Biomolecules

Review

24 pages, 840 KiB

Open AccessEditor’s ChoiceReview

Mechanisms Suggesting a Relationship between Vitamin D and Erectile Dysfunction: An Overview

by Andrea Crafa, Rossella Cannarella, Federica Barbagallo, Claudia Leanza, Roberto Palazzolo, Hunter Ausley Flores, Sandro La Vignera, Rosita A. Condorelli and Aldo E. Calogero

Biomolecules 2023, 13(6), 930; https://doi.org/10.3390/biom13060930 - 1 Jun 2023

Cited by 5 | Viewed by 8271

Abstract

Vitamin D deficiency (VDD) and erectile dysfunction (ED) heavily burden the male population. The higher prevalence of both conditions in the elderly suggests a possible relationship between the two conditions. In addition, in vitro, animal, and human studies have revealed several mechanisms that [...] Read more.

Vitamin D deficiency (VDD) and erectile dysfunction (ED) heavily burden the male population. The higher prevalence of both conditions in the elderly suggests a possible relationship between the two conditions. In addition, in vitro, animal, and human studies have revealed several mechanisms that may relate VDD to ED. The main mechanism by which vitamin D might exert its action on sexual function appears to be through the regulation of endothelial function. Indeed, VDD correlates with several markers of endothelial function. The action of vitamin D on the endothelium would be exercised both indirectly through its intervention in inflammatory processes and through the production of oxygen free radicals, and directly through the regulation of vascular stiffness, the production of nitric oxide, and the regulation of vessel permeability. Furthermore, the ubiquitous distribution of the vitamin D receptor in the human body means that this hormone can also exert a beneficial effect on erectile function by interfering with those comorbidities significantly associated with ED, such as hypertension, diabetes mellitus, hypercholesterolemia, chronic kidney disease, and hypogonadism. In this review, we thoroughly and carefully presented the evidence and mechanisms that would appear to relate vitamin D levels to erectile function. Furthermore, we have summarized the meta-analytic evidence for and against this association to provide a true representation of this topic. Data published to date suggest that low levels of vitamin D could contribute to worsening erectile function through several mechanisms. Therefore, vitamin D levels should be measured in patients with ED and maintained at adequate levels by specific supplementation in case of deficiency. However, the low quality and heterogeneity of clinical trials evaluating the effects of vitamin D administration on erectile function and ED-associated comorbidities do not allow for a univocal conclusion, and indicate the need for further studies to analyze these aspects. Full article

(This article belongs to the Special Issue Vitamin D and Its Analogues: New Insights on Biological Effects, Molecular Mechanisms, and Therapeutic Methods)

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14 pages, 1115 KiB

Open AccessEditor’s ChoiceReview

Microglia NLRP3 Inflammasome and Neuroimmune Signaling in Substance Use Disorders

by Ming-Lei Guo, Soheil Kazemi Roodsari, Yan Cheng, Rachael Elizabeth Dempsey and Wenhui Hu

Biomolecules 2023, 13(6), 922; https://doi.org/10.3390/biom13060922 - 31 May 2023

Cited by 6 | Viewed by 2975

Abstract

During the last decade, substance use disorders (SUDs) have been increasingly recognized as neuroinflammation-related brain diseases. Various types of abused drugs (cocaine, methamphetamine, alcohol, opiate-like drugs, marijuana, etc.) can modulate the activation status of microglia and neuroinflammation levels which are involved in the [...] Read more.

During the last decade, substance use disorders (SUDs) have been increasingly recognized as neuroinflammation-related brain diseases. Various types of abused drugs (cocaine, methamphetamine, alcohol, opiate-like drugs, marijuana, etc.) can modulate the activation status of microglia and neuroinflammation levels which are involved in the pathogenesis of SUDs. Several neuroimmune signaling pathways, including TLR/NF-кB, reactive oxygen species, mitochondria dysfunction, as well as autophagy defection, etc., have been implicated in promoting SUDs. Recently, inflammasome-mediated signaling has been identified as playing critical roles in the microglia activation induced by abused drugs. Among the family of inflammasomes, NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) serves the primary research target due to its abundant expression in microglia. NLRP3 has the capability of integrating multiple external and internal inputs and coordinately determining the intensity of microglia activation under various pathological conditions. Here, we summarize the effects of abused drugs on NLRP3 inflammasomes, as well as others, if any. The research on this topic is still at an infant stage; however, the readily available findings suggest that NLRP3 inflammasome could be a common downstream effector stimulated by various types of abused drugs and play critical roles in determining abused-drug-mediated biological effects through enhancing glia–neuron communications. NLRP3 inflammasome might serve as a novel target for ameliorating the development of SUDs. Full article

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

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56 pages, 2374 KiB

Open AccessEditor’s ChoiceReview

The Janus-Faced Role of Lipid Droplets in Aging: Insights from the Cellular Perspective

by Nikolaus Bresgen, Melanie Kovacs, Angelika Lahnsteiner, Thomas Klaus Felder and Mark Rinnerthaler

Biomolecules 2023, 13(6), 912; https://doi.org/10.3390/biom13060912 - 30 May 2023

Cited by 3 | Viewed by 4780

Abstract

It is widely accepted that nine hallmarks—including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis—exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be [...] Read more.

It is widely accepted that nine hallmarks—including mitochondrial dysfunction, epigenetic alterations, and loss of proteostasis—exist that describe the cellular aging process. Adding to this, a well-described cell organelle in the metabolic context, namely, lipid droplets, also accumulates with increasing age, which can be regarded as a further aging-associated process. Independently of their essential role as fat stores, lipid droplets are also able to control cell integrity by mitigating lipotoxic and proteotoxic insults. As we will show in this review, numerous longevity interventions (such as mTOR inhibition) also lead to strong accumulation of lipid droplets in Saccharomyces cerevisiae, Caenorhabditis elegans, Drosophila melanogaster, and mammalian cells, just to name a few examples. In mammals, due to the variety of different cell types and tissues, the role of lipid droplets during the aging process is much more complex. Using selected diseases associated with aging, such as Alzheimer’s disease, Parkinson’s disease, type II diabetes, and cardiovascular disease, we show that lipid droplets are “Janus”-faced. In an early phase of the disease, lipid droplets mitigate the toxicity of lipid peroxidation and protein aggregates, but in a later phase of the disease, a strong accumulation of lipid droplets can cause problems for cells and tissues. Full article

(This article belongs to the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof. Michael Breitenbach)

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34 pages, 2973 KiB

Open AccessEditor’s ChoiceReview

The Role of Extracellular Vesicles in the Pathogenesis of Hematological Malignancies: Interaction with Tumor Microenvironment; a Potential Biomarker and Targeted Therapy

by Kaushik Das, Tanmoy Mukherjee and Prem Shankar

Biomolecules 2023, 13(6), 897; https://doi.org/10.3390/biom13060897 - 27 May 2023

Cited by 7 | Viewed by 2975

Abstract

The tumor microenvironment (TME) plays an important role in the development and progression of hematological malignancies. In recent years, studies have focused on understanding how tumor cells communicate within the TME. In addition to several factors, such as growth factors, cytokines, extracellular matrix [...] Read more.

The tumor microenvironment (TME) plays an important role in the development and progression of hematological malignancies. In recent years, studies have focused on understanding how tumor cells communicate within the TME. In addition to several factors, such as growth factors, cytokines, extracellular matrix (ECM) molecules, etc., a growing body of evidence has indicated that extracellular vesicles (EVs) play a crucial role in the communication of tumor cells within the TME, thereby contributing to the pathogenesis of hematological malignancies. The present review focuses on how EVs derived from tumor cells interact with the cells in the TME, such as immune cells, stromal cells, endothelial cells, and ECM components, and vice versa, in the context of various hematological malignancies. EVs recovered from the body fluids of cancer patients often carry the bioactive molecules of the originating cells and hence can be considered new predictive biomarkers for specific types of cancer, thereby also acting as potential therapeutic targets. Here, we discuss how EVs influence hematological tumor progression via tumor–host crosstalk and their use as biomarkers for hematological malignancies, thereby benefiting the development of potential therapeutic targets. Full article

(This article belongs to the Special Issue The Role of Tumor Microenvironment in the Pathogenesis and Progression of Hematological Malignancies)

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15 pages, 612 KiB

Open AccessEditor’s ChoiceReview

Thermal Effect on Heat Shock Protein 70 Family to Prevent Atherosclerotic Cardiovascular Disease

by Masayo Nagai and Hidesuke Kaji

Biomolecules 2023, 13(5), 867; https://doi.org/10.3390/biom13050867 - 20 May 2023

Cited by 4 | Viewed by 1640

Abstract

Heat shock protein 70 (HSP70) is a chaperone protein induced by various stresses on cells and is involved in various disease mechanisms. In recent years, the expression of HSP70 in skeletal muscle has attracted attention for its use as a prevention of atherosclerotic [...] Read more.

Heat shock protein 70 (HSP70) is a chaperone protein induced by various stresses on cells and is involved in various disease mechanisms. In recent years, the expression of HSP70 in skeletal muscle has attracted attention for its use as a prevention of atherosclerotic cardiovascular disease (ASCVD) and as a disease marker. We have previously reported the effect of thermal stimulation targeted to skeletal muscles and skeletal muscle-derived cells. In this article, we reported review articles including our research results. HSP70 contributes to the improvement of insulin resistance as well as chronic inflammation which are underlying pathologies of type 2 diabetes, obesity, and atherosclerosis. Thus, induction of HSP70 expression by external stimulation such as heat and exercise may be useful for ASCVD prevention. It may be possible to induce HSP70 by thermal stimulus in those who have difficulty in exercise because of obesity or locomotive syndrome. It requires further investigation to determine whether monitoring serum HSP70 concentration is useful for ASCVD prevention. Full article

(This article belongs to the Special Issue HSP70: From Signaling Mechanisms to Therapeutics)

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18 pages, 977 KiB

Open AccessEditor’s ChoiceReview

Evidence of Metabolic Dysfunction in Amyotrophic Lateral Sclerosis (ALS) Patients and Animal Models

by Katarina Maksimovic, Mohieldin Youssef, Justin You, Hoon-Ki Sung and Jeehye Park

Biomolecules 2023, 13(5), 863; https://doi.org/10.3390/biom13050863 - 19 May 2023

Cited by 6 | Viewed by 4891

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons, leading to muscle weakness, paralysis, and eventual death. Research from the past few decades has appreciated that ALS is not only a disease of the motor neurons but also a disease that involves systemic metabolic dysfunction. This review will examine the foundational research of understanding metabolic dysfunction in ALS and provide an overview of past and current studies in ALS patients and animal models, spanning from full systems to various metabolic organs. While ALS-affected muscle tissue exhibits elevated energy demand and a fuel preference switch from glycolysis to fatty acid oxidation, adipose tissue in ALS undergoes increased lipolysis. Dysfunctions in the liver and pancreas contribute to impaired glucose homeostasis and insulin secretion. The central nervous system (CNS) displays abnormal glucose regulation, mitochondrial dysfunction, and increased oxidative stress. Importantly, the hypothalamus, a brain region that controls whole-body metabolism, undergoes atrophy associated with pathological aggregates of TDP-43. This review will also cover past and present treatment options that target metabolic dysfunction in ALS and provide insights into the future of metabolism research in ALS. Full article

(This article belongs to the Special Issue Stress, Aging and Metabolism)

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26 pages, 9848 KiB

Open AccessEditor’s ChoiceReview

Emerging Quantitative Biochemical, Structural, and Biophysical Methods for Studying Ribosome and Protein–RNA Complex Assembly

by Kavan Gor and Olivier Duss

Biomolecules 2023, 13(5), 866; https://doi.org/10.3390/biom13050866 - 19 May 2023

Cited by 4 | Viewed by 3089

Abstract

Ribosome assembly is one of the most fundamental processes of gene expression and has served as a playground for investigating the molecular mechanisms of how protein–RNA complexes (RNPs) assemble. A bacterial ribosome is composed of around 50 ribosomal proteins, several of which are [...] Read more.

Ribosome assembly is one of the most fundamental processes of gene expression and has served as a playground for investigating the molecular mechanisms of how protein–RNA complexes (RNPs) assemble. A bacterial ribosome is composed of around 50 ribosomal proteins, several of which are co-transcriptionally assembled on a ~4500-nucleotide-long pre-rRNA transcript that is further processed and modified during transcription, the entire process taking around 2 min in vivo and being assisted by dozens of assembly factors. How this complex molecular process works so efficiently to produce an active ribosome has been investigated over decades, resulting in the development of a plethora of novel approaches that can also be used to study the assembly of other RNPs in prokaryotes and eukaryotes. Here, we review biochemical, structural, and biophysical methods that have been developed and integrated to provide a detailed and quantitative understanding of the complex and intricate molecular process of bacterial ribosome assembly. We also discuss emerging, cutting-edge approaches that could be used in the future to study how transcription, rRNA processing, cellular factors, and the native cellular environment shape ribosome assembly and RNP assembly at large. Full article

(This article belongs to the Special Issue Ribosomal Proteins in Ribosome Assembly)

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19 pages, 1589 KiB

Open AccessEditor’s ChoiceReview

Altered Purinergic Signaling in Neurodevelopmental Disorders: Focus on P2 Receptors

by Marta Boccazzi, Stefano Raffaele, Thomas Zanettin, Maria P. Abbracchio and Marta Fumagalli

Biomolecules 2023, 13(5), 856; https://doi.org/10.3390/biom13050856 - 18 May 2023

Cited by 4 | Viewed by 2203

Abstract

With the umbrella term ‘neurodevelopmental disorders’ (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary [...] Read more.

With the umbrella term ‘neurodevelopmental disorders’ (NDDs) we refer to a plethora of congenital pathological conditions generally connected with cognitive, social behavior, and sensory/motor alterations. Among the possible causes, gestational and perinatal insults have been demonstrated to interfere with the physiological processes necessary for the proper development of fetal brain cytoarchitecture and functionality. In recent years, several genetic disorders caused by mutations in key enzymes involved in purine metabolism have been associated with autism-like behavioral outcomes. Further analysis revealed dysregulated purine and pyrimidine levels in the biofluids of subjects with other NDDs. Moreover, the pharmacological blockade of specific purinergic pathways reversed the cognitive and behavioral defects caused by maternal immune activation, a validated and now extensively used rodent model for NDDs. Furthermore, Fragile X and Rett syndrome transgenic animal models as well as models of premature birth, have been successfully utilized to investigate purinergic signaling as a potential pharmacological target for these diseases. In this review, we examine results on the role of the P2 receptor signaling in the etiopathogenesis of NDDs. On this basis, we discuss how this evidence could be exploited to develop more receptor-specific ligands for future therapeutic interventions and novel prognostic markers for the early detection of these conditions. Full article

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

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41 pages, 4159 KiB

Open AccessEditor’s ChoiceReview

(Patho)Physiology of Glycosylphosphatidylinositol-Anchored Proteins I: Localization at Plasma Membranes and Extracellular Compartments

by Günter A. Müller and Timo D. Müller

Biomolecules 2023, 13(5), 855; https://doi.org/10.3390/biom13050855 - 18 May 2023

Cited by 6 | Viewed by 3658

Abstract

Glycosylphosphatidylinositol (GPI)-anchored proteins (APs) are anchored at the outer leaflet of plasma membranes (PMs) of all eukaryotic organisms studied so far by covalent linkage to a highly conserved glycolipid rather than a transmembrane domain. Since their first description, experimental data have been accumulating [...] Read more.

Glycosylphosphatidylinositol (GPI)-anchored proteins (APs) are anchored at the outer leaflet of plasma membranes (PMs) of all eukaryotic organisms studied so far by covalent linkage to a highly conserved glycolipid rather than a transmembrane domain. Since their first description, experimental data have been accumulating for the capability of GPI-APs to be released from PMs into the surrounding milieu. It became evident that this release results in distinct arrangements of GPI-APs which are compatible with the aqueous milieu upon loss of their GPI anchor by (proteolytic or lipolytic) cleavage or in the course of shielding of the full-length GPI anchor by incorporation into extracellular vesicles, lipoprotein-like particles and (lyso)phospholipid- and cholesterol-harboring micelle-like complexes or by association with GPI-binding proteins or/and other full-length GPI-APs. In mammalian organisms, the (patho)physiological roles of the released GPI-APs in the extracellular environment, such as blood and tissue cells, depend on the molecular mechanisms of their release as well as the cell types and tissues involved, and are controlled by their removal from circulation. This is accomplished by endocytic uptake by liver cells and/or degradation by GPI-specific phospholipase D in order to bypass potential unwanted effects of the released GPI-APs or their transfer from the releasing donor to acceptor cells (which will be reviewed in a forthcoming manuscript). Full article

(This article belongs to the Section Biomacromolecules: Proteins)

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18 pages, 3411 KiB

Open AccessEditor’s ChoiceReview

Ribosomal Protein uS5 and Friends: Protein–Protein Interactions Involved in Ribosome Assembly and Beyond

by Anne-Marie Landry-Voyer, Zabih Mir Hassani, Mariano Avino and François Bachand

Biomolecules 2023, 13(5), 853; https://doi.org/10.3390/biom13050853 - 18 May 2023

Cited by 4 | Viewed by 2471

Abstract

Ribosomal proteins are fundamental components of the ribosomes in all living cells. The ribosomal protein uS5 (Rps2) is a stable component of the small ribosomal subunit within all three domains of life. In addition to its interactions with proximal ribosomal proteins and rRNA [...] Read more.

Ribosomal proteins are fundamental components of the ribosomes in all living cells. The ribosomal protein uS5 (Rps2) is a stable component of the small ribosomal subunit within all three domains of life. In addition to its interactions with proximal ribosomal proteins and rRNA inside the ribosome, uS5 has a surprisingly complex network of evolutionarily conserved non-ribosome-associated proteins. In this review, we focus on a set of four conserved uS5-associated proteins: the protein arginine methyltransferase 3 (PRMT3), the programmed cell death 2 (PDCD2) and its PDCD2-like (PDCD2L) paralog, and the zinc finger protein, ZNF277. We discuss recent work that presents PDCD2 and homologs as a dedicated uS5 chaperone and PDCD2L as a potential adaptor protein for the nuclear export of pre-40S subunits. Although the functional significance of the PRMT3–uS5 and ZNF277–uS5 interactions remain elusive, we reflect on the potential roles of uS5 arginine methylation by PRMT3 and on data indicating that ZNF277 and PRMT3 compete for uS5 binding. Together, these discussions highlight the complex and conserved regulatory network responsible for monitoring the availability and the folding of uS5 for the formation of 40S ribosomal subunits and/or the role of uS5 in potential extra-ribosomal functions. Full article

(This article belongs to the Special Issue Ribosomal Proteins in Ribosome Assembly)

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26 pages, 1574 KiB

Open AccessEditor’s ChoiceReview

Microvascular Contributions to Alzheimer Disease Pathogenesis: Is Alzheimer Disease Primarily an Endotheliopathy?

by Rawan Tarawneh

Biomolecules 2023, 13(5), 830; https://doi.org/10.3390/biom13050830 - 13 May 2023

Cited by 2 | Viewed by 4920

Abstract

Alzheimer disease (AD) models are based on the notion that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset, and culminates in neurodegeneration; however, emerging evidence from animal and clinical studies suggests that [...] Read more.

Alzheimer disease (AD) models are based on the notion that abnormal protein aggregation is the primary event in AD, which begins a decade or longer prior to symptom onset, and culminates in neurodegeneration; however, emerging evidence from animal and clinical studies suggests that reduced blood flow due to capillary loss and endothelial dysfunction are early and primary events in AD pathogenesis, which may precede amyloid and tau aggregation, and contribute to neuronal and synaptic injury via direct and indirect mechanisms. Recent data from clinical studies suggests that endothelial dysfunction is closely associated with cognitive outcomes in AD and that therapeutic strategies which promote endothelial repair in early AD may offer a potential opportunity to prevent or slow disease progression. This review examines evidence from clinical, imaging, neuropathological, and animal studies supporting vascular contributions to the onset and progression of AD pathology. Together, these observations support the notion that the onset of AD may be primarily influenced by vascular, rather than neurodegenerative, mechanisms and emphasize the importance of further investigations into the vascular hypothesis of AD. Full article

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

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26 pages, 816 KiB

Open AccessEditor’s ChoiceReview

Cellular Metabolism: A Fundamental Component of Degeneration in the Nervous System

by Kenneth Maiese

Biomolecules 2023, 13(5), 816; https://doi.org/10.3390/biom13050816 - 11 May 2023

Cited by 11 | Viewed by 4110

Abstract

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral [...] Read more.

It is estimated that, at minimum, 500 million individuals suffer from cellular metabolic dysfunction, such as diabetes mellitus (DM), throughout the world. Even more concerning is the knowledge that metabolic disease is intimately tied to neurodegenerative disorders, affecting both the central and peripheral nervous systems as well as leading to dementia, the seventh leading cause of death. New and innovative therapeutic strategies that address cellular metabolism, apoptosis, autophagy, and pyroptosis, the mechanistic target of rapamycin (mTOR), AMP activated protein kinase (AMPK), growth factor signaling with erythropoietin (EPO), and risk factors such as the apolipoprotein E (APOE-ε4) gene and coronavirus disease 2019 (COVID-19) can offer valuable insights for the clinical care and treatment of neurodegenerative disorders impacted by cellular metabolic disease. Critical insight into and modulation of these complex pathways are required since mTOR signaling pathways, such as AMPK activation, can improve memory retention in Alzheimer’s disease (AD) and DM, promote healthy aging, facilitate clearance of β-amyloid (Aß) and tau in the brain, and control inflammation, but also may lead to cognitive loss and long-COVID syndrome through mechanisms that can include oxidative stress, mitochondrial dysfunction, cytokine release, and APOE-ε4 if pathways such as autophagy and other mechanisms of programmed cell death are left unchecked. Full article

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29 pages, 2633 KiB

Open AccessEditor’s ChoiceReview

Therapeutic Strategies for Spinocerebellar Ataxia Type 1

by Laurie M. C. Kerkhof, Bart P. C. van de Warrenburg, Willeke M. C. van Roon-Mom and Ronald A. M. Buijsen

Biomolecules 2023, 13(5), 788; https://doi.org/10.3390/biom13050788 - 2 May 2023

Cited by 1 | Viewed by 4891

Abstract

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the ATXN1 gene and is characterized mostly by a profound loss [...] Read more.

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurodegenerative disorder that affects one or two individuals per 100,000. The disease is caused by an extended CAG repeat in exon 8 of the ATXN1 gene and is characterized mostly by a profound loss of cerebellar Purkinje cells, leading to disturbances in coordination, balance, and gait. At present, no curative treatment is available for SCA1. However, increasing knowledge on the cellular and molecular mechanisms of SCA1 has led the way towards several therapeutic strategies that can potentially slow disease progression. SCA1 therapeutics can be classified as genetic, pharmacological, and cell replacement therapies. These different therapeutic strategies target either the (mutant) ATXN1 RNA or the ataxin-1 protein, pathways that play an important role in downstream SCA1 disease mechanisms or which help restore cells that are lost due to SCA1 pathology. In this review, we will provide a summary of the different therapeutic strategies that are currently being investigated for SCA1. Full article

(This article belongs to the Special Issue Biomolecular Approaches and Drugs for Neurodegeneration)

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19 pages, 435 KiB

Open AccessEditor’s ChoiceReview

Mechanisms Controlling the Expression and Secretion of BDNF

by Juan Carlos Arévalo and Rubén Deogracias

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

Cited by 17 | Viewed by 5110

Abstract

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

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

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

20 pages, 1556 KiB

Open AccessEditor’s ChoiceReview

Role of Angiotensin II in Cardiovascular Diseases: Introducing Bisartans as a Novel Therapy for Coronavirus 2019

by Jordan Swiderski, Laura Kate Gadanec, Vasso Apostolopoulos, Graham J. Moore, Konstantinos Kelaidonis, John M. Matsoukas and Anthony Zulli

Biomolecules 2023, 13(5), 787; https://doi.org/10.3390/biom13050787 - 2 May 2023

Cited by 10 | Viewed by 4985

Abstract

Cardiovascular diseases (CVDs) are the main contributors to global morbidity and mortality. Major pathogenic phenotypes of CVDs include the development of endothelial dysfunction, oxidative stress, and hyper-inflammatory responses. These phenotypes have been found to overlap with the pathophysiological complications of coronavirus disease 2019 [...] Read more.

Cardiovascular diseases (CVDs) are the main contributors to global morbidity and mortality. Major pathogenic phenotypes of CVDs include the development of endothelial dysfunction, oxidative stress, and hyper-inflammatory responses. These phenotypes have been found to overlap with the pathophysiological complications of coronavirus disease 2019 (COVID-19). CVDs have been identified as major risk factors for severe and fatal COVID-19 states. The renin–angiotensin system (RAS) is an important regulatory system in cardiovascular homeostasis. However, its dysregulation is observed in CVDs, where upregulation of angiotensin type 1 receptor (AT₁R) signaling via angiotensin II (AngII) leads to the AngII-dependent pathogenic development of CVDs. Additionally, the interaction between the spike protein of severe acute respiratory syndrome coronavirus 2 with angiotensin-converting enzyme 2 leads to the downregulation of the latter, resulting in the dysregulation of the RAS. This dysregulation favors AngII/AT₁R toxic signaling pathways, providing a mechanical link between cardiovascular pathology and COVID-19. Therefore, inhibiting AngII/AT₁R signaling through angiotensin receptor blockers (ARBs) has been indicated as a promising therapeutic approach to the treatment of COVID-19. Herein, we review the role of AngII in CVDs and its upregulation in COVID-19. We also provide a future direction for the potential implication of a novel class of ARBs called bisartans, which are speculated to contain multifunctional targeting towards COVID-19. Full article

(This article belongs to the Special Issue The Role of Angiotensin in Cardiovascular Disease)

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23 pages, 6079 KiB

Open AccessEditor’s ChoiceReview

Relaxin-like Gonad-Stimulating Peptides in Asteroidea

by Masatoshi Mita

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

Cited by 6 | Viewed by 4014

Abstract

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

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

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

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14 pages, 2601 KiB

Open AccessEditor’s ChoiceReview

Cardiac Imaging Biomarkers in Chronic Kidney Disease

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

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

Cited by 2 | Viewed by 2551

Abstract

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

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

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

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8 pages, 2403 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

by Steven E. Wilson

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

Cited by 5 | Viewed by 2802

Abstract

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

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

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

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18 pages, 1065 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 9 | Viewed by 6361

Abstract

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

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

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

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34 pages, 6792 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

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

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

Cited by 6 | Viewed by 4158

Abstract

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

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

(This article belongs to the Section Molecular Medicine)

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16 pages, 3638 KiB

Open AccessEditor’s ChoiceReview

Recent Advances in Peptidoglycan Synthesis and Regulation in Bacteria

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

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

Cited by 9 | Viewed by 4016

Abstract

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

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

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

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25 pages, 9999 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 11 | Viewed by 3410

Abstract

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

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

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

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14 pages, 977 KiB

Open AccessEditor’s ChoiceReview

An Integrated View of Stressors as Causative Agents in OA Pathogenesis

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

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

Cited by 1 | Viewed by 3454

Abstract

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

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

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

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20 pages, 847 KiB

Open AccessEditor’s ChoiceReview

Vitamin D and Autoimmune Rheumatic Diseases

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

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

Cited by 20 | Viewed by 8271

Abstract

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

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

(This article belongs to the Section Molecular Medicine)

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20 pages, 3079 KiB

Open AccessEditor’s ChoiceReview

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

by Smaragdi Antonopoulou and Constantinos A. Demopoulos

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

Cited by 14 | Viewed by 1971

Abstract

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

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

(This article belongs to the Section Cellular Biochemistry)

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33 pages, 7619 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 4 | Viewed by 2650

Abstract

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

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

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

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30 pages, 2180 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 22 | Viewed by 4170

Abstract

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

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

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

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17 pages, 1129 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 37 | Viewed by 6823

Abstract

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

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

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

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19 pages, 3900 KiB

Open AccessEditor’s ChoiceReview

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

by Yanggu Shi and Jindong Shang

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

Cited by 3 | Viewed by 1890

Abstract

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

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

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

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15 pages, 2396 KiB

Open AccessEditor’s ChoiceReview

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

by Danton H. O'Day

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

Cited by 1 | Viewed by 2047

Abstract

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

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

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

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14 pages, 1040 KiB

Open AccessEditor’s ChoiceReview

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

by Daria Vinokurova and Lionel Apetoh

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

Cited by 3 | Viewed by 2203

Abstract

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

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

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12 pages, 927 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Roles of sPLA₂s in Skin Homeostasis and Disease

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

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

Cited by 1 | Viewed by 1913

Abstract

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

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

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

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15 pages, 1785 KiB

Open AccessEditor’s ChoiceReview

The Hop2-Mnd1 Complex and Its Regulation of Homologous Recombination

by Hideo Tsubouchi

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

Cited by 3 | Viewed by 3158

Abstract

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

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

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

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24 pages, 4390 KiB

Open AccessEditor’s ChoiceReview

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

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

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

Cited by 13 | Viewed by 3269

Abstract

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

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

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

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18 pages, 1251 KiB

Open AccessEditor’s ChoiceReview

Microtubule Regulation in Plants: From Morphological Development to Stress Adaptation

by An-Shan Hsiao and Ji-Ying Huang

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

Cited by 6 | Viewed by 5407

Abstract

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

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

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

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12 pages, 1255 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Regulation of the SUV39H Family Methyltransferases: Insights from Fission Yeast

by Rinko Nakamura and Jun-ichi Nakayama

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

Cited by 1 | Viewed by 2365

Abstract

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

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

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

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20 pages, 2777 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

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

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

Cited by 7 | Viewed by 3202

Abstract

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

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

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

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13 pages, 782 KiB

Open AccessEditor’s ChoiceReview

Mechanical Properties and Functions of Elastin: An Overview

by Hanna Trębacz and Angelika Barzycka

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

Cited by 18 | Viewed by 7604

Abstract

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

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

(This article belongs to the Section Biomacromolecules: Proteins)

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15 pages, 1699 KiB

Open AccessEditor’s ChoiceReview

Heme Scavenging and Delivery: The Role of Human Serum Albumin

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

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

Cited by 5 | Viewed by 4313

Abstract

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

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

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

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14 pages, 1278 KiB

Open AccessEditor’s ChoiceReview

Alternative mRNA Splicing and Promising Therapies in Cancer

by James D. Fackenthal

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

Cited by 7 | Viewed by 2870

Abstract

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

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

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

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14 pages, 828 KiB

Open AccessFeature PaperEditor’s ChoiceReview

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

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

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

Cited by 15 | Viewed by 2967

Abstract

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

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

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

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23 pages, 1711 KiB

Open AccessEditor’s ChoiceReview

Actions and Consequences of Insulin in the Striatum

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

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

Cited by 5 | Viewed by 2670

Abstract

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

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

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

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14 pages, 901 KiB

Open AccessEditor’s ChoiceReview

Melatonin in Health and Disease: A Perspective for Livestock Production

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

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

Cited by 7 | Viewed by 4131

Abstract

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

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

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

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11 pages, 681 KiB

Open AccessEditor’s ChoiceReview

Distinct Roles of SELENOF in Different Human Cancers

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

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

Cited by 4 | Viewed by 2004

Abstract

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

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

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

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21 pages, 968 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Caenorhabditis elegans as a Model System to Study Human Neurodegenerative Disorders

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

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

Cited by 7 | Viewed by 5941

Abstract

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

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

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

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18 pages, 3741 KiB

Open AccessEditor’s ChoiceReview

The Lysophospholipase PNPLA7 Controls Hepatic Choline and Methionine Metabolism

by Sayaka Harada, Yoshitaka Taketomi, Toshiki Aiba, Mai Kawaguchi, Tetsuya Hirabayashi, Baasanjav Uranbileg, Makoto Kurano, Yutaka Yatomi and Makoto Murakami

Biomolecules 2023, 13(3), 471; https://doi.org/10.3390/biom13030471 - 3 Mar 2023

Cited by 6 | Viewed by 2734

Abstract

The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca²⁺-independent phospholipase A₂ (iPLA₂) family, [...] Read more.

The in vivo roles of lysophospholipase, which cleaves a fatty acyl ester of lysophospholipid, remained unclear. Recently, we have unraveled a previously unrecognized physiological role of the lysophospholipase PNPLA7, a member of the Ca²⁺-independent phospholipase A₂ (iPLA₂) family, as a key regulator of the production of glycerophosphocholine (GPC), a precursor of endogenous choline, whose methyl groups are preferentially fluxed into the methionine cycle in the liver. PNPLA7 deficiency in mice markedly decreases hepatic GPC, choline, and several metabolites related to choline/methionine metabolism, leading to various symptoms reminiscent of methionine shortage. Overall metabolic alterations in the liver of Pnpla7-null mice in vivo largely recapitulate those in methionine-deprived hepatocytes in vitro. Reduction of the methyl donor S-adenosylmethionine (SAM) after methionine deprivation decreases the methylation of the PNPLA7 gene promoter, relieves PNPLA7 expression, and thereby increases GPC and choline levels, likely as a compensatory adaptation. In line with the view that SAM prevents the development of liver cancer, the expression of PNPLA7, as well as several enzymes in the choline/methionine metabolism, is reduced in human hepatocellular carcinoma. These findings uncover an unexplored role of a lysophospholipase in hepatic phospholipid catabolism coupled with choline/methionine metabolism. Full article

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

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19 pages, 1044 KiB

Open AccessEditor’s ChoiceReview

Surface Treatments of PEEK for Osseointegration to Bone

by Jay R. Dondani, Janaki Iyer and Simon D. Tran

Biomolecules 2023, 13(3), 464; https://doi.org/10.3390/biom13030464 - 2 Mar 2023

Cited by 21 | Viewed by 3424

Abstract

Polymers, in general, and Poly (Ether-Ether-Ketone) (PEEK) have emerged as potential alternatives to conventional osseous implant biomaterials. Due to its distinct advantages over metallic implants, PEEK has been gaining increasing attention as a prime candidate for orthopaedic and dental implants. However, PEEK has [...] Read more.

Polymers, in general, and Poly (Ether-Ether-Ketone) (PEEK) have emerged as potential alternatives to conventional osseous implant biomaterials. Due to its distinct advantages over metallic implants, PEEK has been gaining increasing attention as a prime candidate for orthopaedic and dental implants. However, PEEK has a highly hydrophobic and bioinert surface that attenuates the differentiation and proliferation of osteoblasts and leads to implant failure. Several improvements have been made to the osseointegration potential of PEEK, which can be classified into three main categories: (1) surface functionalization with bioactive agents by physical or chemical means; (2) incorporation of bioactive materials either as surface coatings or as composites; and (3) construction of three-dimensionally porous structures on its surfaces. The physical treatments, such as plasma treatments of various elements, accelerated neutron beams, or conventional techniques like sandblasting and laser or ultraviolet radiation, change the micro-geometry of the implant surface. The chemical treatments change the surface composition of PEEK and should be titrated at the time of exposure. The implant surface can be incorporated with a bioactive material that should be selected following the desired use, loading condition, and antimicrobial load around the implant. For optimal results, a combination of the methods above is utilized to compensate for the limitations of individual methods. This review summarizes these methods and their combinations for optimizing the surface of PEEK for utilization as an implanted biomaterial. Full article

(This article belongs to the Special Issue Novel Materials for Biomedical Applications)

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12 pages, 902 KiB

Open AccessEditor’s ChoiceReview

Compounds Inhibiting Noppera-bo, a Glutathione S-transferase Involved in Insect Ecdysteroid Biosynthesis: Novel Insect Growth Regulators

by Kana Ebihara and Ryusuke Niwa

Biomolecules 2023, 13(3), 461; https://doi.org/10.3390/biom13030461 - 2 Mar 2023

Cited by 4 | Viewed by 3192

Abstract

Glutathione S-transferases (GSTs) are conserved in a wide range of organisms, including insects. In 2014, an epsilon GST, known as Noppera-bo (Nobo), was shown to regulate the biosynthesis of ecdysteroid, the principal steroid hormone in insects. Studies on fruit flies, Drosophila melanogaster [...] Read more.

Glutathione S-transferases (GSTs) are conserved in a wide range of organisms, including insects. In 2014, an epsilon GST, known as Noppera-bo (Nobo), was shown to regulate the biosynthesis of ecdysteroid, the principal steroid hormone in insects. Studies on fruit flies, Drosophila melanogaster, and silkworms, Bombyx mori, demonstrated that loss-of-function mutants of nobo fail to synthesize ecdysteroid and die during development, consistent with the essential function of ecdysteroids in insect molting and metamorphosis. This genetic evidence suggests that chemical compounds that inhibit activity of Nobo could be insect growth regulators (IGRs) that kill insects by disrupting their molting and metamorphosis. In addition, because nobo is conserved only in Diptera and Lepidoptera, a Nobo inhibitor could be used to target IGRs in a narrow spectrum of insect taxa. Dipterans include mosquitoes, some of which are vectors of diseases such as malaria and dengue fever. Given that mosquito control is essential to reduce mosquito-borne diseases, new IGRs that specifically kill mosquito vectors are always in demand. We have addressed this issue by identifying and characterizing several chemical compounds that inhibit Nobo protein in both D. melanogaster and the yellow fever mosquito, Aedes aegypti. In this review, we summarize our findings from the search for Nobo inhibitors. Full article

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

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13 pages, 692 KiB

Open AccessEditor’s ChoiceReview

The Amyloid Cascade Hypothesis in Alzheimer’s Disease: Should We Change Our Thinking?

by Markku Kurkinen, Michał Fułek, Katarzyna Fułek, Jan Aleksander Beszłej, Donata Kurpas and Jerzy Leszek

Biomolecules 2023, 13(3), 453; https://doi.org/10.3390/biom13030453 - 1 Mar 2023

Cited by 21 | Viewed by 7284

Abstract

Old age increases the risk of Alzheimer’s disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 [...] Read more.

Old age increases the risk of Alzheimer’s disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 million by 2050. Today, healthcare for AD patients consumes 1% of the global economy. According to the amyloid cascade hypothesis, AD begins in the brain by accumulating and aggregating Aβ peptides and forming β-amyloid fibrils (Aβ42). However, in clinical trials, reducing Aβ peptide production and amyloid formation in the brain did not slow cognitive decline or improve daily life in AD patients. Prevention studies in cognitively unimpaired people at high risk or genetically destined to develop AD also have not slowed cognitive decline. These observations argue against the amyloid hypothesis of AD etiology, its development, and disease mechanisms. Here, we look at other avenues in the research of AD, such as the presenilin hypothesis, synaptic glutamate signaling, and the role of astrocytes and the glutamate transporter EAAT2 in the development of AD. Full article

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

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39 pages, 3251 KiB

Open AccessEditor’s ChoiceReview

Actin Bundles Dynamics and Architecture

by Sudeepa Rajan, Dmitri S. Kudryashov and Emil Reisler

Biomolecules 2023, 13(3), 450; https://doi.org/10.3390/biom13030450 - 28 Feb 2023

Cited by 18 | Viewed by 5196

Abstract

Cells use the actin cytoskeleton for many of their functions, including their division, adhesion, mechanosensing, endo- and phagocytosis, migration, and invasion. Actin bundles are the main constituent of actin-rich structures involved in these processes. An ever-increasing number of proteins that crosslink actin into [...] Read more.

Cells use the actin cytoskeleton for many of their functions, including their division, adhesion, mechanosensing, endo- and phagocytosis, migration, and invasion. Actin bundles are the main constituent of actin-rich structures involved in these processes. An ever-increasing number of proteins that crosslink actin into bundles or regulate their morphology is being identified in cells. With recent advances in high-resolution microscopy and imaging techniques, the complex process of bundles formation and the multiple forms of physiological bundles are beginning to be better understood. Here, we review the physiochemical and biological properties of four families of highly conserved and abundant actin-bundling proteins, namely, α-actinin, fimbrin/plastin, fascin, and espin. We describe the similarities and differences between these proteins, their role in the formation of physiological actin bundles, and their properties—both related and unrelated to their bundling abilities. We also review some aspects of the general mechanism of actin bundles formation, which are known from the available information on the activity of the key actin partners involved in this process. Full article

(This article belongs to the Special Issue Actin and Its Associates: Biophysical Aspects in Functional Roles)

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