(This article belongs to the Special Issue Non-coding RNAs in Cancer Biology)
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26 pages, 6801 KiB  
Review
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 4828
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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14 pages, 968 KiB  
Review
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 26 | Viewed by 5126
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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23 pages, 3578 KiB  
Review
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 24 | Viewed by 7534
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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18 pages, 2129 KiB  
Review
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 3232
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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14 pages, 1286 KiB  
Review
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 55 | Viewed by 14571
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  
Review
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 4523
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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27 pages, 764 KiB  
Review
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 27 | Viewed by 5587
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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24 pages, 1808 KiB  
Review
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 4987
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  
Review
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 32 | Viewed by 3739
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  
Review
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 20 | Viewed by 6425
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  
Review
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 10 | Viewed by 4311
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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16 pages, 959 KiB  
Review
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 22 | Viewed by 3667
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  
Review
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 17 | Viewed by 3012
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  
Review
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 4154
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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10 pages, 1938 KiB  
Review
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 17 | Viewed by 5145
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  
Review
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 32 | Viewed by 14881
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  
Review
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 15 | Viewed by 3300
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 CuB and CuA 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 CuB and CuA 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 CuA 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 CuA 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  
Review
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 3140
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 CaV1.1 (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 CaV1.1 (in skeletal muscle) and CaV1.2 (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, CaV 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  
Review
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 9 | Viewed by 3927
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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15 pages, 1521 KiB  
Review
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 5353
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  
Review
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 34 | Viewed by 3301
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  
Review
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 3079
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  
Review
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 30 | Viewed by 7689
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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17 pages, 2500 KiB  
Review
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 2736
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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21 pages, 3531 KiB  
Review
Site-Specific Proteasome Inhibitors
by Alexei F. Kisselev
Biomolecules 2022, 12(1), 54; https://doi.org/10.3390/biom12010054 - 31 Dec 2021
Cited by 30 | Viewed by 4023
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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17 pages, 1305 KiB  
Review
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 20 | Viewed by 4439
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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12 pages, 588 KiB  
Review
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 2978
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  
Review
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 41 | Viewed by 5784
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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15 pages, 784 KiB  
Review
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 19 | Viewed by 4510
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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14 pages, 1097 KiB  
Review
Diagnostic and Therapeutic Values of Angiogenic Factors in Endometrial Cancer
by Luka Roškar, Irena Roškar, Tea Lanišnik Rižner and Špela Smrkolj
Biomolecules 2022, 12(1), 7; https://doi.org/10.3390/biom12010007 - 21 Dec 2021
Cited by 12 | Viewed by 4225
Abstract
Endometrial cancer (EC) is the most frequent gynecological malignancy in developed countries and requires a relatively invasive diagnostic evaluation and operative therapy as the primary therapeutic approach. Angiogenesis is one of the main processes needed for cancer growth and spread. The production of [...] Read more.
Endometrial cancer (EC) is the most frequent gynecological malignancy in developed countries and requires a relatively invasive diagnostic evaluation and operative therapy as the primary therapeutic approach. Angiogenesis is one of the main processes needed for cancer growth and spread. The production of angiogenic factors (AFs) appears early in the process of carcinogenesis. The detection of AFs in plasma and tissue and a better understanding of the angiogenic properties of EC may contribute not only to earlier but also more specific diagnosis and consequently tailored and individual therapeutic approaches. AFs and their receptors also have high potential as binding sites for targeted cancer therapy. In this review, we discuss angiogenesis in EC and the characteristics of the AFs that most contribute to angiogenesis in EC. We also highlight therapeutic strategies that target angiogenesis as potential EC therapy. Full article
(This article belongs to the Special Issue Risk Prediction Tools and Biomarkers in Gynaecological Cancer)
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19 pages, 1064 KiB  
Review
The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies
by Hans Felix Staehle, Heike Luise Pahl and Jonas Samuel Jutzi
Biomolecules 2021, 11(12), 1911; https://doi.org/10.3390/biom11121911 - 20 Dec 2021
Cited by 4 | Viewed by 3455
Abstract
Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone [...] Read more.
Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting. Full article
(This article belongs to the Special Issue Jumonji Domain-Containing Proteins in Cancer Progression)
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18 pages, 14701 KiB  
Review
Insulin-Responsive Transcription Factors
by Gerald Thiel, Lisbeth A. Guethlein and Oliver G. Rössler
Biomolecules 2021, 11(12), 1886; https://doi.org/10.3390/biom11121886 - 15 Dec 2021
Cited by 14 | Viewed by 5180
Abstract
The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor [...] Read more.
The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor activates intracellular signaling cascades involving the enzymes extracellular signal-regulated protein kinase-1/2 (ERK1/2), phosphatidylinositol 3-kinase, protein kinase B/Akt, and phospholipase Cγ as signal transducers. Insulin receptor stimulation is correlated with multiple physiological and biochemical functions, including glucose transport, glucose homeostasis, food intake, proliferation, glycolysis, and lipogenesis. This review article focuses on the activation of gene transcription as a result of insulin receptor stimulation. Signal transducers such as protein kinases or the GLUT4-induced influx of glucose connect insulin receptor stimulation with transcription. We discuss insulin-responsive transcription factors that respond to insulin receptor activation and generate a transcriptional network executing the metabolic functions of insulin. Importantly, insulin receptor stimulation induces transcription of genes encoding essential enzymes of glycolysis and lipogenesis and inhibits genes encoding essential enzymes of gluconeogenesis. Overall, the activation or inhibition of insulin-responsive transcription factors is an essential aspect of orchestrating a wide range of insulin-induced changes in the biochemistry and physiology of insulin-responsive tissues. Full article
(This article belongs to the Special Issue Obesity, Diabetes, and Cancer: The Role of the Insulin/IGF Axis; Mechanisms and Clinical Implications)
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14 pages, 1176 KiB  
Review
Physiological and Pathophysiological Roles of Mitochondrial Na+-Ca2+ Exchanger, NCLX, in Hearts
by Ayako Takeuchi and Satoshi Matsuoka
Biomolecules 2021, 11(12), 1876; https://doi.org/10.3390/biom11121876 - 14 Dec 2021
Cited by 13 | Viewed by 2980
Abstract
It has been over 10 years since SLC24A6/SLC8B1, coding the Na+/Ca2+/Li+ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na+-Ca2+ exchange, a major Ca2+ efflux system in cardiac mitochondria. This molecular [...] Read more.
It has been over 10 years since SLC24A6/SLC8B1, coding the Na+/Ca2+/Li+ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na+-Ca2+ exchange, a major Ca2+ efflux system in cardiac mitochondria. This molecular identification enabled us to determine structure–function relationships, as well as physiological/pathophysiological contributions, and our understandings have dramatically increased. In this review, we provide an overview of the recent achievements in relation to NCLX, focusing especially on its heart-specific characteristics, biophysical properties, and spatial distribution in cardiomyocytes, as well as in cardiac mitochondria. In addition, we discuss the roles of NCLX in cardiac functions under physiological and pathophysiological conditions—the generation of rhythmicity, the energy metabolism, the production of reactive oxygen species, and the opening of mitochondrial permeability transition pores. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)
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17 pages, 1386 KiB  
Review
Role of Epithelium-Derived Cytokines in Atopic Dermatitis and Psoriasis: Evidence and Therapeutic Perspectives
by Francesco Borgia, Paolo Custurone, Lucia Peterle, Giovanni Pioggia and Sebastiano Gangemi
Biomolecules 2021, 11(12), 1843; https://doi.org/10.3390/biom11121843 - 7 Dec 2021
Cited by 11 | Viewed by 3473
Abstract
Atopic dermatitis and psoriasis are two of the most common chronic skin conditions. Current target therapies represent viable and safe solutions for the most severe cases of these two dermatoses but, presently, several limitations exist in terms of efficacy and side effects. A [...] Read more.
Atopic dermatitis and psoriasis are two of the most common chronic skin conditions. Current target therapies represent viable and safe solutions for the most severe cases of these two dermatoses but, presently, several limitations exist in terms of efficacy and side effects. A new class of products, epithelium-derived cytokines (TSLP, IL-25, IL-33), show an increasing potential for use in target therapy for these patients, and demonstrate a direct link between a generalized inflammatory and oxidative stress status and the human skin. A review was conducted to better understand their role in the aforementioned conditions. Of these three molecules, TSLP led has been most often considered in studies regarding target therapies, and most of the results in the literature are related to this cytokine. These three cytokines share common stimuli and are linked to each other in both acute and chronic phases of these diseases, and have been challenged as target therapies or biomarkers of disease activity. The results lead to the conclusion that epithelium-derived cytokines could represent a therapeutic opportunity for these patients, especially in itch control. Furthermore, they might work better when paired together with currently available therapies or in combination with in-development treatments. Further studies are needed in order to verify the efficacy and safety of the biologic treatments currently under development. Full article
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23 pages, 1422 KiB  
Review
Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence
by Teresa Salvatore, Raffaele Galiero, Alfredo Caturano, Erica Vetrano, Luca Rinaldi, Francesca Coviello, Anna Di Martino, Gaetana Albanese, Raffaele Marfella, Celestino Sardu and Ferdinando Carlo Sasso
Biomolecules 2021, 11(12), 1834; https://doi.org/10.3390/biom11121834 - 4 Dec 2021
Cited by 53 | Viewed by 8870
Abstract
Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the [...] Read more.
Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved. Full article
(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)
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15 pages, 2992 KiB  
Review
Diet Impact on Obesity beyond Calories and Trefoil Factor Family 2 (TFF2) as an Illustration: Metabolic Implications and Potential Applications
by Abdelaziz Ghanemi, Mayumi Yoshioka and Jonny St-Amand
Biomolecules 2021, 11(12), 1830; https://doi.org/10.3390/biom11121830 - 4 Dec 2021
Cited by 5 | Viewed by 2874
Abstract
Obesity is a health problem with increasing impacts on public health, economy and even social life. In order to reestablish the energy balance, obesity management focuses mainly on two pillars; exercise and diet. Beyond the contribution to the caloric intake, the diet nutrients [...] Read more.
Obesity is a health problem with increasing impacts on public health, economy and even social life. In order to reestablish the energy balance, obesity management focuses mainly on two pillars; exercise and diet. Beyond the contribution to the caloric intake, the diet nutrients and composition govern a variety of properties. This includes the energy balance-independent properties and the indirect metabolic effects. Whereas the energy balance-independent properties are close to “pharmacological” effects and include effects such as antioxidant and anti-inflammatory, the indirect metabolic effects represent the contribution a diet can have on energy metabolism beyond the caloric contribution itself, which include the food intake control and metabolic changes. As an illustration, we also described the metabolic implication and hypothetical pathways of the high-fat diet-induced gene Trefoil Factor Family 2. The properties the diet has can have a variety of applications mainly in pharmacology and nutrition and further explore the “pharmacologically” active food towards potential therapeutic applications. Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Eating Disorders and Obesity)
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17 pages, 6521 KiB  
Review
Hyperbaric Oxygen Treatment: Effects on Mitochondrial Function and Oxidative Stress
by Nofar Schottlender, Irit Gottfried and Uri Ashery
Biomolecules 2021, 11(12), 1827; https://doi.org/10.3390/biom11121827 - 3 Dec 2021
Cited by 48 | Viewed by 7491
Abstract
Hyperbaric oxygen treatment (HBOT)—the administration of 100% oxygen at atmospheric pressure (ATA) greater than 1 ATA—increases the proportion of dissolved oxygen in the blood five- to twenty-fold. This increase in accessible oxygen places the mitochondrion—the organelle that consumes most of the oxygen that [...] Read more.
Hyperbaric oxygen treatment (HBOT)—the administration of 100% oxygen at atmospheric pressure (ATA) greater than 1 ATA—increases the proportion of dissolved oxygen in the blood five- to twenty-fold. This increase in accessible oxygen places the mitochondrion—the organelle that consumes most of the oxygen that we breathe—at the epicenter of HBOT’s effects. As the mitochondrion is also a major site for the production of reactive oxygen species (ROS), it is possible that HBOT will increase also oxidative stress. Depending on the conditions of the HBO treatment (duration, pressure, umber of treatments), short-term treatments have been shown to have deleterious effects on both mitochondrial activity and production of ROS. Long-term treatment, on the other hand, improves mitochondrial activity and leads to a decrease in ROS levels, partially due to the effects of HBOT, which increases antioxidant defense mechanisms. Many diseases and conditions are characterized by mitochondrial dysfunction and imbalance between ROS and antioxidant scavengers, suggesting potential therapeutic intervention for HBOT. In the present review, we will present current views on the effects of HBOT on mitochondrial function and oxidative stress, the interplay between them and the implications for several diseases. Full article
(This article belongs to the Special Issue Oxygen Therapy)
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16 pages, 1314 KiB  
Review
Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimers
by Roberto Maggio, Irene Fasciani, Marco Carli, Francesco Petragnano, Francesco Marampon, Mario Rossi and Marco Scarselli
Biomolecules 2021, 11(12), 1828; https://doi.org/10.3390/biom11121828 - 3 Dec 2021
Cited by 7 | Viewed by 2763
Abstract
Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex [...] Read more.
Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex orchestrated responses is a major challenge for modern cell biology. In complex organisms, cell to cell communication occurs mostly through neurotransmitters and hormones, and receptors are responsible for signal recognition at the membrane level and information transduction inside the cell. The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 genes coding for these proteins. The recognition that GPCRs may physically interact with each other has led to the hypothesis that their dimeric state can provide the framework for temporal coincidence in signaling pathways. Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing distinct cell compartments along the plasma membrane where confined increases in second messengers may be perceived and discriminated. Here, we summarize evidence that supports these conjectures, fostering new ideas about the physiological role played by receptor homo- and hetero-oligomerization in cell biology. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
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15 pages, 1000 KiB  
Review
Mollusc N-glycosylation: Structures, Functions and Perspectives
by Erika Staudacher
Biomolecules 2021, 11(12), 1820; https://doi.org/10.3390/biom11121820 - 3 Dec 2021
Cited by 11 | Viewed by 2460
Abstract
Molluscs display a sophisticated N-glycan pattern on their proteins, which is, in terms of involved structural features, even more diverse than that of vertebrates. This review summarises the current knowledge of mollusc N-glycan structures, with a focus on the functional aspects of the [...] Read more.
Molluscs display a sophisticated N-glycan pattern on their proteins, which is, in terms of involved structural features, even more diverse than that of vertebrates. This review summarises the current knowledge of mollusc N-glycan structures, with a focus on the functional aspects of the corresponding glycoproteins. Furthermore, the potential of mollusc-derived biomolecules for medical applications is addressed, emphasising the importance of mollusc research. Full article
(This article belongs to the Special Issue Glycosylation—The Most Diverse Post-Translational Modification)
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24 pages, 2494 KiB  
Review
Ubiquitin Ligase Redundancy and Nuclear-Cytoplasmic Localization in Yeast Protein Quality Control
by Carolyn Allain Breckel and Mark Hochstrasser
Biomolecules 2021, 11(12), 1821; https://doi.org/10.3390/biom11121821 - 3 Dec 2021
Cited by 19 | Viewed by 4469
Abstract
The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways [...] Read more.
The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways are responsible for the repair or destruction of these abnormal proteins. Most commonly, the ubiquitin-proteasome system (UPS) is employed to recognize and degrade those proteins that cannot be refolded by molecular chaperones. Misfolded substrates are ubiquitylated by a subset of ubiquitin ligases (also called E3s) that operate in different cellular compartments. Recent research in Saccharomyces cerevisiae has shown that the most prominent ligases mediating cytoplasmic and nuclear PQC have overlapping yet distinct substrate specificities. Many substrates have been characterized that can be targeted by more than one ubiquitin ligase depending on their localization, and cytoplasmic PQC substrates can be directed to the nucleus for ubiquitylation and degradation. Here, we review some of the major yeast PQC ubiquitin ligases operating in the nucleus and cytoplasm, as well as current evidence indicating how these ligases can often function redundantly toward substrates in these compartments. Full article
(This article belongs to the Special Issue Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control)
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10 pages, 1581 KiB  
Review
L-Type Ca2+ Channel Regulation by Calmodulin and CaBP1
by James B. Ames
Biomolecules 2021, 11(12), 1811; https://doi.org/10.3390/biom11121811 - 2 Dec 2021
Cited by 15 | Viewed by 2545
Abstract
L-type voltage-gated Ca2+ channels (CaV1.2 and CaV1.3, called CaV) interact with the Ca2+ sensor proteins, calmodulin (CaM) and Ca2+ binding Protein 1 (CaBP1), that oppositely control Ca2+-dependent channel activity. CaM and CaBP1 can each bind to the IQ-motif [...] Read more.
L-type voltage-gated Ca2+ channels (CaV1.2 and CaV1.3, called CaV) interact with the Ca2+ sensor proteins, calmodulin (CaM) and Ca2+ binding Protein 1 (CaBP1), that oppositely control Ca2+-dependent channel activity. CaM and CaBP1 can each bind to the IQ-motif within the C-terminal cytosolic domain of CaV, which promotes increased channel open probability under basal conditions. At elevated cytosolic Ca2+ levels (caused by CaV channel opening), Ca2+-bound CaM binding to CaV is essential for promoting rapid Ca2+-dependent channel inactivation (CDI). By contrast, CaV binding to CaBP1 prevents CDI and promotes Ca2+-induced channel opening (called CDF). In this review, I provide an overview of the known structures of CaM and CaBP1 and their structural interactions with the IQ-motif to help understand how CaM promotes CDI, whereas CaBP1 prevents CDI and instead promotes CDF. Previous electrophysiology studies suggest that Ca2+-free forms of CaM and CaBP1 may pre-associate with CaV under basal conditions. However, previous Ca2+ binding data suggest that CaM and CaBP1 are both calculated to bind to Ca2+ with an apparent dissociation constant of ~100 nM when CaM or CaBP1 is bound to the IQ-motif. Since the neuronal basal cytosolic Ca2+ concentration is ~100 nM, nearly half of the neuronal CaV channels are suggested to be bound to Ca2+-bound forms of either CaM or CaBP1 under basal conditions. The pre-association of CaV with calcified forms of CaM or CaBP1 are predicted here to have functional implications. The Ca2+-bound form of CaBP1 is proposed to bind to CaV under basal conditions to block CaV binding to CaM, which could explain how CaBP1 might prevent CDI. Full article
(This article belongs to the Collection Advances in Metal Binding Proteins)
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16 pages, 1437 KiB  
Review
The Use of Fluorescent Anti-CEA Antibodies to Label, Resect and Treat Cancers: A Review
by Michael A. Turner, Thinzar M. Lwin, Siamak Amirfakhri, Hiroto Nishino, Robert M. Hoffman, Paul J. Yazaki and Michael Bouvet
Biomolecules 2021, 11(12), 1819; https://doi.org/10.3390/biom11121819 - 2 Dec 2021
Cited by 12 | Viewed by 2569
Abstract
A major barrier to the diagnosis and effective treatment of solid-tumor cancers is the difficulty in detection and visualization of tumor margins in primary and metastatic disease. The use of fluorescence can augment the surgeon’s ability to detect cancer and aid in its [...] Read more.
A major barrier to the diagnosis and effective treatment of solid-tumor cancers is the difficulty in detection and visualization of tumor margins in primary and metastatic disease. The use of fluorescence can augment the surgeon’s ability to detect cancer and aid in its resection. Several cancer types express carcinoembryonic antigen (CEA) including colorectal, pancreatic and gastric cancer. Antibodies to CEA have been developed and tagged with near-infrared fluorescent dyes. This review article surveyed the use of CEA antibodies conjugated to fluorescent probes for in vivo studies since 1990. PubMed and Google Scholar databases were queried, and 900 titles and abstracts were screened. Fifty-nine entries were identified as possibly meeting inclusion/exclusion criteria and were reviewed in full. Forty articles were included in the review and their citations were screened for additional entries. A total of 44 articles were included in the final review. The use of fluorescent anti-CEA antibodies has been shown to improve detection and resection of tumors in both murine models and clinically. The cumulative results indicate that fluorescent-conjugated anti-CEA antibodies have important potential to improve cancer diagnosis and surgery. In an emerging technology, anti-CEA fluorescent antibodies have also been successfully used for photoimmunotherapy treatment for cancer. Full article
(This article belongs to the Special Issue Feature Paper from Biomolecules Journal Reviewers)
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