Biomolecules

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 10 | Viewed by 4180

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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15 pages, 2180 KiB

Open AccessEditor’s ChoiceArticle

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

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

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

Cited by 13 | Viewed by 4416

Abstract

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

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

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

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18 pages, 4933 KiB

Open AccessEditor’s ChoiceArticle

Novel scFv against Notch Ligand JAG1 Suitable for Development of Cell Therapies toward JAG1-Positive Tumors

by Gabriela Silva, Ana F. Rodrigues, Susana Ferreira, Carolina Matos, Rute P. Eleutério, Gonçalo Marques, Khrystyna Kucheryava, Ana R. Lemos, Pedro M. F. Sousa, Rute Castro, Ana Barbas, Daniel Simão and Paula M. Alves

Biomolecules 2023, 13(3), 459; https://doi.org/10.3390/biom13030459 - 2 Mar 2023

Cited by 4 | Viewed by 3770

Abstract

The Notch signaling ligand JAG1 is overexpressed in various aggressive tumors and is associated with poor clinical prognosis. Hence, therapies targeting oncogenic JAG1 hold great potential for the treatment of certain tumors. Here, we report the identification of specific anti-JAG1 single-chain variable fragments [...] Read more.

The Notch signaling ligand JAG1 is overexpressed in various aggressive tumors and is associated with poor clinical prognosis. Hence, therapies targeting oncogenic JAG1 hold great potential for the treatment of certain tumors. Here, we report the identification of specific anti-JAG1 single-chain variable fragments (scFvs), one of them endowing chimeric antigen receptor (CAR) T cells with cytotoxicity against JAG1-positive cells. Anti-JAG1 scFvs were identified from human phage display libraries, reformatted into full-length monoclonal antibodies (Abs), and produced in mammalian cells. The characterization of these Abs identified two specific anti-JAG1 Abs (J1.B5 and J1.F1) with nanomolar affinities. Cloning the respective scFv sequences in our second- and third-generation CAR backbones resulted in six anti-JAG1 CAR constructs, which were screened for JAG1-mediated T-cell activation in Jurkat T cells in coculture assays with JAG1-positive cell lines. Studies in primary T cells demonstrated that one CAR harboring the J1.B5 scFv significantly induced effective T-cell activation in the presence of JAG1-positive, but not in JAG1-knockout, cancer cells, and enabled specific killing of JAG1-positive cells. Thus, this new anti-JAG1 scFv represents a promising candidate for the development of cell therapies against JAG1-positive tumors. Full article

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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 9 | Viewed by 4632

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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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 49 | Viewed by 6270

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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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 48 | Viewed by 12013

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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13 pages, 3375 KiB

Open AccessEditor’s ChoiceArticle

Protein Design Using Physics Informed Neural Networks

by Sara Ibrahim Omar, Chen Keasar, Ariel J. Ben-Sasson and Eldad Haber

Biomolecules 2023, 13(3), 457; https://doi.org/10.3390/biom13030457 - 1 Mar 2023

Cited by 6 | Viewed by 4826

Abstract

The inverse protein folding problem, also known as protein sequence design, seeks to predict an amino acid sequence that folds into a specific structure and performs a specific function. Recent advancements in machine learning techniques have been successful in generating functional sequences, outperforming [...] Read more.

The inverse protein folding problem, also known as protein sequence design, seeks to predict an amino acid sequence that folds into a specific structure and performs a specific function. Recent advancements in machine learning techniques have been successful in generating functional sequences, outperforming previous energy function-based methods. However, these machine learning methods are limited in their interoperability and robustness, especially when designing proteins that must function under non-ambient conditions, such as high temperature, extreme pH, or in various ionic solvents. To address this issue, we propose a new Physics-Informed Neural Networks (PINNs)-based protein sequence design approach. Our approach combines all-atom molecular dynamics simulations, a PINNs MD surrogate model, and a relaxation of binary programming to solve the protein design task while optimizing both energy and the structural stability of proteins. We demonstrate the effectiveness of our design framework in designing proteins that can function under non-ambient conditions. Full article

(This article belongs to the Special Issue Advances in Drug Design and Development for Human Therapeutics Using Artificial Intelligence II)

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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 41 | Viewed by 8654

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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23 pages, 2023 KiB

Open AccessEditor’s ChoiceReview

Industrial Production of Proteins with Pichia pastoris—Komagataella phaffii

by Giovanni Davide Barone, Anita Emmerstorfer-Augustin, Antonino Biundo, Isabella Pisano, Paola Coccetti, Valeria Mapelli and Andrea Camattari

Biomolecules 2023, 13(3), 441; https://doi.org/10.3390/biom13030441 - 26 Feb 2023

Cited by 72 | Viewed by 14514

Abstract

Since the mid-1960s, methylotrophic yeast Komagataella phaffii (previously described as Pichia pastoris) has received increasing scientific attention. The interest for the industrial production of proteins for different applications (e.g., feed, food additives, detergent, waste treatment processes, and textile) is a well-consolidated scientific topic, [...] Read more.

Since the mid-1960s, methylotrophic yeast Komagataella phaffii (previously described as Pichia pastoris) has received increasing scientific attention. The interest for the industrial production of proteins for different applications (e.g., feed, food additives, detergent, waste treatment processes, and textile) is a well-consolidated scientific topic, and the importance for this approach is rising in the current era of environmental transition in human societies. This review aims to summarize fundamental and specific information in this scientific field. Additionally, an updated description of the relevant products produced with K. phaffii at industrial levels by a variety of companies—describing how the industry has leveraged its key features, from products for the ingredients of meat-free burgers (e.g., IMPOSSIBLE™ FOODS, USA) to diabetes therapeutics (e.g., Biocon, India)—is provided. Furthermore, active patents and the typical workflow for industrial protein production with this strain are reported. Full article

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

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16 pages, 2074 KiB

Open AccessEditor’s ChoiceArticle

LC-MS/MS-Based Proteomics Approach for the Identification of Candidate Serum Biomarkers in Patients with Narcolepsy Type 1

by Akeem Sanni, Mona Goli, Jingfu Zhao, Junyao Wang, Chloe Barsa, Samer El Hayek, Farid Talih, Bartolo Lanuzza, Firas Kobeissy, Giuseppe Plazzi, Monica Moresco, Stefania Mondello, Raffaele Ferri and Yehia Mechref

Biomolecules 2023, 13(3), 420; https://doi.org/10.3390/biom13030420 - 23 Feb 2023

Cited by 13 | Viewed by 7562

Abstract

Narcolepsy type 1 (NT1) is the most common type of narcolepsy known to be caused by the loss of specific neurons responsible for producing peptide neurotransmitters (orexins/hypocretins), resulting in a sleep-wake cycle disorder. It is characterized by its association with cataplexy and abnormalities [...] Read more.

Narcolepsy type 1 (NT1) is the most common type of narcolepsy known to be caused by the loss of specific neurons responsible for producing peptide neurotransmitters (orexins/hypocretins), resulting in a sleep-wake cycle disorder. It is characterized by its association with cataplexy and abnormalities in rapid eye movement. To date, no cure has been established for this life-threatening condition. Misdiagnosis of NT1 is also quite common, although it is not exceedingly rare. Therefore, successfully identifying candidate serum biomarkers for NT1 would be a head start for accurate diagnosis and development of therapeutics for this disorder. This study aims to identify such potential serum biomarkers. A depletion protocol was employed for 27 human serum samples (16 NT1 and 11 healthy controls), followed by applying LC-MS/MS bottom-up proteomics analysis, then LC-PRM-MS for validation. The comparison of the proteome profiles of the low-abundant proteins in the samples was then investigated based on age, sex, sample groups, and the presence of the Human Leukocyte Antigen (HLA) DQB1*0602 allele. The results were tracked to gene expression studies as well as system biology to identify key proteins and understand their relationship in the pathogenesis of NT1. Our results revealed 36 proteins significantly and differentially expressed. Among the impaired pathways and bioprocesses, the complement activation pathway is impaired by six of the differentially expressed proteins (DEPs). They are coded by the genes C2, CFB, C5, C1R, C1S, and MASP1, while 11 DEPs are involved in Acute Phase Response Signaling (APRS), which are coded by the genes FN1, AMBP, APOH, CFB, CP, ITIH2, C5, C2, F2, C1, and ITIH4. The combined AUCs of the downregulated and upregulated DEPs are 0.95 and 0.76, respectively. Overall, this study reveals potential serum-protein biomarkers of NT1 and explains the possible correlation between the biomarkers and pathophysiological effects, as well as important biochemical pathways involved in NT1. Full article

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17 pages, 745 KiB

Open AccessEditor’s ChoiceReview

Molecular Targets in Campylobacter Infections

by Markus M. Heimesaat, Steffen Backert, Thomas Alter and Stefan Bereswill

Biomolecules 2023, 13(3), 409; https://doi.org/10.3390/biom13030409 - 22 Feb 2023

Cited by 17 | Viewed by 5458

Abstract

Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients [...] Read more.

Human campylobacteriosis results from foodborne infections with Campylobacter bacteria such as Campylobacter jejuni and Campylobacter coli, and represents a leading cause of bacterial gastroenteritis worldwide. After consumption of contaminated poultry meat, constituting the major source of pathogenic transfer to humans, infected patients develop abdominal pain and diarrhea. Post-infectious disorders following acute enteritis may occur and affect the nervous system, the joints or the intestines. Immunocompromising comorbidities in infected patients favor bacteremia, leading to vascular inflammation and septicemia. Prevention of human infection is achieved by hygiene measures focusing on the reduction of pathogenic food contamination. Molecular targets for the treatment and prevention of campylobacteriosis include bacterial pathogenicity and virulence factors involved in motility, adhesion, invasion, oxygen detoxification, acid resistance and biofilm formation. This repertoire of intervention measures has recently been completed by drugs dampening the pro-inflammatory immune responses induced by the Campylobacter endotoxin lipo-oligosaccharide. Novel pharmaceutical strategies will combine anti-pathogenic and anti-inflammatory effects to reduce the risk of both anti-microbial resistance and post-infectious sequelae of acute enteritis. Novel strategies and actual trends in the combat of Campylobacter infections are presented in this review, alongside molecular targets applied for prevention and treatment strategies. Full article

(This article belongs to the Special Issue Molecular Targets in Campylobacter Infections)

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20 pages, 1533 KiB

Open AccessEditor’s ChoiceReview

Cellular Pathogenesis of Hepatic Encephalopathy: An Update

by Kaihui Lu

Biomolecules 2023, 13(2), 396; https://doi.org/10.3390/biom13020396 - 19 Feb 2023

Cited by 30 | Viewed by 17399

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been [...] Read more.

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions. Full article

(This article belongs to the Special Issue The Contribution of Astrocytes to Neuropathology)

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23 pages, 2110 KiB

Open AccessEditor’s ChoiceArticle

Using GPT-3 to Build a Lexicon of Drugs of Abuse Synonyms for Social Media Pharmacovigilance

by Kristy A. Carpenter and Russ B. Altman

Biomolecules 2023, 13(2), 387; https://doi.org/10.3390/biom13020387 - 18 Feb 2023

Cited by 20 | Viewed by 6194

Abstract

Drug abuse is a serious problem in the United States, with over 90,000 drug overdose deaths nationally in 2020. A key step in combating drug abuse is detecting, monitoring, and characterizing its trends over time and location, also known as pharmacovigilance. While federal [...] Read more.

Drug abuse is a serious problem in the United States, with over 90,000 drug overdose deaths nationally in 2020. A key step in combating drug abuse is detecting, monitoring, and characterizing its trends over time and location, also known as pharmacovigilance. While federal reporting systems accomplish this to a degree, they often have high latency and incomplete coverage. Social-media-based pharmacovigilance has zero latency, is easily accessible and unfiltered, and benefits from drug users being willing to share their experiences online pseudo-anonymously. However, unlike highly structured official data sources, social media text is rife with misspellings and slang, making automated analysis difficult. Generative Pretrained Transformer 3 (GPT-3) is a large autoregressive language model specialized for few-shot learning that was trained on text from the entire internet. We demonstrate that GPT-3 can be used to generate slang and common misspellings of terms for drugs of abuse. We repeatedly queried GPT-3 for synonyms of drugs of abuse and filtered the generated terms using automated Google searches and cross-references to known drug names. When generated terms for alprazolam were manually labeled, we found that our method produced 269 synonyms for alprazolam, 221 of which were new discoveries not included in an existing drug lexicon for social media. We repeated this process for 98 drugs of abuse, of which 22 are widely-discussed drugs of abuse, building a lexicon of colloquial drug synonyms that can be used for pharmacovigilance on social media. Full article

(This article belongs to the Special Issue Biomolecular Data Science—in Honor of Professor Philip E. Bourne)

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14 pages, 1452 KiB

Open AccessEditor’s ChoiceReview

Granzyme B in Autoimmune Skin Disease

by Anna Gleave and David J. Granville

Biomolecules 2023, 13(2), 388; https://doi.org/10.3390/biom13020388 - 18 Feb 2023

Cited by 18 | Viewed by 5129

Abstract

Autoimmune diseases often present with cutaneous symptoms that contribute to dysfunction, disfigurement, and in many cases, reduced quality-of-life. Unfortunately, treatment options for many autoimmune skin diseases are limited. Local and systemic corticosteroids remain the current standard-of-care but are associated with significant adverse effects. [...] Read more.

Autoimmune diseases often present with cutaneous symptoms that contribute to dysfunction, disfigurement, and in many cases, reduced quality-of-life. Unfortunately, treatment options for many autoimmune skin diseases are limited. Local and systemic corticosteroids remain the current standard-of-care but are associated with significant adverse effects. Hence, there is an unmet need for novel therapies that block molecular drivers of disease in a local and/or targeted manner. Granzyme B (GzmB) is a serine protease with known cytotoxic activity and emerging extracellular functions, including the cleavage of cell–cell junctions, basement membranes, cell receptors, and other structural proteins. While minimal to absent in healthy skin, GzmB is markedly elevated in alopecia areata, interface dermatitis, pemphigoid disease, psoriasis, systemic sclerosis, and vitiligo. This review will discuss the role of GzmB in immunity, blistering, apoptosis, and barrier dysfunction in the context of autoimmune skin disease. GzmB plays a causal role in the development of pemphigoid disease and carries diagnostic and prognostic significance in cutaneous lupus erythematosus, vitiligo, and alopecia areata. Taken together, these data support GzmB as a promising therapeutic target for autoimmune skin diseases impacted by impaired barrier function, inflammation, and/or blistering. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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22 pages, 1726 KiB

Open AccessEditor’s ChoiceReview

Mitochondrial Neurodegeneration: Lessons from Drosophila melanogaster Models

by Michele Brischigliaro, Erika Fernandez-Vizarra and Carlo Viscomi

Biomolecules 2023, 13(2), 378; https://doi.org/10.3390/biom13020378 - 16 Feb 2023

Cited by 8 | Viewed by 8517

Abstract

The fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely [...] Read more.

The fruit fly—i.e., Drosophila melanogaster—has proven to be a very useful model for the understanding of basic physiological processes, such as development or ageing. The availability of straightforward genetic tools that can be used to produce engineered individuals makes this model extremely interesting for the understanding of the mechanisms underlying genetic diseases in physiological models. Mitochondrial diseases are a group of yet-incurable genetic disorders characterized by the malfunction of the oxidative phosphorylation system (OXPHOS), which is the highly conserved energy transformation system present in mitochondria. The generation of D. melanogaster models of mitochondrial disease started relatively recently but has already provided relevant information about the molecular mechanisms and pathological consequences of mitochondrial dysfunction. Here, we provide an overview of such models and highlight the relevance of D. melanogaster as a model to study mitochondrial disorders. Full article

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

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15 pages, 2604 KiB

Open AccessEditor’s ChoiceReview

Opposing Roles of FACT for Euchromatin and Heterochromatin in Yeast

by Shinya Takahata and Yota Murakami

Biomolecules 2023, 13(2), 377; https://doi.org/10.3390/biom13020377 - 16 Feb 2023

Cited by 3 | Viewed by 3929

Abstract

DNA is stored in the nucleus of a cell in a folded state; however, only the necessary genetic information is extracted from the required group of genes. The key to extracting genetic information is chromatin ambivalence. Depending on the chromosomal region, chromatin is [...] Read more.

DNA is stored in the nucleus of a cell in a folded state; however, only the necessary genetic information is extracted from the required group of genes. The key to extracting genetic information is chromatin ambivalence. Depending on the chromosomal region, chromatin is characterized into low-density “euchromatin” and high-density “heterochromatin”, with various factors being involved in its regulation. Here, we focus on chromatin regulation and gene expression by the yeast FACT complex, which functions in both euchromatin and heterochromatin. FACT is known as a histone H2A/H2B chaperone and was initially reported as an elongation factor associated with RNA polymerase II. In budding yeast, FACT activates promoter chromatin by interacting with the transcriptional activators SBF/MBF via the regulation of G1/S cell cycle genes. In fission yeast, FACT plays an important role in the formation of higher-order chromatin structures and transcriptional repression by binding to Swi6, an HP1 family protein, at heterochromatin. This FACT property, which refers to the alternate chromatin-regulation depending on the binding partner, is an interesting phenomenon. Further analysis of nucleosome regulation within heterochromatin is expected in future studies. Full article

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

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14 pages, 541 KiB

Open AccessEditor’s ChoiceReview

Complement as a Biomarker for Systemic Lupus Erythematosus

by Masahiro Ayano and Takahiko Horiuchi

Biomolecules 2023, 13(2), 367; https://doi.org/10.3390/biom13020367 - 15 Feb 2023

Cited by 41 | Viewed by 14736

Abstract

Systemic lupus erythematosus (SLE) is a disease of immune complex deposition; therefore, complement plays a vital role in the pathogenesis of SLE. In general, complement levels in blood and complement deposition in histological tests are used for the management of SLE. Thus, the [...] Read more.

Systemic lupus erythematosus (SLE) is a disease of immune complex deposition; therefore, complement plays a vital role in the pathogenesis of SLE. In general, complement levels in blood and complement deposition in histological tests are used for the management of SLE. Thus, the evaluation of complement status can be useful in the diagnosis of SLE, assessment of disease activity, and prediction of treatment response and prognosis. In addition, novel complement biomarkers, such as split products and cell-bound complement activation products, are considered to be more sensitive than traditional complement markers, such as serum C3 and C4 levels and total complement activity (CH50), which become more widely used. In this review, we report the complement testing in the management of SLE over the last decade and summarize their utility. Full article

(This article belongs to the Special Issue Biomarkers in Systemic Lupus Erythematosus)

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17 pages, 9451 KiB

Open AccessEditor’s ChoiceArticle

Commonly Used Therapeutics Associated with Changes in Arousal Inhibit GABA_AR Activation

by Anling Kaplan, Abigail I. Nash, Amanda A. H. Freeman, Lauren G. Lewicki, David B. Rye, Lynn Marie Trotti, Asher L. Brandt and Andrew Jenkins

Biomolecules 2023, 13(2), 365; https://doi.org/10.3390/biom13020365 - 15 Feb 2023

Cited by 6 | Viewed by 4015

Abstract

GABA_A receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABA_A receptor negative allosteric modulators (GABA_ARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABA [...] Read more.

GABA_A receptor-positive modulators are well-known to induce sedation, sleep, and general anesthesia. Conversely, GABA_A receptor negative allosteric modulators (GABA_ARNAMs) can increase arousal and induce seizures. Motivated by our studies with patients with hypersomnia, and our discovery that two GABA_ARNAMs can restore the Excitation/Inhibition (E/I) balance in vitro and arousal in vivo, we chose to screen 11 compounds that have been reported to modulate arousal, to see if they shared a GABA-related mechanism. We determined modulation with both conventional and microfluidic patch clamp methods. We found that receptor activation was variably modulated by all 11 compounds: Rifampicin (RIF), Metronidazole (MET), Minocycline (MIN), Erythromycin (ERY), Ofloxacin (OFX), Chloroquine (CQ), Hydroxychloroquine sulfate (HCQ), Flumazenil (FLZ), Pentylenetetrazol (PTZ), (-)-Epigallocatechin Gallate (EGCG), and clarithromycin (CLR). The computational modeling of modulator–receptor interactions predicted drug action at canonical binding sites and novel orphan sites on the receptor. Our findings suggest that multiple avenues of investigation are now open to investigate large and brain-penetrant molecules for the treatment of patients with diminished CNS E/I balance. Full article

(This article belongs to the Special Issue GABA(A) Receptors: Structure and Function)

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19 pages, 2944 KiB

Open AccessEditor’s ChoiceReview

Schizophrenia Animal Modeling with Epidermal Growth Factor and Its Homologs: Their Connections to the Inflammatory Pathway and the Dopamine System

by Hidekazu Sotoyama, Hisaaki Namba, Manavu Tohmi and Hiroyuki Nawa

Biomolecules 2023, 13(2), 372; https://doi.org/10.3390/biom13020372 - 15 Feb 2023

Cited by 12 | Viewed by 4151

Abstract

Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the [...] Read more.

Epidermal growth factor (EGF) and its homologs, such as neuregulins, bind to ErbB (Her) receptor kinases and regulate glial differentiation and dopaminergic/GABAergic maturation in the brain and are therefore implicated in schizophrenia neuropathology involving these cell abnormalities. In this review, we summarize the biological activities of the EGF family and its neuropathologic association with schizophrenia, mainly overviewing our previous model studies and the related articles. Transgenic mice as well as the rat/monkey models established by perinatal challenges of EGF or its homologs consistently exhibit various behavioral endophenotypes relevant to schizophrenia. In particular, post-pubertal elevation in baseline dopaminergic activity may illustrate the abnormal behaviors relevant to positive and negative symptoms as well as to the timing of this behavioral onset. With the given molecular interaction and transactivation of ErbB receptor kinases with Toll-like receptors (TLRs), EGF/ErbB signals are recruited by viral infection and inflammatory diseases such as COVID-19-mediated pneumonia and poxvirus-mediated fibroma and implicated in the immune–inflammatory hypothesis of schizophrenia. Finally, we also discuss the interaction of clozapine with ErbB receptor kinases as well as new antipsychotic development targeting these receptors. Full article

(This article belongs to the Special Issue Neurotrophic Factors and Growth Factors - Historical Perspective and New Directions for Medical Use)

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21 pages, 2296 KiB

Open AccessEditor’s ChoiceArticle

Targeting of the Interleukin-13 Receptor (IL-13R)α2 Expressing Prostate Cancer by a Novel Hybrid Lytic Peptide

by Riaz Jannoo, Zhidao Xia, Paula E. Row and Venkateswarlu Kanamarlapudi

Biomolecules 2023, 13(2), 356; https://doi.org/10.3390/biom13020356 - 12 Feb 2023

Cited by 7 | Viewed by 2707

Abstract

The IL-13Rα2 cell surface receptor is highly expressed in tumours such as prostate cancer. In this report, we evaluated the hypothesis that prostate cancer cells with enhanced IL-13Rα2 expression are a suitable target for the hybrid lytic peptide (Pep-1-Phor21) peptide, which is generated [...] Read more.

The IL-13Rα2 cell surface receptor is highly expressed in tumours such as prostate cancer. In this report, we evaluated the hypothesis that prostate cancer cells with enhanced IL-13Rα2 expression are a suitable target for the hybrid lytic peptide (Pep-1-Phor21) peptide, which is generated by fusing the IL-13Rα2 specific ligand (Pep-1) and a cell membrane disrupting lytic peptide (Phor21). The expression of IL-13Rα2 mRNA and protein in prostate cancer tissues and cell lines was assessed via real-time PCR (RT-PCR) and immunoblotting. The effect of Pep-1-Phor21 on the viability of prostate cancer cells grown in monolayers (2D) and microtissue spheroids (3D) was assessed via CellTox green cytotoxic assay. IL-13Rα2 expression and Pep-1-Phor21-mediated killing were also determined in the cells treated with epigenetic regulators (Trichostatin A (TSA) and 5-aza-2 deoxycytidine (5-Aza-dC)). The hybrid lytic peptide cytotoxic activity correlated with the expression of IL-13Rα2 in prostate cancer cell lines cultured as monolayers (2D) or 3D spheroids. In addition, TSA or 5-Aza-dC treatment of prostate cancer cells, particularly those with low expression of IL-13Rα2, enhanced the cells’ sensitivity to the lytic peptide by increasing IL-13Rα2 expression. These results demonstrate that the Pep-1-Phor21 hybrid lytic peptide has potent and selective anticancer properties against IL-13Rα2-expressing prostate cancer cells. Full article

(This article belongs to the Special Issue Functional Peptides and Their Interactions: From Molecules to Systems)

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20 pages, 44518 KiB

Open AccessEditor’s ChoiceArticle

Mechanistic Analysis of CCP1 in Generating ΔC2 α-Tubulin in Mammalian Cells and Photoreceptor Neurons

by Takashi Hotta, Alexandra Plemmons, Margo Gebbie, Trevor A. Ziehm, Teresa Lynne Blasius, Craig Johnson, Kristen J. Verhey, Jillian N. Pearring and Ryoma Ohi

Biomolecules 2023, 13(2), 357; https://doi.org/10.3390/biom13020357 - 12 Feb 2023

Cited by 5 | Viewed by 2924

Abstract

An important post-translational modification (PTM) of α-tubulin is the removal of amino acids from its C-terminus. Removal of the C-terminal tyrosine residue yields detyrosinated α-tubulin, and subsequent removal of the penultimate glutamate residue produces ΔC2-α-tubulin. These PTMs alter the ability of the α-tubulin [...] Read more.

An important post-translational modification (PTM) of α-tubulin is the removal of amino acids from its C-terminus. Removal of the C-terminal tyrosine residue yields detyrosinated α-tubulin, and subsequent removal of the penultimate glutamate residue produces ΔC2-α-tubulin. These PTMs alter the ability of the α-tubulin C-terminal tail to interact with effector proteins and are thereby thought to change microtubule dynamics, stability, and organization. The peptidase(s) that produces ΔC2-α-tubulin in a physiological context remains unclear. Here, we take advantage of the observation that ΔC2-α-tubulin accumulates to high levels in cells lacking tubulin tyrosine ligase (TTL) to screen for cytosolic carboxypeptidases (CCPs) that generate ΔC2-α-tubulin. We identify CCP1 as the sole peptidase that produces ΔC2-α-tubulin in TTLΔ HeLa cells. Interestingly, we find that the levels of ΔC2-α-tubulin are only modestly reduced in photoreceptors of ccp1^−/− mice, indicating that other peptidases act synergistically with CCP1 to produce ΔC2-α-tubulin in post-mitotic cells. Moreover, the production of ΔC2-α-tubulin appears to be under tight spatial control in the photoreceptor cilium: ΔC2-α-tubulin persists in the connecting cilium of ccp1^−/− but is depleted in the distal portion of the photoreceptor. This work establishes the groundwork to pinpoint the function of ΔC2-α-tubulin in proliferating and post-mitotic mammalian cells. Full article

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

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15 pages, 4316 KiB

Open AccessEditor’s ChoiceArticle

Time- and Sex-Dependent Effects of Fingolimod Treatment in a Mouse Model of Alzheimer’s Disease

by Pablo Bascuñana, Mirjam Brackhan, Luisa Möhle, Jingyun Wu, Thomas Brüning, Ivan Eiriz, Baiba Jansone and Jens Pahnke

Biomolecules 2023, 13(2), 331; https://doi.org/10.3390/biom13020331 - 9 Feb 2023

Cited by 10 | Viewed by 3410

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia. Fingolimod has previously shown beneficial effects in different animal models of AD. However, it has shown contradictory effects when it has been applied at early disease stages. Our objective was to evaluate fingolimod in two different treatment paradigms. To address this aim, we treated male and female APP-transgenic mice for 50 days, starting either before plaque deposition at 50 days of age (early) or at 125 days of age (late). To evaluate the effects, we investigated the neuroinflammatory and glial markers, the Aβ load, and the concentration of the brain-derived neurotrophic factor (BDNF). We found a reduced Aβ load only in male animals in the late treatment paradigm. These animals also showed reduced microglia activation and reduced IL-1β. No other treatment group showed any difference in comparison to the controls. On the other hand, we detected a linear correlation between BDNF and the brain Aβ concentrations. The fingolimod treatment has shown beneficial effects in AD models, but the outcome depends on the neuroinflammatory state at the start of the treatment. Thus, according to our data, a fingolimod treatment would be effective after the onset of the first AD symptoms, mainly affecting the neuroinflammatory reaction to the ongoing Aβ deposition. Full article

(This article belongs to the Special Issue New Advances in the Molecular Mechanism and Target Therapy in Alzheimer’s Diseases)

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18 pages, 2619 KiB

Open AccessEditor’s ChoiceArticle

Novel Green Fluorescent Polyamines to Analyze ATP13A2 and ATP13A3 Activity in the Mammalian Polyamine Transport System

by Marine Houdou, Nathalie Jacobs, Jonathan Coene, Mujahid Azfar, Roeland Vanhoutte, Chris Van den Haute, Jan Eggermont, Veronique Daniëls, Steven H. L. Verhelst and Peter Vangheluwe

Biomolecules 2023, 13(2), 337; https://doi.org/10.3390/biom13020337 - 9 Feb 2023

Cited by 14 | Viewed by 4400

Abstract

Cells acquire polyamines putrescine (PUT), spermidine (SPD) and spermine (SPM) via the complementary actions of polyamine uptake and synthesis pathways. The endosomal P_5B-type ATPases ATP13A2 and ATP13A3 emerge as major determinants of mammalian polyamine uptake. Our biochemical evidence shows that fluorescently [...] Read more.

Cells acquire polyamines putrescine (PUT), spermidine (SPD) and spermine (SPM) via the complementary actions of polyamine uptake and synthesis pathways. The endosomal P_5B-type ATPases ATP13A2 and ATP13A3 emerge as major determinants of mammalian polyamine uptake. Our biochemical evidence shows that fluorescently labeled polyamines are genuine substrates of ATP13A2. They can be used to measure polyamine uptake in ATP13A2- and ATP13A3-dependent cell models resembling radiolabeled polyamine uptake. We further report that ATP13A3 enables faster and stronger cellular polyamine uptake than does ATP13A2. We also compared the uptake of new green fluorescent PUT, SPD and SPM analogs using different coupling strategies (amide, triazole or isothiocyanate) and fluorophores (symmetrical BODIPY, BODIPY-FL and FITC). ATP13A2 promotes the uptake of various SPD and SPM analogs, whereas ATP13A3 mainly stimulates the uptake of PUT and SPD conjugates. However, the polyamine linker and coupling position on the fluorophore impacts the transport capacity, whereas replacing the fluorophore affects polyamine selectivity. The highest uptake in ATP13A2 or ATP13A3 cells is observed with BODIPY-FL-amide conjugated to SPD, whereas BODIPY-PUT analogs are specifically taken up via ATP13A3. We found that P_5B-type ATPase isoforms transport fluorescently labeled polyamine analogs with a distinct structure–activity relationship (SAR), suggesting that isoform-specific polyamine probes can be designed. Full article

(This article belongs to the Special Issue Polyamine Metabolism and Function)

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19 pages, 2650 KiB

Open AccessEditor’s ChoiceArticle

Do Amino Acid Antiporters Have Asymmetric Substrate Specificity?

by Gregory Gauthier-Coles, Stephen J. Fairweather, Angelika Bröer and Stefan Bröer

Biomolecules 2023, 13(2), 301; https://doi.org/10.3390/biom13020301 - 6 Feb 2023

Cited by 9 | Viewed by 2650

Abstract

Amino acid antiporters mediate the 1:1 exchange of groups of amino acids. Whether substrate specificity can be different for the inward and outward facing conformation has not been investigated systematically, although examples of asymmetric transport have been reported. Here we used LC–MS to [...] Read more.

Amino acid antiporters mediate the 1:1 exchange of groups of amino acids. Whether substrate specificity can be different for the inward and outward facing conformation has not been investigated systematically, although examples of asymmetric transport have been reported. Here we used LC–MS to detect the movement of ¹²C- and ¹³C-labelled amino acid mixtures across the plasma membrane of Xenopus laevis oocytes expressing a variety of amino acid antiporters. Differences of substrate specificity between transporter paralogs were readily observed using this method. Our results suggest that antiporters are largely symmetric, equalizing the pools of their substrate amino acids. Exceptions are the antiporters y⁺LAT1 and y⁺LAT2 where neutral amino acids are co-transported with Na⁺ ions, favouring their import. For the antiporters ASCT1 and ASCT2 glycine acted as a selective influx substrate, while proline was a selective influx substrate of ASCT1. These data show that antiporters can display non-canonical modes of transport. Full article

(This article belongs to the Special Issue Recent Advances in Amino Acid Transporters)

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17 pages, 3315 KiB

Open AccessEditor’s ChoiceReview

The Actin Network Interfacing Diverse Integrin-Mediated Adhesions

by Benjamin Geiger, Rajaa Boujemaa-Paterski, Sabina E. Winograd-Katz, Jubina Balan Venghateri, Wen-Lu Chung and Ohad Medalia

Biomolecules 2023, 13(2), 294; https://doi.org/10.3390/biom13020294 - 4 Feb 2023

Cited by 12 | Viewed by 4597

Abstract

The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and mechanical sensors of the cell’s microenvironment. Focal adhesion-like structures of diverse cell types, podosomes in osteoclasts, and invadopodia of [...] Read more.

The interface between the cellular actin network and diverse forms of integrin-mediated cell adhesions displays a unique capacity to serve as accurate chemical and mechanical sensors of the cell’s microenvironment. Focal adhesion-like structures of diverse cell types, podosomes in osteoclasts, and invadopodia of invading cancer cells display distinct morphologies and apparent functions. Yet, all three share a similar composition and mode of coupling between a protrusive structure (the lamellipodium, the core actin bundle of the podosome, and the invadopodia protrusion, respectively), and a nearby adhesion site. Cytoskeletal or external forces, applied to the adhesion sites, trigger a cascade of unfolding and activation of key adhesome components (e.g., talin, vinculin, integrin), which in turn, trigger the assembly of adhesion sites and generation of adhesion-mediated signals that affect cell behavior and fate. The structural and molecular mechanisms underlying the dynamic crosstalk between the actin cytoskeleton and the adhesome network are discussed. Full article

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

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19 pages, 2829 KiB

Open AccessEditor’s ChoiceArticle

Copper Binding and Redox Activity of α-Synuclein in Membrane-Like Environment

by Chiara Bacchella, Francesca Camponeschi, Paulina Kolkowska, Arian Kola, Isabella Tessari, Maria Camilla Baratto, Marco Bisaglia, Enrico Monzani, Luigi Bubacco, Stefano Mangani, Luigi Casella, Simone Dell’Acqua and Daniela Valensin

Biomolecules 2023, 13(2), 287; https://doi.org/10.3390/biom13020287 - 3 Feb 2023

Cited by 12 | Viewed by 3071

Abstract

α-Synuclein (αSyn) constitutes the main protein component of Lewy bodies, which are the pathologic hallmark in Parkinson’s disease. αSyn is unstructured in solution but the interaction of αSyn with lipid membrane modulates its conformation by inducing an α-helical structure of the N-terminal [...] Read more.

α-Synuclein (αSyn) constitutes the main protein component of Lewy bodies, which are the pathologic hallmark in Parkinson’s disease. αSyn is unstructured in solution but the interaction of αSyn with lipid membrane modulates its conformation by inducing an α-helical structure of the N-terminal region. In addition, the interaction with metal ions can trigger αSyn conformation upon binding and/or through the metal-promoted generation of reactive oxygen species which lead to a cascade of structural alterations. For these reasons, the ternary interaction between αSyn, copper, and membranes needs to be elucidated in detail. Here, we investigated the structural properties of copper-αSyn binding through NMR, EPR, and XAS analyses, with particular emphasis on copper(I) coordination since the reduced state is particularly relevant for oxygen activation chemistry. The analysis was performed in different membrane model systems, such as micellar sodium dodecyl sulfate (SDS) and unilamellar vesicles, comparing the binding of full-length αSyn and N-terminal peptide fragments. The presence of membrane-like environments induced the formation of a copper:αSyn = 1:2 complex where Cu⁺ was bound to the Met1 and Met5 residues of two helical peptide chains. In this coordination, Cu⁺ is stabilized and is unreactive in the presence of O₂ in catechol substrate oxidation. Full article

(This article belongs to the Special Issue Synuclein Proteins, 2nd Edition)

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18 pages, 1505 KiB

Open AccessEditor’s ChoiceReview

Comparative Research: Regulatory Mechanisms of Ribosomal Gene Transcription in Saccharomyces cerevisiae and Schizosaccharomyces pombe

by Hayato Hirai and Kunihiro Ohta

Biomolecules 2023, 13(2), 288; https://doi.org/10.3390/biom13020288 - 3 Feb 2023

Cited by 8 | Viewed by 4311

Abstract

Restricting ribosome biosynthesis and assembly in response to nutrient starvation is a universal phenomenon that enables cells to survive with limited intracellular resources. When cells experience starvation, nutrient signaling pathways, such as the target of rapamycin (TOR) and protein kinase A (PKA), become [...] Read more.

Restricting ribosome biosynthesis and assembly in response to nutrient starvation is a universal phenomenon that enables cells to survive with limited intracellular resources. When cells experience starvation, nutrient signaling pathways, such as the target of rapamycin (TOR) and protein kinase A (PKA), become quiescent, leading to several transcription factors and histone modification enzymes cooperatively and rapidly repressing ribosomal genes. Fission yeast has factors for heterochromatin formation similar to mammalian cells, such as H3K9 methyltransferase and HP1 protein, which are absent in budding yeast. However, limited studies on heterochromatinization in ribosomal genes have been conducted on fission yeast. Herein, we shed light on and compare the regulatory mechanisms of ribosomal gene transcription in two species with the latest insights. Full article

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

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16 pages, 1862 KiB

Open AccessEditor’s ChoiceReview

Recent Developments in Biopolymer-Based Hydrogels for Tissue Engineering Applications

by Rikako Hama, Anudari Ulziibayar, James W. Reinhardt, Tatsuya Watanabe, John Kelly and Toshiharu Shinoka

Biomolecules 2023, 13(2), 280; https://doi.org/10.3390/biom13020280 - 2 Feb 2023

Cited by 68 | Viewed by 5972

Abstract

Hydrogels are being investigated for their application in inducing the regeneration of various tissues, and suitable conditions for each tissue are becoming more apparent. Conditions such as the mechanical properties, degradation period, degradation mechanism, and cell affinity can be tailored by changing the [...] Read more.

Hydrogels are being investigated for their application in inducing the regeneration of various tissues, and suitable conditions for each tissue are becoming more apparent. Conditions such as the mechanical properties, degradation period, degradation mechanism, and cell affinity can be tailored by changing the molecular structure, especially in the case of polymers. Furthermore, many high-functional hydrogels with drug delivery systems (DDSs), in which drugs or bioactive substances are contained in controlled hydrogels, have been reported. This review focuses on the molecular design and function of biopolymer-based hydrogels and introduces recent developments in functional hydrogels for clinical applications. Full article

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

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17 pages, 5756 KiB

Open AccessEditor’s ChoiceArticle

Oligodendrocytes Prune Axons Containing α-Synuclein Aggregates In Vivo: Lewy Neurites as Precursors of Glial Cytoplasmic Inclusions in Multiple System Atrophy?

by Francesco De Nuccio, Marianna Kashyrina, Francesca Serinelli, Florent Laferrière, Dario Domenico Lofrumento, Francesca De Giorgi and François Ichas

Biomolecules 2023, 13(2), 269; https://doi.org/10.3390/biom13020269 - 1 Feb 2023

Cited by 9 | Viewed by 8886

Abstract

α-Synucleinopathies are spreading neurodegenerative disorders characterized by the intracellular accumulation of insoluble aggregates populated by α-Synuclein (α-Syn) fibrils. In Parkinson’s disease (PD) and dementia with Lewy bodies, intraneuronal α-Syn aggregates are referred to as Lewy bodies in the somata and as Lewy neurites [...] Read more.

α-Synucleinopathies are spreading neurodegenerative disorders characterized by the intracellular accumulation of insoluble aggregates populated by α-Synuclein (α-Syn) fibrils. In Parkinson’s disease (PD) and dementia with Lewy bodies, intraneuronal α-Syn aggregates are referred to as Lewy bodies in the somata and as Lewy neurites in the neuronal processes. In multiple system atrophy (MSA) α-Syn aggregates are also found within mature oligodendrocytes (OLs) where they form Glial Cytoplasmic Inclusions (GCIs). However, the origin of GCIs remains enigmatic: (i) mature OLs do not express α-Syn, precluding the seeding and the buildup of inclusions and (ii) the artificial overexpression of α-Syn in OLs of transgenic mice results in a burden of soluble phosphorylated α-Syn but fails to form α-Syn fibrils. In contrast, mass spectrometry of α-Syn fibrillar aggregates from MSA patients points to the neuronal origin of the proteins intimately associated with the fibrils within the GCIs. This suggests that GCIs are preassembled in neurons and only secondarily incorporated into OLs. Interestingly, we recently isolated a synthetic human α-Syn fibril strain (1B fibrils) capable of seeding a type of neuronal inclusion observed early and specifically during MSA. Our goal was thus to investigate whether the neuronal α-Syn pathology seeded by 1B fibrils could eventually be transmitted to OLs to form GCIs in vivo. After confirming that mature OLs did not express α-Syn to detectable levels in the adult mouse brain, a series of mice received unilateral intra-striatal injections of 1B fibrils. The resulting α-Syn pathology was visualized using phospho-S129 α-Syn immunoreactivity (pSyn). We found that even though 1B fibrils were injected unilaterally, many pSyn-positive neuronal somas were present in layer V of the contralateral perirhinal cortex after 6 weeks. This suggested a fast retrograde spread of the pathology along the axons of crossing cortico-striatal neurons. We thus scrutinized the posterior limb of the anterior commissure, i.e., the myelinated interhemispheric tract containing the axons of these neurons: we indeed observed numerous pSyn-positive linear Lewy Neurites oriented parallel to the commissural axis, corresponding to axonal segments filled with aggregated α-Syn, with no obvious signs of OL α-Syn pathology at this stage. After 6 months however, the commissural Lewy neurites were no longer parallel but fragmented, curled up, sometimes squeezed in-between two consecutive OLs in interfascicular strands, or even engulfed inside OL perikarya, thus forming GCIs. We conclude that the 1B fibril strain can rapidly induce an α-Syn pathology typical of MSA in mice, in which the appearance of GCIs results from the pruning of diseased axonal segments containing aggregated α-Syn. Full article

(This article belongs to the Special Issue α-Synuclein Amyloids & Parkinson’s Disease: On Growth, Spread, and Neurodegeneration 2.0)

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18 pages, 5401 KiB

Open AccessEditor’s ChoiceArticle

Oxaliplatin-Induced Damage to the Gastric Innervation: Role in Nausea and Vomiting

by Ahmed A. Rahman, Philenkosini Masango, Rhian Stavely, Paul Bertrand, Amanda Page and Kulmira Nurgali

Biomolecules 2023, 13(2), 276; https://doi.org/10.3390/biom13020276 - 1 Feb 2023

Cited by 9 | Viewed by 2976

Abstract

Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of [...] Read more.

Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of oxaliplatin treatment on the stomach. In this study, the in vivo effects of oxaliplatin treatment on eating behaviour, stomach content, intrinsic gastric neuronal population, extrinsic innervation to the stomach, levels of mucosal serotonin (5-hydroxytryptamine, 5-HT), and parasympathetic vagal efferent nerve activity were analysed. Chronic systemic oxaliplatin treatment in mice resulted in pica, indicated by increased kaolin consumption and a reduction in body weight. Oxaliplatin treatment significantly increased the stomach weight and content. The total number of myenteric and nitric oxide synthase-immunoreactive neurons as well as the density of sympathetic, parasympathetic, and sensory fibres in the stomach were decreased significantly with oxaliplatin treatment. Oxaliplatin treatment significantly increased the levels in mucosal 5-HT and the number of enterochromaffin-like cells. Chronic oxaliplatin treatment also caused a significant increase in the vagal efferent nerve activity. The findings of this study indicate that oxaliplatin exposure has adverse effects on multiple components of gastric innervation, which could be responsible for pica and gastric dysmotility. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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44 pages, 5252 KiB

Open AccessEditor’s ChoiceReview

Cellular and Molecular Mechanisms of Pathogenesis Underlying Inherited Retinal Dystrophies

by Andrew Manley, Bahar I. Meshkat, Monica M. Jablonski and T.J. Hollingsworth

Biomolecules 2023, 13(2), 271; https://doi.org/10.3390/biom13020271 - 1 Feb 2023

Cited by 28 | Viewed by 6899

Abstract

Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The [...] Read more.

Inherited retinal dystrophies (IRDs) are congenital retinal degenerative diseases that have various inheritance patterns, including dominant, recessive, X-linked, and mitochondrial. These diseases are most often the result of defects in rod and/or cone photoreceptor and retinal pigment epithelium function, development, or both. The genes associated with these diseases, when mutated, produce altered protein products that have downstream effects in pathways critical to vision, including phototransduction, the visual cycle, photoreceptor development, cellular respiration, and retinal homeostasis. The aim of this manuscript is to provide a comprehensive review of the underlying molecular mechanisms of pathogenesis of IRDs by delving into many of the genes associated with IRD development, their protein products, and the pathways interrupted by genetic mutation. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

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16 pages, 1293 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease

by Kyle S. McCommis and Brian N. Finck

Biomolecules 2023, 13(2), 261; https://doi.org/10.3390/biom13020261 - 31 Jan 2023

Cited by 11 | Viewed by 6000

Abstract

Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become [...] Read more.

Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism. In this review, we focus on the role of the MPC and related metabolic pathways in the liver in regulating hepatic and systemic energy metabolism and summarize the current state of targeting this pathway to treat diseases of the liver. Available evidence suggests that inhibiting the MPC in hepatocytes and other cells of the liver produces a variety of beneficial effects for treating type 2 diabetes and nonalcoholic steatohepatitis. We also highlight areas where our understanding is incomplete regarding the pleiotropic effects of MPC inhibition. Full article

(This article belongs to the Special Issue Advances in Mitochondrial Transport Research)

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13 pages, 1037 KiB

Open AccessEditor’s ChoiceReview

Parietal Epithelial Cell Behavior and Its Modulation by microRNA-193a

by Joyita Bharati, Praveen N. Chander and Pravin C. Singhal

Biomolecules 2023, 13(2), 266; https://doi.org/10.3390/biom13020266 - 31 Jan 2023

Cited by 6 | Viewed by 4011

Abstract

Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, [...] Read more.

Glomerular parietal epithelial cells (PECs) have been increasingly recognized to have crucial functions. Lineage tracking in animal models showed the expression of a podocyte phenotype by PECs during normal glomerular growth and after acute podocyte injury, suggesting a reparative role of PECs. Conversely, activated PECs are speculated to be pathogenic and comprise extracapillary proliferation in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CrescGN). The reparative and pathogenic roles of PECs seem to represent two sides of PEC behavior directed by the local milieu and mediators. Recent studies suggest microRNA-193a (miR193a) is involved in the pathogenesis of FSGS and CrescGN. In a mouse model of primary FSGS, the induction of miR193a caused the downregulation of Wilms’ tumor protein, leading to the dedifferentiation of podocytes. On the other hand, the inhibition of miR193a resulted in reduced crescent lesions in a mouse model of CrescGN. Interestingly, in vitro studies report that the downregulation of miR193a induces trans-differentiation of PECs into a podocyte phenotype. This narrative review highlights the critical role of PEC behavior in health and during disease and its modulation by miR193a. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

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23 pages, 992 KiB

Open AccessEditor’s ChoiceReview

Nuclear PTEN’s Functions in Suppressing Tumorigenesis: Implications for Rare Cancers

by Casey G. Langdon

Biomolecules 2023, 13(2), 259; https://doi.org/10.3390/biom13020259 - 30 Jan 2023

Cited by 12 | Viewed by 5375

Abstract

Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect [...] Read more.

Phosphatase and tensin homolog (PTEN) encodes a tumor-suppressive phosphatase with both lipid and protein phosphatase activity. The tumor-suppressive functions of PTEN are lost through a variety of mechanisms across a wide spectrum of human malignancies, including several rare cancers that affect pediatric and adult populations. Originally discovered and characterized as a negative regulator of the cytoplasmic, pro-oncogenic phosphoinositide-3-kinase (PI3K) pathway, PTEN is also localized to the nucleus where it can exert tumor-suppressive functions in a PI3K pathway-independent manner. Cancers can usurp the tumor-suppressive functions of PTEN to promote oncogenesis by disrupting homeostatic subcellular PTEN localization. The objective of this review is to describe the changes seen in PTEN subcellular localization during tumorigenesis, how PTEN enters the nucleus, and the spectrum of impacts and consequences arising from disrupted PTEN nuclear localization on tumor promotion. This review will highlight the immediate need in understanding not only the cytoplasmic but also the nuclear functions of PTEN to gain more complete insights into how important PTEN is in preventing human cancers. Full article

(This article belongs to the Special Issue Molecular and Cellular Basis for Rare Genetic Diseases)

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13 pages, 2560 KiB

Open AccessEditor’s ChoiceArticle

Identification of Inhibitors of Tubulin Polymerization Using a CRISPR-Edited Cell Line with Endogenous Fluorescent Tagging of β-Tubulin and Histone H1

by Harutyun Khachatryan, Bartlomiej Olszowy, Carlos A. Barrero, John Gordon and Oscar Perez-Leal

Biomolecules 2023, 13(2), 249; https://doi.org/10.3390/biom13020249 - 29 Jan 2023

Cited by 9 | Viewed by 8763

Abstract

Tubulin is a protein that plays a critical role in maintaining cellular structure and facilitating cell division. Inhibiting tubulin polymerization has been shown to be an effective strategy for inhibiting the proliferation of cancer cells. In the past, identifying compounds that could inhibit [...] Read more.

Tubulin is a protein that plays a critical role in maintaining cellular structure and facilitating cell division. Inhibiting tubulin polymerization has been shown to be an effective strategy for inhibiting the proliferation of cancer cells. In the past, identifying compounds that could inhibit tubulin polymerization has required the use of in vitro assays utilizing purified tubulin or immunofluorescence of fixed cells. This study presents a novel approach for identifying tubulin polymerization inhibitors using a CRISPR-edited cell line that expresses fluorescently tagged β-tubulin and a nuclear protein, enabling the visualization of tubulin polymerization dynamics via high-content imaging analysis (HCI). The cells were treated with known tubulin polymerization inhibitors, colchicine, and vincristine, and the resulting phenotypic changes indicative of tubulin polymerization inhibition were confirmed using HCI. Furthermore, a library of 429 kinase inhibitors was screened, resulting in the identification of three compounds (ON-01910, HMN-214, and KX2-391) that inhibit tubulin polymerization. Live cell tracking analysis confirmed that compound treatment leads to rapid tubulin depolymerization. These findings suggest that CRISPR-edited cells with fluorescently tagged endogenous β-tubulin can be utilized to screen large compound libraries containing diverse chemical families for the identification of novel tubulin polymerization inhibitors. Full article

(This article belongs to the Section Molecular Biology)

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14 pages, 870 KiB

Open AccessEditor’s ChoiceReview

Organismal Roles of Hsp90

by Patricija van Oosten-Hawle

Biomolecules 2023, 13(2), 251; https://doi.org/10.3390/biom13020251 - 29 Jan 2023

Cited by 18 | Viewed by 3777

Abstract

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation [...] Read more.

Heat shock protein 90 (Hsp90) is a highly conserved molecular chaperone that assists in the maturation of many client proteins involved in cellular signal transduction. As a regulator of cellular signaling processes, it is vital for the maintenance of cellular proteostasis and adaptation to environmental stresses. Emerging research shows that Hsp90 function in an organism goes well beyond intracellular proteostasis. In metazoans, Hsp90, as an environmentally responsive chaperone, is involved in inter-tissue stress signaling responses that coordinate and safeguard cell nonautonomous proteostasis and organismal health. In this way, Hsp90 has the capacity to influence evolution and aging, and effect behavioral responses to facilitate tissue-defense systems that ensure organismal survival. In this review, I summarize the literature on the organismal roles of Hsp90 uncovered in multicellular organisms, from plants to invertebrates and mammals. Full article

(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)

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14 pages, 2704 KiB

Open AccessEditor’s ChoiceArticle

Metabolic Pathway Analysis: Advantages and Pitfalls for the Functional Interpretation of Metabolomics and Lipidomics Data

by Sofia Tsouka and Mojgan Masoodi

Biomolecules 2023, 13(2), 244; https://doi.org/10.3390/biom13020244 - 27 Jan 2023

Cited by 12 | Viewed by 7082

Abstract

Over the past decades, pathway analysis has become one of the most commonly used approaches for the functional interpretation of metabolomics data. Although the approach is widely used, it is not well standardized and the impact of different methodologies on the functional outcome [...] Read more.

Over the past decades, pathway analysis has become one of the most commonly used approaches for the functional interpretation of metabolomics data. Although the approach is widely used, it is not well standardized and the impact of different methodologies on the functional outcome is not well understood. Using four publicly available datasets, we investigated two main aspects of topological pathway analysis, namely the consideration of non-human native enzymatic reactions (e.g., from microbiota) and the interconnectivity of individual pathways. The exclusion of non-human native reactions led to detached and poorly represented reaction networks and to loss of information. The consideration of connectivity between pathways led to better emphasis of certain central metabolites in the network; however, it occasionally overemphasized the hub compounds. We proposed and examined a penalization scheme to diminish the effect of such compounds in the pathway evaluation. In order to compare and assess the results between different methodologies, we also performed over-representation analysis of the same datasets. We believe that our findings will raise awareness on both the capabilities and shortcomings of the currently used pathway analysis practices in metabolomics. Additionally, it will provide insights on various methodologies and strategies that should be considered for the analysis and interpretation of metabolomics data. Full article

(This article belongs to the Collection Metabolomics and Integrated Multi-Omics in Health and Disease)

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16 pages, 3321 KiB

Open AccessEditor’s ChoiceArticle

The Role of the Hydrogen Bond Network in Maintaining Heme Pocket Stability and Protein Function Specificity of C. diphtheriae Coproheme Decarboxylase

by Federico Sebastiani, Chiara Baroni, Gaurav Patil, Andrea Dali, Maurizio Becucci, Stefan Hofbauer and Giulietta Smulevich

Biomolecules 2023, 13(2), 235; https://doi.org/10.3390/biom13020235 - 25 Jan 2023

Cited by 9 | Viewed by 5145

Abstract

Monoderm bacteria accumulate heme b via the coproporphyrin-dependent biosynthesis pathway. In the final step, in the presence of two molecules of H₂O₂, the propionate groups of coproheme at positions 2 and 4 are decarboxylated to form vinyl groups by [...] Read more.

Monoderm bacteria accumulate heme b via the coproporphyrin-dependent biosynthesis pathway. In the final step, in the presence of two molecules of H₂O₂, the propionate groups of coproheme at positions 2 and 4 are decarboxylated to form vinyl groups by coproheme decarboxylase (ChdC), in a stepwise process. Decarboxylation of propionate 2 produces an intermediate that rotates by 90° inside the protein pocket, bringing propionate 4 near the catalytic tyrosine, to allow the second decarboxylation step. The active site of ChdCs is stabilized by an extensive H-bond network involving water molecules, specific amino acid residues, and the propionate groups of the porphyrin. To evaluate the role of these H-bonds in the pocket stability and enzyme functionality, we characterized, via resonance Raman and electronic absorption spectroscopies, single and double mutants of the actinobacterial pathogen Corynebacterium diphtheriae ChdC complexed with coproheme and heme b. The selective elimination of the H-bond interactions between propionates 2, 4, 6, and 7 and the polar residues of the pocket allowed us to establish the role of each H-bond in the catalytic reaction and to follow the changes in the interactions from the substrate to the product. 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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27 pages, 2700 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Mitochondrial Modulators: The Defender

by Emmanuel Makinde, Linlin Ma, George D. Mellick and Yunjiang Feng

Biomolecules 2023, 13(2), 226; https://doi.org/10.3390/biom13020226 - 24 Jan 2023

Cited by 17 | Viewed by 4972

Abstract

Mitochondria are widely considered the “power hub” of the cell because of their pivotal roles in energy metabolism and oxidative phosphorylation. However, beyond the production of ATP, which is the major source of chemical energy supply in eukaryotes, mitochondria are also central to [...] Read more.

Mitochondria are widely considered the “power hub” of the cell because of their pivotal roles in energy metabolism and oxidative phosphorylation. However, beyond the production of ATP, which is the major source of chemical energy supply in eukaryotes, mitochondria are also central to calcium homeostasis, reactive oxygen species (ROS) balance, and cell apoptosis. The mitochondria also perform crucial multifaceted roles in biosynthetic pathways, serving as an important source of building blocks for the biosynthesis of fatty acid, cholesterol, amino acid, glucose, and heme. Since mitochondria play multiple vital roles in the cell, it is not surprising that disruption of mitochondrial function has been linked to a myriad of diseases, including neurodegenerative diseases, cancer, and metabolic disorders. In this review, we discuss the key physiological and pathological functions of mitochondria and present bioactive compounds with protective effects on the mitochondria and their mechanisms of action. We highlight promising compounds and existing difficulties limiting the therapeutic use of these compounds and potential solutions. We also provide insights and perspectives into future research windows on mitochondrial modulators. Full article

(This article belongs to the Special Issue Advances in the Role of Mitochondria in Regulated Cell Death Dysfunctions Associated with Human Pathologies)

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15 pages, 3130 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Hazard Assessment of Polystyrene Nanoplastics in Primary Human Nasal Epithelial Cells, Focusing on the Autophagic Effects

by Balasubramanyam Annangi, Aliro Villacorta, Montserrat López-Mesas, Victor Fuentes-Cebrian, Ricard Marcos and Alba Hernández

Biomolecules 2023, 13(2), 220; https://doi.org/10.3390/biom13020220 - 23 Jan 2023

Cited by 29 | Viewed by 4268

Abstract

The human health risks posed by micro/nanoplastics (MNPLs), as emerging pollutants of environmental/health concern, need to be urgently addressed as part of a needed hazard assessment. The routes of MNPL exposure in humans could mainly come from oral, inhalation, or dermal means. Among [...] Read more.

The human health risks posed by micro/nanoplastics (MNPLs), as emerging pollutants of environmental/health concern, need to be urgently addressed as part of a needed hazard assessment. The routes of MNPL exposure in humans could mainly come from oral, inhalation, or dermal means. Among them, inhalation exposure to MNPLs is the least studied area, even though their widespread presence in the air is dramatically increasing. In this context, this study focused on the potential hazard of polystyrene nanoplastics (PSNPLs with sizes 50 and 500 nm) in human primary nasal epithelial cells (HNEpCs), with the first line of cells acting as a physical and immune barrier in the respiratory system. Primarily, cellular internalization was evaluated by utilizing laboratory-labeled fluorescence PSNPLs with iDye, a commercial, pink-colored dye, using confocal microscopy, and found PSNPLs to be significantly internalized by HNEpCs. After, various cellular effects, such as the induction of intracellular reactive oxygen species (iROS), the loss of mitochondrial membrane potential (MMP), and the modulation of the autophagy pathway in the form of the accumulation of autophagosomes (LC3-II) and p62 markers (a ubiquitin involved in the clearance of cell debris), were evaluated after cell exposure. The data demonstrated significant increases in iROS, a decrease in MMP, as well as a greater accumulation of LC3-II and p62 in the presence of PSNPLs. Notably, the autophagic effects did indicate the implications of PSNPLs in defective or insufficient autophagy. This is the first study showing the autophagy pathway as a possible target for PSNPL-induced adverse effects in HNEpCs. When taken together, this study proved the cellular effects of PSNPLs in HNEpCs and adds value to the existing studies as a part of the respiratory risk assessment of MNPLs. Full article

(This article belongs to the Special Issue How Environmental Plastic Particles and Their Adsorbed Contaminants Interact with Biomolecules?)

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13 pages, 2207 KiB

Open AccessEditor’s ChoiceArticle

Aquaporin-1 and Aquaporin-4 Expression in Ependyma, Choroid Plexus and Surrounding Transition Zones in the Human Brain

by Ronja Bihlmaier, Felix Deffner, Ulrich Mattheus, Peter H. Neckel, Bernhard Hirt and Andreas F. Mack

Biomolecules 2023, 13(2), 212; https://doi.org/10.3390/biom13020212 - 22 Jan 2023

Cited by 12 | Viewed by 3784

Abstract

The choroid plexus (CP) is a structure in the brain ventricles that produces the main part of the cerebrospinal fluid (CSF). It is covered with specialized cells which show epithelial characteristics and are the site of the blood–CSF barrier. These cells form a [...] Read more.

The choroid plexus (CP) is a structure in the brain ventricles that produces the main part of the cerebrospinal fluid (CSF). It is covered with specialized cells which show epithelial characteristics and are the site of the blood–CSF barrier. These cells form a contiguous cell sheet with ventricle-lining ependymal cells which are known to express aquaporin-4 (AQP4). In contrast, CP epithelial cells express aquaporin-1 (AQP1) apically. We investigated the expression patterns of aquaporins in the CP-ependyma transition from human body donors using immunofluorescence and electron microscopy. Ependymal cells and subependymal astrocytes at the base of the CP showed a particularly high AQP4 immunoreactivity. Astrocytic processes formed a dense meshwork or glial plate around the blood vessels entering the CP. Interestingly, some of these astrocytic processes were in direct contact with the CP stroma, which contains fenestrated blood vessels, separated only by a basal lamina. Electron microscopy confirmed the continuity of the subastrocytic basal lamina with the CP epithelium. We also probed for components of the AQP4 anchoring dystrophin–dystroglycan complex. Immunolabeling for dystrophin and AQP4 showed an overlapping staining pattern in the glial plate but not in previously reported AQP4-positive CP epithelial cells. In contrast, dystroglycan expression was associated with laminin staining in the glial plate and the CP epithelium. This suggests different mechanisms for AQP4 anchoring in the cell membrane. The high AQP4 density in the connecting glial plate might facilitate the transport of water in and out of the CP stroma and could possibly serve as a drainage and clearing pathway for metabolites. Full article

(This article belongs to the Special Issue Aquaporins in the CNS–in Honor of the 30th Anniversary of the Discovery of Aquaporins)

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21 pages, 2060 KiB

Open AccessEditor’s ChoiceArticle

Updated Virophage Taxonomy and Distinction from Polinton-like Viruses

by Simon Roux, Matthias G. Fischer, Thomas Hackl, Laura A. Katz, Frederik Schulz and Natalya Yutin

Biomolecules 2023, 13(2), 204; https://doi.org/10.3390/biom13020204 - 19 Jan 2023

Cited by 22 | Viewed by 6420

Abstract

Virophages are small dsDNA viruses that hijack the machinery of giant viruses during the co-infection of a protist (i.e., microeukaryotic) host and represent an exceptional case of “hyperparasitism” in the viral world. While only a handful of virophages have been isolated, a vast [...] Read more.

Virophages are small dsDNA viruses that hijack the machinery of giant viruses during the co-infection of a protist (i.e., microeukaryotic) host and represent an exceptional case of “hyperparasitism” in the viral world. While only a handful of virophages have been isolated, a vast diversity of virophage-like sequences have been uncovered from diverse metagenomes. Their wide ecological distribution, idiosyncratic infection and replication strategy, ability to integrate into protist and giant virus genomes and potential role in antiviral defense have made virophages a topic of broad interest. However, one limitation for further studies is the lack of clarity regarding the nomenclature and taxonomy of this group of viruses. Specifically, virophages have been linked in the literature to other “virophage-like” mobile genetic elements and viruses, including polinton-like viruses (PLVs), but there are no formal demarcation criteria and proper nomenclature for either group, i.e., virophage or PLVs. Here, as part of the ICTV Virophage Study Group, we leverage a large set of genomes gathered from published datasets as well as newly generated protist genomes to propose delineation criteria and classification methods at multiple taxonomic ranks for virophages ‘sensu stricto’, i.e., genomes related to the prototype isolates Sputnik and mavirus. Based on a combination of comparative genomics and phylogenetic analyses, we show that this group of virophages forms a cohesive taxon that we propose to establish at the class level and suggest a subdivision into four orders and seven families with distinctive ecogenomic features. Finally, to illustrate how the proposed delineation criteria and classification method would be used, we apply these to two recently published datasets, which we show include both virophages and other virophage-related elements. Overall, we see this proposed classification as a necessary first step to provide a robust taxonomic framework in this area of the virosphere, which will need to be expanded in the future to cover other virophage-related viruses such as PLVs. 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, 2656 KiB

Open AccessEditor’s ChoiceArticle

Chronic Exposure to Low-Molecular-Weight Polycyclic Aromatic Hydrocarbons Promotes Lipid Accumulation and Metabolic Inflammation

by Asia Bright, Fenfen Li, Miranda Movahed, Hang Shi and Bingzhong Xue

Biomolecules 2023, 13(2), 196; https://doi.org/10.3390/biom13020196 - 18 Jan 2023

Cited by 28 | Viewed by 3334

Abstract

2-naphthol is a low-molecular-weight (LMW) polycyclic aromatic hydrocarbon (PAH) and air pollutant associated with childhood obesity. There has been a recent emergence of studies on the consequences of PAHs on human health. Current epidemiological reports suggest LMW-PAHs may contribute to obesity incidences in [...] Read more.

2-naphthol is a low-molecular-weight (LMW) polycyclic aromatic hydrocarbon (PAH) and air pollutant associated with childhood obesity. There has been a recent emergence of studies on the consequences of PAHs on human health. Current epidemiological reports suggest LMW-PAHs may contribute to obesity incidences in children, yet most studies focus on high-molecular-weight PAHs. This study explores 2-naphthol’s impact on obesity and obesity-associated metabolic disorders. To investigate 2-naphthol’s effect on lipid metabolism and inflammation, we employed 3T3-L1 and BAT1 cell lines to model white and brown adipocytes, respectively, alongside a murine macrophage cell line (RAW264.7). We found that 2-naphthol increased the expression of key adipogenic and lipogenic genes while decreasing lipolytic gene expression in chronically treated 3T3-L1 and BAT1 adipocytes. In addition, chronic 2-naphthol treatment also suppressed adrenergic-stimulated thermogenic gene expression in BAT1 brown adipocytes. In consistence, an increase in lipid accumulation was demonstrated in BODIPY and Oil Red O-stained adipocytes. Additionally, 3T3-L1 adipocytes and RAW264.7 macrophages chronically exposed to 2-naphthol showed upregulated mRNA expression of major inflammatory cytokines (e.g., tumor necrosis factor α (Tnfα), interleukin-1β (Il-1β), and Il-6). In summary, chronic exposure to 2-naphthol stimulates lipid accumulation in adipocytes and inflammation in adipocytes and macrophages. These findings support previous research that demonstrates 2-naphthol has obesogenic potential. Full article

(This article belongs to the Collection Molecular Mechanisms of Obesity, Diabetes, Inflammation and Aging)

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22 pages, 958 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Type 2 Diabetes and Alzheimer’s Disease: The Emerging Role of Cellular Lipotoxicity

by Nicola Marrano, Giuseppina Biondi, Anna Borrelli, Martina Rella, Tommaso Zambetta, Ludovico Di Gioia, Mariangela Caporusso, Giancarlo Logroscino, Sebastio Perrini, Francesco Giorgino and Annalisa Natalicchio

Biomolecules 2023, 13(1), 183; https://doi.org/10.3390/biom13010183 - 16 Jan 2023

Cited by 26 | Viewed by 6827

Abstract

Type 2 diabetes (T2D) and Alzheimer’s diseases (AD) represent major health issues that have reached alarming levels in the last decades. Although growing evidence demonstrates that AD is a significant comorbidity of T2D, and there is a ~1.4–2-fold increase in the risk of [...] Read more.

Type 2 diabetes (T2D) and Alzheimer’s diseases (AD) represent major health issues that have reached alarming levels in the last decades. Although growing evidence demonstrates that AD is a significant comorbidity of T2D, and there is a ~1.4–2-fold increase in the risk of developing AD among T2D patients, the involvement of possible common triggers in the pathogenesis of these two diseases remains largely unknown. Of note, recent mechanistic insights suggest that lipotoxicity could represent the missing ring in the pathogenetic mechanisms linking T2D to AD. Indeed, obesity, which represents the main cause of lipotoxicity, has been recognized as a major risk factor for both pathological conditions. Lipotoxicity can lead to inflammation, insulin resistance, oxidative stress, ceramide and amyloid accumulation, endoplasmic reticulum stress, ferroptosis, and autophagy, which are shared biological events in the pathogenesis of T2D and AD. In the current review, we try to provide a critical and comprehensive view of the common molecular pathways activated by lipotoxicity in T2D and AD, attempting to summarize how these mechanisms can drive future research and open the way to new therapeutic perspectives. Full article

(This article belongs to the Special Issue Role of Fatty Acid-Induced Multi-Organ Damage on Diabetes Onset and Progression: Implications for Therapeutic Strategies)

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15 pages, 1822 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Is Glial Dysfunction the Key Pathogenesis of LRRK2-Linked Parkinson’s Disease?

by Tatou Iseki, Yuzuru Imai and Nobutaka Hattori

Biomolecules 2023, 13(1), 178; https://doi.org/10.3390/biom13010178 - 15 Jan 2023

Cited by 11 | Viewed by 4250

Abstract

Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson’s disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with [...] Read more.

Leucine rich-repeat kinase 2 (LRRK2) is the most well-known etiologic gene for familial Parkinson’s disease (PD). Its gene product is a large kinase with multiple functional domains that phosphorylates a subset of Rab small GTPases. However, studies of autopsy cases with LRRK2 mutations indicate a varied pathology, and the molecular functions of LRRK2 and its relationship to PD pathogenesis are largely unknown. Recently, non-autonomous neurodegeneration associated with glial cell dysfunction has attracted attention as a possible mechanism of dopaminergic neurodegeneration. Molecular studies of LRRK2 in astrocytes and microglia have also suggested that LRRK2 is involved in the regulation of lysosomal and other organelle dynamics and inflammation. In this review, we describe the proposed functions of LRRK2 in glial cells and discuss its involvement in the pathomechanisms of PD. Full article

(This article belongs to the Special Issue Pathological Roles of LRRK2)

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26 pages, 1670 KiB

Open AccessEditor’s ChoiceReview

The Double-Edged Role of Extracellular Vesicles in the Hallmarks of Aging

by Nekane Romero-García, Javier Huete-Acevedo, Cristina Mas-Bargues, Jorge Sanz-Ros, Mar Dromant and Consuelo Borrás

Biomolecules 2023, 13(1), 165; https://doi.org/10.3390/biom13010165 - 13 Jan 2023

Cited by 14 | Viewed by 4723

Abstract

The exponential growth in the elderly population and their associated socioeconomic burden have recently brought aging research into the spotlight. To integrate current knowledge and guide potential interventions, nine biochemical pathways are summarized under the term hallmarks of aging. These hallmarks are deeply [...] Read more.

The exponential growth in the elderly population and their associated socioeconomic burden have recently brought aging research into the spotlight. To integrate current knowledge and guide potential interventions, nine biochemical pathways are summarized under the term hallmarks of aging. These hallmarks are deeply inter-related and act together to drive the aging process. Altered intercellular communication is particularly relevant since it explains how damage at the cellular level translates into age-related loss of function at the organismal level. As the main effectors of intercellular communication, extracellular vesicles (EVs) might play a key role in the aggravation or mitigation of the hallmarks of aging. This review aims to summarize this role and to provide context for the multiple emerging EV-based gerotherapeutic strategies that are currently under study. Full article

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15 pages, 1926 KiB

Open AccessEditor’s ChoiceArticle

Glycosylated Lipopeptides—Synthesis and Evaluation of Antimicrobial Activity and Cytotoxicity

by Karol Sikora, Marta Bauer, Sylwia Bartoszewska, Damian Neubauer and Wojciech Kamysz

Biomolecules 2023, 13(1), 172; https://doi.org/10.3390/biom13010172 - 13 Jan 2023

Cited by 4 | Viewed by 3073

Abstract

Ultrashort cationic lipopeptides (USCLs) are promising antimicrobial agents that may be used to combat pathogens such as bacteria and fungi. USCLs consist of a few basic amino acid residues and at least one lipid moiety, usually a fatty acid chain. Generally, USCLs are [...] Read more.

Ultrashort cationic lipopeptides (USCLs) are promising antimicrobial agents that may be used to combat pathogens such as bacteria and fungi. USCLs consist of a few basic amino acid residues and at least one lipid moiety, usually a fatty acid chain. Generally, USCLs are potent antimicrobials but their major shortcoming is a relatively high cytotoxicity and hemolytic activity. Glycopeptide antibiotics (e.g. vancomycin) are essential in combating bacterial infections and are popular in medicinal practice. However, literature concerning the effect of glycosylation of peptides on their antimicrobial activity is rather scarce. For the first time, this study highlights the effect of USCLs glycosylation on in vitro biological activity. The aim of this study was to evaluate the impact of glycosylation of a series of USCLs on antimicrobial activity, cytotoxicity and hemolytic activity. Straight-chain fatty acids (C14, C16, C18) were attached to the N-terminal amino group of tripeptides—SRR-NH₂, RSR-NH₂ and RRS-NH₂. Two groups of the lipopeptides were synthetized, the first with unmodified L-serine (USCLs) and the other with L-serine O-glycosylated by N-acetyl-β-d-glucosamine to produce new class of glycosylated ultrashort cationic lipopeptide (gUSCLs). Both USCLs and gUSCLs were tested against planktonic and biofilm cultures of ESKAPE strains (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp.) and Candida glabrata, and hemolytic activity on human erythrocytes and cytotoxicity against the HaCaT cell line was examined. Generally, USCLs and gUSCLs proved to be active against all the tested strains. The highest activity displayed was by lipopeptides containing the C18 fatty acid. Antimicrobial, hemolytic and cytotoxic activities were mainly correlated with amino acid sequence (position of serine/glycosylated serine) and hydrophobicity of molecule and were found to be highly strain-dependent. In general, glycosylation did not guarantee an increased antimicrobial activity or a decreased hemolytic and cytotoxic activities. However, in some cases, gUSCLs proved to be superior to their USCLs analogs. The most pronounced differences were found for peptides with C18 fatty acid and serine at the first and second position against both planktonic cells and biofilm of C. glabrata, as well as the second and third position against S. aureus. It is noteworthy that gUSCLs were also more active against biofilm than were USCLs. Full article

(This article belongs to the Special Issue Nature Inspired Peptides in Medical Sciences)

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25 pages, 1260 KiB

Open AccessEditor’s ChoiceReview

The Challenges and Prospects of p53-Based Therapies in Ovarian Cancer

by Bryce Wallis, Katherine Redd Bowman, Phong Lu and Carol S. Lim

Biomolecules 2023, 13(1), 159; https://doi.org/10.3390/biom13010159 - 12 Jan 2023

Cited by 33 | Viewed by 9204

Abstract

It has been well established that mutations in the tumor suppressor gene, p53, occur readily in a vast majority of cancer tumors, including ovarian cancer. Typically diagnosed in stages three or four, ovarian cancer is the fifth leading cause of death in women, [...] Read more.

It has been well established that mutations in the tumor suppressor gene, p53, occur readily in a vast majority of cancer tumors, including ovarian cancer. Typically diagnosed in stages three or four, ovarian cancer is the fifth leading cause of death in women, despite accounting for only 2.5% of all female malignancies. The overall 5-year survival rate for ovarian cancer is around 47%; however, this drops to an abysmal 29% for the most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC). HGSOC has upwards of 96% of cases expressing mutations in p53. Therefore, wild-type (WT) p53 and p53-based therapies have been explored as treatment options via a plethora of drug delivery vehicles including nanoparticles, viruses, polymers, and liposomes. However, previous p53 therapeutics have faced many challenges, which have resulted in their limited translational success to date. This review highlights a selection of these historical p53-targeted therapeutics for ovarian cancer, why they failed, and what the future could hold for a new generation of this class of therapies. Full article

(This article belongs to the Collection p53 Function and Dysfunction in Human Health and Diseases)

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12 pages, 2632 KiB

Open AccessEditor’s ChoiceArticle

Sub-Millisecond Photoinduced Dynamics of Free and EL222-Bound FMN by Stimulated Raman and Visible Absorption Spectroscopies

by Yingliang Liu, Aditya S. Chaudhari, Aditi Chatterjee, Prokopis C. Andrikopoulos, Alessandra Picchiotti, Mateusz Rebarz, Miroslav Kloz, Victor A. Lorenz-Fonfria, Bohdan Schneider and Gustavo Fuertes

Biomolecules 2023, 13(1), 161; https://doi.org/10.3390/biom13010161 - 12 Jan 2023

Cited by 7 | Viewed by 3555

Abstract

Time-resolved femtosecond-stimulated Raman spectroscopy (FSRS) provides valuable information on the structural dynamics of biomolecules. However, FSRS has been applied mainly up to the nanoseconds regime and above 700 cm⁻¹, which covers only part of the spectrum of biologically relevant time scales [...] Read more.

Time-resolved femtosecond-stimulated Raman spectroscopy (FSRS) provides valuable information on the structural dynamics of biomolecules. However, FSRS has been applied mainly up to the nanoseconds regime and above 700 cm⁻¹, which covers only part of the spectrum of biologically relevant time scales and Raman shifts. Here we report on a broadband (~200–2200 cm⁻¹) dual transient visible absorption (visTA)/FSRS set-up that can accommodate time delays from a few femtoseconds to several hundreds of microseconds after illumination with an actinic pump. The extended time scale and wavenumber range allowed us to monitor the complete excited-state dynamics of the biological chromophore flavin mononucleotide (FMN), both free in solution and embedded in two variants of the bacterial light-oxygen-voltage (LOV) photoreceptor EL222. The observed lifetimes and intermediate states (singlet, triplet, and adduct) are in agreement with previous time-resolved infrared spectroscopy experiments. Importantly, we found evidence for additional dynamical events, particularly upon analysis of the low-frequency Raman region below 1000 cm⁻¹. We show that fs-to-sub-ms visTA/FSRS with a broad wavenumber range is a useful tool to characterize short-lived conformationally excited states in flavoproteins and potentially other light-responsive proteins. Full article

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

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15 pages, 3374 KiB

Open AccessEditor’s ChoiceArticle

Combining Semi-Targeted Metabolomics and Machine Learning to Identify Metabolic Alterations in the Serum and Urine of Hospitalized Patients with COVID-19

by Gerard Baiges-Gaya, Simona Iftimie, Helena Castañé, Elisabet Rodríguez-Tomàs, Andrea Jiménez-Franco, Ana F. López-Azcona, Antoni Castro, Jordi Camps and Jorge Joven

Biomolecules 2023, 13(1), 163; https://doi.org/10.3390/biom13010163 - 12 Jan 2023

Cited by 14 | Viewed by 3668

Abstract

Viral infections cause metabolic dysregulation in the infected organism. The present study used metabolomics techniques and machine learning algorithms to retrospectively analyze the alterations of a broad panel of metabolites in the serum and urine of a cohort of 126 patients hospitalized with [...] Read more.

Viral infections cause metabolic dysregulation in the infected organism. The present study used metabolomics techniques and machine learning algorithms to retrospectively analyze the alterations of a broad panel of metabolites in the serum and urine of a cohort of 126 patients hospitalized with COVID-19. Results were compared with those of 50 healthy subjects and 45 COVID-19-negative patients but with bacterial infectious diseases. Metabolites were analyzed by gas chromatography coupled to quadrupole time-of-flight mass spectrometry. The main metabolites altered in the sera of COVID-19 patients were those of pentose glucuronate interconversion, ascorbate and fructose metabolism, nucleotide sugars, and nucleotide and amino acid metabolism. Alterations in serum maltose, mannonic acid, xylitol, or glyceric acid metabolites segregated positive patients from the control group with high diagnostic accuracy, while succinic acid segregated positive patients from those with other disparate infectious diseases. Increased lauric acid concentrations were associated with the severity of infection and death. Urine analyses could not discriminate between groups. Targeted metabolomics and machine learning algorithms facilitated the exploration of the metabolic alterations underlying COVID-19 infection, and to identify the potential biomarkers for the diagnosis and prognosis of the disease. Full article

(This article belongs to the Special Issue Metabolic Pathways and COVID-19: Mechanisms and Clinical Implications)

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