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Editor’s Choice Articles

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

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Review

21 pages, 1443 KiB  
Review
Immune Checkpoint Inhibitors and RAS–ERK Pathway-Targeted Drugs as Combined Therapy for the Treatment of Melanoma
by Marta Morante, Atanasio Pandiella, Piero Crespo and Ana Herrero
Biomolecules 2022, 12(11), 1562; https://doi.org/10.3390/biom12111562 - 26 Oct 2022
Cited by 7 | Viewed by 4776
Abstract
Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy [...] Read more.
Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy entails an increment in the overall survival rates. However, melanoma cells respond with evasive molecular mechanisms. ERK cascade inhibitors are also used in metastatic melanoma treatment, with the RAF activity blockade being the main therapeutic approach for such purpose, and in combination with MEK inhibitors improves many parameters of clinical efficacy. Despite their efficacy in inhibiting ERK signaling, the rewiring of the melanoma cell-signaling results in disease relapse, constituting the reinstatement of ERK activation, which is a common cause of some resistance mechanisms. Recent studies revealed that the combination of RAS–ERK pathway inhibitors and ICI therapy present promising advantages for metastatic melanoma treatment. Here, we present a recompilation of the combined therapies clinically evaluated in patients. Full article
(This article belongs to the Section Molecular Medicine)
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12 pages, 3317 KiB  
Review
Synthesis of Protein-Oligonucleotide Conjugates
by Emma E. Watson and Nicolas Winssinger
Biomolecules 2022, 12(10), 1523; https://doi.org/10.3390/biom12101523 - 20 Oct 2022
Cited by 2 | Viewed by 3411
Abstract
Nucleic acids and proteins form two of the key classes of functional biomolecules. Through the ability to access specific protein-oligonucleotide conjugates, a broader range of functional molecules becomes accessible which leverages both the programmability and recognition potential of nucleic acids and the structural, [...] Read more.
Nucleic acids and proteins form two of the key classes of functional biomolecules. Through the ability to access specific protein-oligonucleotide conjugates, a broader range of functional molecules becomes accessible which leverages both the programmability and recognition potential of nucleic acids and the structural, chemical and functional diversity of proteins. Herein, we summarize the available conjugation strategies to access such chimeric molecules and highlight some key case study examples within the field to showcase the power and utility of such technology. Full article
(This article belongs to the Collection Feature Papers in Biomacromolecules: Nucleic Acids)
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12 pages, 758 KiB  
Review
Cyclosporine A Delivery Platform for Veterinary Ophthalmology—A New Concept for Advanced Ophthalmology
by Martyna Padjasek, Badr Qasem, Anna Cisło-Pakuluk and Krzysztof Marycz
Biomolecules 2022, 12(10), 1525; https://doi.org/10.3390/biom12101525 - 20 Oct 2022
Cited by 7 | Viewed by 3302
Abstract
Cyclosporine A (CsA) is a selective and reversible immunosuppressant agent that is widely used as a medication for a wide spectrum of diseases in humans such as graft versus host disease, non-infectious uveitis, rheumatoid arthritis, psoriasis, and atopic dermatitis. Furthermore, the CsA is [...] Read more.
Cyclosporine A (CsA) is a selective and reversible immunosuppressant agent that is widely used as a medication for a wide spectrum of diseases in humans such as graft versus host disease, non-infectious uveitis, rheumatoid arthritis, psoriasis, and atopic dermatitis. Furthermore, the CsA is used to treat keratoconjunctivitis sicca, chronic superficial keratitis, immune-mediated keratitis and equine recurrent uveitis in animals. The selective activity of Cyclosporine A (CsA) was demonstrated to be an immunomodulation characteristic of T-lymphocyte proliferation and inhibits cytokine gene expression. Moreover, the lipophilic characteristics with poor bioavailability and low solubility in water, besides the side effects, force the need to develop new formulations and devices that will provide adequate penetration into the anterior and posterior segments of the eye. This review aims to summarize the effectiveness and safety of cyclosporine A delivery platforms in veterinary ophthalmology. Full article
(This article belongs to the Special Issue Cyclodextrin-Based Drug Release and Drug Delivery Systems)
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20 pages, 1745 KiB  
Review
Copper-Dependent Kinases and Their Role in Cancer Inception, Progression and Metastasis
by Alessandra Vitaliti, Anastasia De Luca and Luisa Rossi
Biomolecules 2022, 12(10), 1520; https://doi.org/10.3390/biom12101520 - 20 Oct 2022
Cited by 8 | Viewed by 2858
Abstract
In recent years, copper function has been expanded beyond its consolidated role as a cofactor of enzyme catalysis. Recent papers have demonstrated a new dynamic role for copper in the regulation of cell signaling pathways through direct interaction with protein kinases, modulating their [...] Read more.
In recent years, copper function has been expanded beyond its consolidated role as a cofactor of enzyme catalysis. Recent papers have demonstrated a new dynamic role for copper in the regulation of cell signaling pathways through direct interaction with protein kinases, modulating their activity. The activation of these pathways is exacerbated in cancer cells to sustain the different steps of tumor growth and dissemination. This review will focus on a novel proposed role for the transition metal copper as a regulator of cell signaling pathways through direct interaction with known protein kinases, which exhibit binding domains for this metal. Activation of these pathways in cancer cells supports both tumor growth and dissemination. In addition to the description of the results recently reported in the literature on the subject, relevance will be given to the possibility of controlling the cellular levels of copper and its homeostatic regulators. Overall, these findings may be of central relevance in order to propose copper and its homeostatic regulators as possible targets for novel therapies, which may act synergistically to those already existing to control cancer growth and dissemination. Full article
(This article belongs to the Special Issue Kinases Signaling in Cancers)
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12 pages, 283 KiB  
Review
Prognostic Value of High-Sensitivity Cardiac Troponin in Women
by Giandomenico Bisaccia, Fabrizio Ricci, Mohammed Y. Khanji, Giulia Gaggi, Andrea Di Credico, Sabina Gallina, Angela Di Baldassarre and Barbara Ghinassi
Biomolecules 2022, 12(10), 1496; https://doi.org/10.3390/biom12101496 - 17 Oct 2022
Cited by 1 | Viewed by 3201
Abstract
High-sensitivity cardiac troponin assays have become the gold standard for diagnosing acute and chronic myocardial injury. The detection of troponin levels beyond the 99th percentile is included in the fourth universal definition of myocardial infarction, specifically recommending the use of sex-specific thresholds. Measurable [...] Read more.
High-sensitivity cardiac troponin assays have become the gold standard for diagnosing acute and chronic myocardial injury. The detection of troponin levels beyond the 99th percentile is included in the fourth universal definition of myocardial infarction, specifically recommending the use of sex-specific thresholds. Measurable concentrations below the proposed diagnostic thresholds have been shown to inform prognosis in different categories of inpatients and outpatients. However, clinical investigations from the last twenty years have yielded conflicting results regarding the incremental value of using different cut-offs for men and women. While advocates of a sex-specific approach claim it may help reduce gender bias in cardiovascular medicine, particularly in acute coronary syndromes, other groups question the alleged incremental diagnostic and prognostic value of sex-specific thresholds, ultimately asserting that less is more. In the present review, we aimed to synthesize our current understanding of sex-based differences in cardiac troponin levels and to reappraise the available evidence with regard to (i) the prognostic significance of sex-specific diagnostic thresholds of high-sensitivity cardiac troponin assays compared to common cut-offs in both men and women undergoing cardiovascular disease risk assessment, and (ii) the clinical utility of high-sensitivity cardiac troponin assays for cardiovascular disease prevention in women. Full article
(This article belongs to the Special Issue Biomolecules and Cardiovascular Disease in Women)
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Graphical abstract

26 pages, 2182 KiB  
Review
Current Challenges for Biological Treatment of Pharmaceutical-Based Contaminants with Oxidoreductase Enzymes: Immobilization Processes, Real Aqueous Matrices and Hybrid Techniques
by Helena Sá, Michele Michelin, Teresa Tavares and Bruna Silva
Biomolecules 2022, 12(10), 1489; https://doi.org/10.3390/biom12101489 - 15 Oct 2022
Cited by 13 | Viewed by 2291
Abstract
The worldwide access to pharmaceuticals and their continuous release into the environment have raised a serious global concern. Pharmaceuticals remain active even at low concentrations, therefore their occurrence in waterbodies may lead to successive deterioration of water quality with adverse impacts on the [...] Read more.
The worldwide access to pharmaceuticals and their continuous release into the environment have raised a serious global concern. Pharmaceuticals remain active even at low concentrations, therefore their occurrence in waterbodies may lead to successive deterioration of water quality with adverse impacts on the ecosystem and human health. To address this challenge, there is currently an evolving trend toward the search for effective methods to ensure efficient purification of both drinking water and wastewater. Biocatalytic transformation of pharmaceuticals using oxidoreductase enzymes, such as peroxidase and laccase, is a promising environmentally friendly solution for water treatment, where fungal species have been used as preferred producers due to their ligninolytic enzymatic systems. Enzyme-catalyzed degradation can transform micropollutants into more bioavailable or even innocuous products. Enzyme immobilization on a carrier generally increases its stability and catalytic performance, allowing its reuse, being a promising approach to ensure applicability to an industrial scale process. Moreover, coupling biocatalytic processes to other treatment technologies have been revealed to be an effective approach to achieve the complete removal of pharmaceuticals. This review updates the state-of-the-art of the application of oxidoreductases enzymes, namely laccase, to degrade pharmaceuticals from spiked water and real wastewater. Moreover, the advances concerning the techniques used for enzyme immobilization, the operation in bioreactors, the use of redox mediators, the application of hybrid techniques, as well as the discussion of transformation mechanisms and ending toxicity, are addressed. Full article
(This article belongs to the Special Issue Fungal Metabolism—Enzymes and Bioactive Compounds II)
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25 pages, 9721 KiB  
Review
Biomimetic Artificial Proton Channels
by Iuliana-Marilena Andrei and Mihail Barboiu
Biomolecules 2022, 12(10), 1473; https://doi.org/10.3390/biom12101473 - 13 Oct 2022
Cited by 5 | Viewed by 2776
Abstract
One of the most common biochemical processes is the proton transfer through the cell membranes, having significant physiological functions in living organisms. The proton translocation mechanism has been extensively studied; however, mechanistic details of this transport are still needed. During the last decades, [...] Read more.
One of the most common biochemical processes is the proton transfer through the cell membranes, having significant physiological functions in living organisms. The proton translocation mechanism has been extensively studied; however, mechanistic details of this transport are still needed. During the last decades, the field of artificial proton channels has been in continuous growth, and understanding the phenomena of how confined water and channel components mediate proton dynamics is very important. Thus, proton transfer continues to be an active area of experimental and theoretical investigations, and acquiring insights into the proton transfer mechanism is important as this enlightenment will provide direct applications in several fields. In this review, we present an overview of the development of various artificial proton channels, focusing mostly on their design, self-assembly behavior, proton transport activity performed on bilayer membranes, and comparison with protein proton channels. In the end, we discuss their potential applications as well as future development and perspectives. Full article
(This article belongs to the Special Issue Proton and Proton-Coupled Transport)
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31 pages, 3167 KiB  
Review
Lung Organoids in Smoking Research: Current Advances and Future Promises
by Hina Agraval and Hong Wei Chu
Biomolecules 2022, 12(10), 1463; https://doi.org/10.3390/biom12101463 - 12 Oct 2022
Cited by 4 | Viewed by 5259
Abstract
Tobacco smoking has been established to contribute to the pathogenesis of various respiratory diseases including chronic obstructive pulmonary disease (COPD), lung cancer, and asthma. However, major hurdles in mechanistic studies on the role of smoking in human lungs remain in part due to [...] Read more.
Tobacco smoking has been established to contribute to the pathogenesis of various respiratory diseases including chronic obstructive pulmonary disease (COPD), lung cancer, and asthma. However, major hurdles in mechanistic studies on the role of smoking in human lungs remain in part due to the lack of ex vivo experimental models and ambiguous data from animal models that can best recapitulate the architecture and pathophysiology of the human lung. Recent development of the lung organoid culture system has opened new avenues for respiratory disease research as organoids are proving to be a sophisticated ex vivo model that functionally and structurally mimics the human lungs better than other traditionally used models. This review will discuss how recent advances in lung organoid systems may help us better determine the injurious and immunological effect of smoking on human lungs and will provide some suggestions for future research directions. Full article
(This article belongs to the Special Issue Molecular Mechanisms in Lung Injury, Repair, and Remodeling)
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22 pages, 690 KiB  
Review
Sex Differences in the Neuropsychiatric Effects and Pharmacokinetics of Cannabidiol: A Scoping Review
by Justin Matheson, Zoe Bourgault and Bernard Le Foll
Biomolecules 2022, 12(10), 1462; https://doi.org/10.3390/biom12101462 - 12 Oct 2022
Cited by 13 | Viewed by 3669
Abstract
Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as [...] Read more.
Cannabidiol (CBD) is a non-intoxicating cannabinoid compound with diverse molecular targets and potential therapeutic effects, including effects relevant to the treatment of psychiatric disorders. In this scoping review, we sought to determine the extent to which sex and gender have been considered as potential moderators of the neuropsychiatric effects and pharmacokinetics of CBD. In this case, 300 articles were screened, retrieved from searches in PubMed/Medline, Scopus, Google Scholar, PsycInfo and CINAHL, though only 12 met our eligibility criteria: eight studies in preclinical models and four studies in humans. Among the preclinical studies, three suggested that sex may influence long-term effects of gestational or adolescent exposure to CBD; two found no impact of sex on CBD modulation of addiction-relevant effects of Δ⁹-tetrahydrocannabinol (THC); two found antidepressant-like effects of CBD in males only; and one found greater plasma and liver CBD concentrations in females compared to males. Among the human studies, two found no sex difference in CBD pharmacokinetics in patient samples, one found greater plasma CBD concentrations in healthy females compared to males, and one found no evidence of sex differences in the effects of CBD on responses to trauma recall in patients with post-traumatic stress disorder (PTSD). No studies were identified that considered the role of gender in CBD treatment effects. We discuss potential implications and current limitations of the existing literature. Full article
(This article belongs to the Special Issue Recent Advances in Central Nervous System Drug Discovery)
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15 pages, 1541 KiB  
Review
An Overview of Molecular Mechanisms in Fabry Disease
by Federica Amodio, Martina Caiazza, Emanuele Monda, Marta Rubino, Laura Capodicasa, Flavia Chiosi, Vincenzo Simonelli, Francesca Dongiglio, Fabio Fimiani, Nicola Pepe, Cristina Chimenti, Paolo Calabrò and Giuseppe Limongelli
Biomolecules 2022, 12(10), 1460; https://doi.org/10.3390/biom12101460 - 12 Oct 2022
Cited by 7 | Viewed by 4845
Abstract
Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation [...] Read more.
Fabry disease (FD) (OMIM #301500) is a rare genetic lysosomal storage disorder (LSD). LSDs are characterized by inappropriate lipid accumulation in lysosomes due to specific enzyme deficiencies. In FD, the defective enzyme is α-galactosidase A (α-Gal A), which is due to a mutation in the GLA gene on the X chromosome. The enzyme deficiency leads to a continuous deposition of neutral glycosphingolipids (globotriaosylceramide) in the lysosomes of numerous tissues and organs, including endothelial cells, smooth muscle cells, corneal epithelial cells, renal glomeruli and tubules, cardiac muscle and ganglion cells of the nervous system. This condition leads to progressive organ failure and premature death. The increasing understanding of FD, and LSD in general, has led in recent years to the introduction of enzyme replacement therapy (ERT), which aims to slow, if not halt, the progression of the metabolic disorder. In this review, we provide an overview of the main features of FD, focusing on its molecular mechanism and the role of biomarkers. Full article
(This article belongs to the Collection Feature Papers in Molecular Genetics)
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25 pages, 1639 KiB  
Review
Immunosenescence, Inflammaging, and Lung Senescence in Asthma in the Elderly
by Tomoyuki Soma and Makoto Nagata
Biomolecules 2022, 12(10), 1456; https://doi.org/10.3390/biom12101456 - 11 Oct 2022
Cited by 18 | Viewed by 3635
Abstract
Prevalence of asthma in older adults is growing along with increasing global life expectancy. Due to poor clinical consequences such as high mortality, advancement in understanding the pathophysiology of asthma in older patients has been sought to provide prompt treatment for them. Age-related [...] Read more.
Prevalence of asthma in older adults is growing along with increasing global life expectancy. Due to poor clinical consequences such as high mortality, advancement in understanding the pathophysiology of asthma in older patients has been sought to provide prompt treatment for them. Age-related alterations of functions in the immune system and lung parenchyma occur throughout life. Alterations with advancing age are promoted by various stimuli, including pathobionts, fungi, viruses, pollutants, and damage-associated molecular patterns derived from impaired cells, abandoned cell debris, and senescent cells. Age-related changes in the innate and adaptive immune response, termed immunosenescence, includes impairment of phagocytosis and antigen presentation, enhancement of proinflammatory mediator generation, and production of senescence-associated secretory phenotype. Immnunosenescence could promote inflammaging (chronic low-grade inflammation) and contribute to late-onset adult asthma and asthma in the elderly, along with age-related pulmonary disease, such as chronic obstructive pulmonary disease and pulmonary fibrosis, due to lung parenchyma senescence. Aged patients with asthma exhibit local and systemic type 2 and non-type 2 inflammation, associated with clinical manifestations. Here, we discuss immunosenescence’s contribution to the immune response and the combination of type 2 inflammation and inflammaging in asthma in the elderly and present an overview of age-related features in the immune system and lung structure. Full article
(This article belongs to the Special Issue Eosinophils in Allergy and Related Diseases—Selected Papers from “The Workshop on Eosinophils in Allergy and Related Diseases 2021”)
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29 pages, 2771 KiB  
Review
Introduction to Traditional Medicine and Their Role in Prevention and Treatment of Emerging and Re-Emerging Diseases
by Syed A. A. Rizvi, George P. Einstein, Orien L. Tulp, Frantz Sainvil and Rolando Branly
Biomolecules 2022, 12(10), 1442; https://doi.org/10.3390/biom12101442 - 9 Oct 2022
Cited by 17 | Viewed by 3813
Abstract
Infectious diseases have been a threat to human health globally. The relentless efforts and research have enabled us to overcome most of the diseases through the use of antiviral and antibiotic agents discovered and employed. Unfortunately, the microorganisms have the capability to adapt [...] Read more.
Infectious diseases have been a threat to human health globally. The relentless efforts and research have enabled us to overcome most of the diseases through the use of antiviral and antibiotic agents discovered and employed. Unfortunately, the microorganisms have the capability to adapt and mutate over time and antibiotic and antiviral resistance ensues. There are many challenges in treating infections such as failure of the microorganisms to respond to the therapeutic agents, which has led to more chronic infections, complications, and preventable loss of life. Thus, a multidisciplinary approach and collaboration is warranted to create more potent, effective, and versatile therapies to prevent and eradicate the old and newly emerging diseases. In the recent past, natural medicine has proven its effectiveness against various illnesses. Most of the pharmaceutical agents currently used can trace their origin to the natural products in one way, shape, or form. The full potential of natural products is yet to be realized, as numerous natural resources have not been explored and analyzed. This merits continuous support in research and analysis of ancient treatment systems to explore their full potential and employ them as an alternative or principal therapy. Full article
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Graphical abstract

16 pages, 2061 KiB  
Review
Galectin-10 as a Potential Biomarker for Eosinophilic Diseases
by Hiroki Tomizawa, Yoshiyuki Yamada, Misaki Arima, Yui Miyabe, Mineyo Fukuchi, Haruka Hikichi, Rossana C. N. Melo, Takechiyo Yamada and Shigeharu Ueki
Biomolecules 2022, 12(10), 1385; https://doi.org/10.3390/biom12101385 - 27 Sep 2022
Cited by 14 | Viewed by 4107
Abstract
Galectin-10 is a member of the lectin family and one of the most abundant cytoplasmic proteins in human eosinophils. Except for some myeloid leukemia cells, basophils, and minor T cell populations, galectin-10 is exclusively present in eosinophils in the human body. Galectin-10 forms [...] Read more.
Galectin-10 is a member of the lectin family and one of the most abundant cytoplasmic proteins in human eosinophils. Except for some myeloid leukemia cells, basophils, and minor T cell populations, galectin-10 is exclusively present in eosinophils in the human body. Galectin-10 forms Charcot–Leyden crystals, which are observed in various eosinophilic diseases. Accumulating studies have indicated that galectin-10 acts as a new biomarker for disease activity, diagnosis, and treatment effectiveness in asthma, eosinophilic esophagitis, rhinitis, sinusitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis. The extracellular release of galectin-10 is not mediated through conventional secretory processes (piecemeal degranulation or exocytosis), but rather by extracellular trap cell death (ETosis), which is an active cell death program. Eosinophils undergoing ETosis rapidly disintegrate their plasma membranes to release the majority of galectin-10. Therefore, elevated galectin-10 levels in serum and tissue suggest a high degree of eosinophil ETosis. To date, several studies have shown that galectin-10/Charcot–Leyden crystals are more than just markers for eosinophilic inflammation, but play functional roles in immunity. In this review, we focus on the close relationship between eosinophils and galectin-10, highlighting this protein as a potential new biomarker in eosinophilic diseases. Full article
(This article belongs to the Special Issue Eosinophils in Allergy and Related Diseases—Selected Papers from “The Workshop on Eosinophils in Allergy and Related Diseases 2021”)
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18 pages, 1714 KiB  
Review
Radiobiological Aspects of FLASH Radiotherapy
by Eline Hageman, Pei-Pei Che, Max Dahele, Ben J. Slotman and Peter Sminia
Biomolecules 2022, 12(10), 1376; https://doi.org/10.3390/biom12101376 - 26 Sep 2022
Cited by 17 | Viewed by 5324
Abstract
Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal tissue is the cornerstone of reducing toxicity. Advances in physical [...] Read more.
Radiotherapy (RT) is one of the primary treatment modalities for cancer patients. The clinical use of RT requires a balance to be struck between tumor effect and the risk of toxicity. Sparing normal tissue is the cornerstone of reducing toxicity. Advances in physical targeting and dose-shaping technology have helped to achieve this. FLASH RT is a promising, novel treatment technique that seeks to exploit a potential normal tissue-sparing effect of ultra-high dose rate irradiation. A significant body of in vitro and in vivo data has highlighted a decrease in acute and late radiation toxicities, while preserving the radiation effect in tumor cells. The underlying biological mechanisms of FLASH RT, however, remain unclear. Three main mechanisms have been hypothesized to account for this differential FLASH RT effect between the tumor and healthy tissue: the oxygen depletion, the DNA damage, and the immune-mediated hypothesis. These hypotheses and molecular mechanisms have been evaluated both in vitro and in vivo. Furthermore, the effect of ultra-high dose rate radiation with extremely short delivery times on the dynamic tumor microenvironment involving circulating blood cells and immune cells in humans is essentially unknown. Therefore, while there is great interest in FLASH RT as a means of targeting tumors with the promise of an increased therapeutic ratio, evidence of a generalized FLASH effect in humans and data to show that FLASH in humans is safe and at least effective against tumors as standard photon RT is currently lacking. FLASH RT needs further preclinical investigation and well-designed in-human studies before it can be introduced into clinical practice. Full article
(This article belongs to the Special Issue New Therapeutic Approaches in Gastrointestinal Cancers: A Step toward the Personalized Medicine)
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17 pages, 1437 KiB  
Review
Antipsychotic Drug Fluphenazine against Human Cancer Cells
by Diana Duarte and Nuno Vale
Biomolecules 2022, 12(10), 1360; https://doi.org/10.3390/biom12101360 - 23 Sep 2022
Cited by 5 | Viewed by 2813
Abstract
Drug repurposing is a strategy that can speed up and find novel clinical uses for already-approved drugs for several diseases, such as cancer. This process is accelerated compared to the development of new drugs because these compounds have already been tested in clinical [...] Read more.
Drug repurposing is a strategy that can speed up and find novel clinical uses for already-approved drugs for several diseases, such as cancer. This process is accelerated compared to the development of new drugs because these compounds have already been tested in clinical trials and data related to their pharmacokinetics is already described, reducing the costs and time associated with the development of new anticancer therapeutics. Several studies suggest that the repurposing of fluphenazine for cancer therapy may be a promising approach, as this drug proved to reduce the viability of diverse cancer cell lines. In this review, intensive research of the literature was performed related to the anticancer potential of fluphenazine in different human cancer cells. We have found several research articles on the cytotoxic effect of fluphenazine in lung, breast, colon, liver, brain, leukemia, oral, ovarian, and skin cancer and have summarized the main findings in this review. Taken together, these findings suggest that fluphenazine may regulate the cell cycle, reduce cell proliferation, and cause apoptosis in several types of cancer cells, besides being an established calmodulin inhibitor. It was also found that this drug is able to target cancer-related proteins, such as ABCB1 and P-glycoprotein as well as to regulate the Akt and Wnt signaling pathways. Some studies also refer this drug causes DNA alterations and interferes with cell invasion and migration ability as well as with ROS generation. Collectively, these results imply that fluphenazine may be a favorable compound for further research in oncologic therapy. Full article
(This article belongs to the Special Issue New Advances in Drug Repurposing for Oncology)
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22 pages, 1872 KiB  
Review
GPCRs in Intracellular Compartments: New Targets for Drug Discovery
by Irene Fasciani, Marco Carli, Francesco Petragnano, Francesco Colaianni, Gabriella Aloisi, Roberto Maggio, Marco Scarselli and Mario Rossi
Biomolecules 2022, 12(10), 1343; https://doi.org/10.3390/biom12101343 - 22 Sep 2022
Cited by 15 | Viewed by 4041
Abstract
The architecture of eukaryotic cells is defined by extensive membrane-delimited compartments, which entails separate metabolic processes that would otherwise interfere with each other, leading to functional differences between cells. G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors, and their [...] Read more.
The architecture of eukaryotic cells is defined by extensive membrane-delimited compartments, which entails separate metabolic processes that would otherwise interfere with each other, leading to functional differences between cells. G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors, and their signal transduction is traditionally viewed as a chain of events initiated from the plasma membrane. Furthermore, their intracellular trafficking, internalization, and recycling were considered only to regulate receptor desensitization and cell surface expression. On the contrary, accumulating data strongly suggest that GPCRs also signal from intracellular compartments. GPCRs localize in the membranes of endosomes, nucleus, Golgi and endoplasmic reticulum apparatuses, mitochondria, and cell division compartments. Importantly, from these sites they have shown to orchestrate multiple signals that regulate different cell pathways. In this review, we summarize the current knowledge of this fascinating phenomenon, explaining how GPCRs reach the intracellular sites, are stimulated by the endogenous ligands, and their potential physiological/pathophysiological roles. Finally, we illustrate several mechanisms involved in the modulation of the compartmentalized GPCR signaling by drugs and endogenous ligands. Understanding how GPCR signaling compartmentalization is regulated will provide a unique opportunity to develop novel pharmaceutical approaches to target GPCRs and potentially lead the way towards new therapeutic approaches. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)
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25 pages, 1978 KiB  
Review
From Small Peptides to Large Proteins against Alzheimer’sDisease
by Pasquale Picone, Tiziana Sanfilippo, Sonya Vasto, Sara Baldassano, Rossella Guggino, Domenico Nuzzo, Donatella Bulone, Pier Luigi San Biagio, Emanuela Muscolino, Roberto Monastero, Clelia Dispenza and Daniela Giacomazza
Biomolecules 2022, 12(10), 1344; https://doi.org/10.3390/biom12101344 - 22 Sep 2022
Cited by 6 | Viewed by 2297
Abstract
Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly. The two cardinal neuropathological hallmarks of AD are the senile plaques, which are extracellular deposits mainly constituted by beta-amyloids, and neurofibrillary tangles formed by abnormally phosphorylated Tau (p-Tau) located [...] Read more.
Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly. The two cardinal neuropathological hallmarks of AD are the senile plaques, which are extracellular deposits mainly constituted by beta-amyloids, and neurofibrillary tangles formed by abnormally phosphorylated Tau (p-Tau) located in the cytoplasm of neurons. Although the research has made relevant progress in the management of the disease, the treatment is still lacking. Only symptomatic medications exist for the disease, and, in the meantime, laboratories worldwide are investigating disease-modifying treatments for AD. In the present review, results centered on the use of peptides of different sizes involved in AD are presented. Full article
(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)
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12 pages, 978 KiB  
Review
Biomolecular Mechanisms of Cardiorenal Protection with Sodium-Glucose Co-Transporter 2 Inhibitors
by Francesca Romana Prandi, Lucy Barone, Dalgisio Lecis, Martina Belli, Domenico Sergi, Marialucia Milite, Stamatios Lerakis, Francesco Romeo and Francesco Barillà
Biomolecules 2022, 12(10), 1349; https://doi.org/10.3390/biom12101349 - 22 Sep 2022
Cited by 6 | Viewed by 2322
Abstract
Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia and associated with an increased risk of morbidity and mortality, primarily from cardiovascular and renal diseases. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) are novel drugs for the treatment of type 2 DM and [...] Read more.
Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia and associated with an increased risk of morbidity and mortality, primarily from cardiovascular and renal diseases. Sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) are novel drugs for the treatment of type 2 DM and heart failure (HF). SGLT2-Is mediate protective effects on both the renal and cardiovascular systems. This review addresses the current knowledge on the biomolecular mechanisms of the cardiorenal protective effects of SGLT2-Is, which appear to act mainly through non-glucose-mediated pathways. Cardiorenal protection mechanisms lead to reduced chronic renal disease progression and improved myocardial and coronary endothelial function. Concomitantly, it is possible to observe reflected changes in biomarkers linked with diabetic kidney disease and HF. Full article
(This article belongs to the Special Issue Biomarkers Profile and Biomolecular Signaling in Heart Failure and Cardiomyopathies)
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20 pages, 1127 KiB  
Review
Roles of Two-Component Signal Transduction Systems in Shigella Virulence
by Martina Pasqua, Marco Coluccia, Yoko Eguchi, Toshihide Okajima, Milena Grossi, Gianni Prosseda, Ryutaro Utsumi and Bianca Colonna
Biomolecules 2022, 12(9), 1321; https://doi.org/10.3390/biom12091321 - 18 Sep 2022
Cited by 13 | Viewed by 4061
Abstract
Two-component signal transduction systems (TCSs) are widespread types of protein machinery, typically consisting of a histidine kinase membrane sensor and a cytoplasmic transcriptional regulator that can sense and respond to environmental signals. TCSs are responsible for modulating genes involved in a multitude of [...] Read more.
Two-component signal transduction systems (TCSs) are widespread types of protein machinery, typically consisting of a histidine kinase membrane sensor and a cytoplasmic transcriptional regulator that can sense and respond to environmental signals. TCSs are responsible for modulating genes involved in a multitude of bacterial functions, including cell division, motility, differentiation, biofilm formation, antibiotic resistance, and virulence. Pathogenic bacteria exploit the capabilities of TCSs to reprogram gene expression according to the different niches they encounter during host infection. This review focuses on the role of TCSs in regulating the virulence phenotype of Shigella, an intracellular pathogen responsible for severe human enteric syndrome. The pathogenicity of Shigella is the result of the complex action of a wide number of virulence determinants located on the chromosome and on a large virulence plasmid. In particular, we will discuss how five TCSs, EnvZ/OmpR, CpxA/CpxR, ArcB/ArcA, PhoQ/PhoP, and EvgS/EvgA, contribute to linking environmental stimuli to the expression of genes related to virulence and fitness within the host. Considering the relevance of TCSs in the expression of virulence in pathogenic bacteria, the identification of drugs that inhibit TCS function may represent a promising approach to combat bacterial infections. Full article
(This article belongs to the Special Issue Theme Issue Honoring Scientist Louis Pasteur on His 200th Birthday)
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18 pages, 1763 KiB  
Review
Galectokines: The Promiscuous Relationship between Galectins and Cytokines
by Lucía Sanjurjo, Esmee C. Broekhuizen, Rory R. Koenen and Victor L. J. L. Thijssen
Biomolecules 2022, 12(9), 1286; https://doi.org/10.3390/biom12091286 - 13 Sep 2022
Cited by 13 | Viewed by 2428
Abstract
Galectins, a family of glycan-binding proteins, are well-known for their role in shaping the immune microenvironment. They can directly affect the activity and survival of different immune cell subtypes. Recent evidence suggests that galectins also indirectly affect the immune response by binding to [...] Read more.
Galectins, a family of glycan-binding proteins, are well-known for their role in shaping the immune microenvironment. They can directly affect the activity and survival of different immune cell subtypes. Recent evidence suggests that galectins also indirectly affect the immune response by binding to members of another immunoregulatory protein family, i.e., cytokines. Such galectin-cytokine heterodimers, here referred to as galectokines, add a new layer of complexity to the regulation of immune homeostasis. Here, we summarize the current knowledge with regard to galectokine formation and function. We describe the known and potential mechanisms by which galectokines can help to shape the immune microenvironment. Finally, the outstanding questions and challenges for future research regarding the role of galectokines in immunomodulation are discussed. Full article
(This article belongs to the Collection Galectins and Cancer)
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21 pages, 1830 KiB  
Review
Molecular Determinants Underlying the Anti-Cancer Efficacy of CD38 Monoclonal Antibodies in Hematological Malignancies
by Nurulhuda Mustafa, Muhamad Irfan Azaman, Giselle G. K. Ng and Wee Joo Chng
Biomolecules 2022, 12(9), 1261; https://doi.org/10.3390/biom12091261 - 8 Sep 2022
Cited by 3 | Viewed by 3025
Abstract
CD38 was first discovered as a T-cell antigen and has since been found ubiquitously expressed in various hematopoietic cells, including plasma cells, NK cells, B cells, and granulocytes. More importantly, CD38 expression levels on malignant hematopoietic cells are significantly higher than counterpart healthy [...] Read more.
CD38 was first discovered as a T-cell antigen and has since been found ubiquitously expressed in various hematopoietic cells, including plasma cells, NK cells, B cells, and granulocytes. More importantly, CD38 expression levels on malignant hematopoietic cells are significantly higher than counterpart healthy cells, thus presenting itself as a promising therapeutic target. In fact, for many aggressive hematological cancers, including CLL, DLBCL, T-ALL, and NKTL, CD38 expression is significantly associated with poorer prognosis and a hyperproliferative or metastatic phenotype. Studies have shown that, beyond being a biomarker, CD38 functionally mediates dysregulated survival, adhesion, and migration signaling pathways, as well as promotes an immunosuppressive microenvironment conducive for tumors to thrive. Thus, targeting CD38 is a rational approach to overcoming these malignancies. However, clinical trials have surprisingly shown that daratumumab monotherapy has not been very effective in these other blood malignancies. Furthermore, extensive use of daratumumab in MM is giving rise to a subset of patients now refractory to daratumumab treatment. Thus, it is important to consider factors modulating the determinants of response to CD38 targeting across different blood malignancies, encompassing both the transcriptional and post-transcriptional levels so that we can diversify the strategy to enhance daratumumab therapeutic efficacy, which can ultimately improve patient outcomes. Full article
(This article belongs to the Special Issue Immunotherapy and Cancer)
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40 pages, 2341 KiB  
Review
Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery
by Yeon Sun Lee
Biomolecules 2022, 12(9), 1241; https://doi.org/10.3390/biom12091241 - 5 Sep 2022
Cited by 8 | Viewed by 3151
Abstract
Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs [...] Read more.
Despite various advantages, opioid peptides have been limited in their therapeutic uses due to the main drawbacks in metabolic stability, blood-brain barrier permeability, and bioavailability. Therefore, extensive studies have focused on overcoming the problems and optimizing the therapeutic potential. Currently, numerous peptide-based drugs are being marketed thanks to new synthetic strategies for optimizing metabolism and alternative routes of administration. This tutorial review briefly introduces the history and role of natural opioid peptides and highlights the key findings on their structure-activity relationships for the opioid receptors. It discusses details on opioid peptidomimetics applied to develop therapeutic candidates for the treatment of pain from the pharmacological and structural points of view. The main focus is the current status of various mimetic tools and the successful applications summarized in tables and figures. Full article
(This article belongs to the Special Issue Recent Advances in Central Nervous System Drug Discovery)
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15 pages, 1583 KiB  
Review
Role of Reactive Oxygen Species in Glucose Metabolism Disorder in Diabetic Pancreatic β-Cells
by Eri Mukai, Shimpei Fujimoto and Nobuya Inagaki
Biomolecules 2022, 12(9), 1228; https://doi.org/10.3390/biom12091228 - 2 Sep 2022
Cited by 22 | Viewed by 4740
Abstract
The dysfunction of pancreatic β-cells plays a central role in the onset and progression of type 2 diabetes mellitus (T2DM). Insulin secretory defects in β-cells are characterized by a selective impairment of glucose stimulation, and a reduction in glucose-induced ATP production, which is [...] Read more.
The dysfunction of pancreatic β-cells plays a central role in the onset and progression of type 2 diabetes mellitus (T2DM). Insulin secretory defects in β-cells are characterized by a selective impairment of glucose stimulation, and a reduction in glucose-induced ATP production, which is essential for insulin secretion. High glucose metabolism for insulin secretion generates reactive oxygen species (ROS) in mitochondria. In addition, the expression of antioxidant enzymes is very low in β-cells. Therefore, β-cells are easily exposed to oxidative stress. In islet studies using a nonobese T2DM animal model that exhibits selective impairment of glucose-induced insulin secretion (GSIS), quenching ROS generated by glucose stimulation and accumulated under glucose toxicity can improve impaired GSIS. Acute ROS generation and toxicity cause glucose metabolism disorders through different molecular mechanisms. Nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor, is a master regulator of antioxidant defense and a potential therapeutic target in oxidative stress-related diseases, suggesting the possible involvement of Nrf2 in β-cell dysfunction caused by ROS. In this review, we describe the mechanisms of insulin secretory defects induced by oxidative stress in diabetic β-cells. Full article
(This article belongs to the Special Issue The Pancreatic Beta Cell)
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14 pages, 514 KiB  
Review
Plasma of Argon Treatment of the Implant Surface, Systematic Review of In Vitro Studies
by Massimo Carossa, Davide Cavagnetto, Francesca Mancini, Alessandro Mosca Balma and Federico Mussano
Biomolecules 2022, 12(9), 1219; https://doi.org/10.3390/biom12091219 - 1 Sep 2022
Cited by 18 | Viewed by 2219
Abstract
This paper aims to review the evidence of the cellular activity on titanium samples exposed to Plasma of Argon (PoA) treatment. A systematic review was carried out based on the PRISMA statement by searching the Cochrane Library, PubMed, Web of Science, EMBASE and [...] Read more.
This paper aims to review the evidence of the cellular activity on titanium samples exposed to Plasma of Argon (PoA) treatment. A systematic review was carried out based on the PRISMA statement by searching the Cochrane Library, PubMed, Web of Science, EMBASE and Scopus, up to October 2020. Papers were selected according to PICOS format that is: Population (P): osteoblasts, fibroblasts, gingival cells; Intervention (I): PoA disinfection treatment; Comparison (C): untreated controls; Outcome (O): cell culture; Setting (S): in vitro assays. The quality assessment was performed according to the CRIS Guidelines (Checklist for Reporting In vitro Studies). A total of 661 articles were found, of which 16 were included. The quality assessment revealed an overall poor quality of the studies analyzed. In vitro studies on the potential of PoA showed a potential effect in promoting higher cell adhesion and protein adsorption in the earliest times (hours). This outcome was not so evident when later stages of cell growth on the surfaces were tested and compared to the control groups. Only one study was conducted in vivo on a human sample regarding abutment cleaning. No meta-analysis was conducted because of the variety of experimental settings, mixed methods and different cell lines studied. PoA seems to be effective in promoting cell adhesion and protein adsorption. The duration of this effect remains unclear. Further evidence is required to demonstrate the long-term efficacy of the treatment and to support the use of PoA treatment in clinical practice. Full article
(This article belongs to the Special Issue 3D Printing Biological and Medical Application)
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19 pages, 1507 KiB  
Review
The Next Frontier in Health Disparities—A Closer Look at Exploring Sex Differences in Glioma Data and Omics Analysis, from Bench to Bedside and Back
by Maria Diaz Rosario, Harpreet Kaur, Erdal Tasci, Uma Shankavaram, Mary Sproull, Ying Zhuge, Kevin Camphausen and Andra Krauze
Biomolecules 2022, 12(9), 1203; https://doi.org/10.3390/biom12091203 - 30 Aug 2022
Cited by 2 | Viewed by 2123
Abstract
Sex differences are increasingly being explored and reported in oncology, and glioma is no exception. As potentially meaningful sex differences are uncovered, existing gender-derived disparities mirror data generated in retrospective and prospective trials, real-world large-scale data sets, and bench work involving animals and [...] Read more.
Sex differences are increasingly being explored and reported in oncology, and glioma is no exception. As potentially meaningful sex differences are uncovered, existing gender-derived disparities mirror data generated in retrospective and prospective trials, real-world large-scale data sets, and bench work involving animals and cell lines. The resulting disparities at the data level are wide-ranging, potentially resulting in both adverse outcomes and failure to identify and exploit therapeutic benefits. We set out to analyze the literature on women’s data disparities in glioma by exploring the origins of data in this area to understand the representation of women in study samples and omics analyses. Given the current emphasis on inclusive study design and research, we wanted to explore if sex bias continues to exist in present-day data sets and how sex differences in data may impact conclusions derived from large-scale data sets, omics, biospecimen analysis, novel interventions, and standard of care management. Full article
(This article belongs to the Special Issue Sex Differences in Biomedical Research)
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14 pages, 1609 KiB  
Review
Palmitoylethanolamide and Related ALIAmides for Small Animal Health: State of the Art
by Giorgia della Rocca and Giovanni Re
Biomolecules 2022, 12(9), 1186; https://doi.org/10.3390/biom12091186 - 26 Aug 2022
Cited by 3 | Viewed by 2974
Abstract
ALIAmides are a family of fatty acid amides whose name comes from their mechanism of action, i.e., the Autacoid Local Injury Antagonism (ALIA). Actually, the ALIAmide parent molecule, palmitoylethanolamide (PEA), is locally produced on demand from a cell membrane precursor in order to [...] Read more.
ALIAmides are a family of fatty acid amides whose name comes from their mechanism of action, i.e., the Autacoid Local Injury Antagonism (ALIA). Actually, the ALIAmide parent molecule, palmitoylethanolamide (PEA), is locally produced on demand from a cell membrane precursor in order to control immune-inflammatory cell responses, avert chronic non-resolving inflammation, and limit the resulting clinical signs. ALIAmide sister compounds, such as Adelmidrol and palmitoylglucosamine, share mechanisms of action with PEA and may also increase endogenous levels of PEA. Provided that their respective bioavailability is properly addressed (e.g., through decreasing the particle size through micronization), exogenously administered ALIAmides thus mimic or sustain the prohomeostatic functions of endogenous PEA. The aim of the present paper is to review the main findings on the use of ALIAmides in small animals as a tribute to the man of vision who first believed in this “according-to-nature” approach, namely Francesco della Valle. After briefly presenting some key issues on the molecular targets, metabolism, and pharmacokinetics of PEA and related ALIAmides, here we will focus on the preclinical and clinical studies performed in dogs and cats. Although more data are still needed, ALIAmides may represent a novel and promising approach to small animal health. Full article
(This article belongs to the Special Issue To Go Where Nature Leads: Focus on Palmitoylethanolamide and Related ALIAmides As Innovative Approach to Neuroinflammatory and Pain-Related Disease States in Honor of Doctor Francesco Della Valle)
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23 pages, 1993 KiB  
Review
Lipotoxicity as a Barrier for T Cell-Based Therapies
by Romy Böttcher-Loschinski, Judit Rial Saborido, Martin Böttcher, Sascha Kahlfuss and Dimitrios Mougiakakos
Biomolecules 2022, 12(9), 1182; https://doi.org/10.3390/biom12091182 - 25 Aug 2022
Viewed by 2648
Abstract
Nowadays, T-cell-based approaches play an increasing role in cancer treatment. In particular, the use of (genetically engineered) T-cells has heralded a novel era for various diseases with previously poor outcomes. Concurrently, the relationship between the functional behavior of immune cells and their metabolic [...] Read more.
Nowadays, T-cell-based approaches play an increasing role in cancer treatment. In particular, the use of (genetically engineered) T-cells has heralded a novel era for various diseases with previously poor outcomes. Concurrently, the relationship between the functional behavior of immune cells and their metabolic state, known as immunometabolism, has been found to be an important determinant for the success of immunotherapy. In this context, immune cell metabolism is not only controlled by the expression of transcription factors, enzymes and transport proteins but also by nutrient availability and the presence of intermediate metabolites. The lack of as well as an oversupply of nutrients can be detrimental and lead to cellular dysfunction and damage, potentially resulting in reduced metabolic fitness and/or cell death. This review focusses on the detrimental effects of excessive exposure of T cells to fatty acids, known as lipotoxicity, in the context of an altered lipid tumor microenvironment. Furthermore, implications of T cell-related lipotoxicity for immunotherapy will be discussed, as well as potential therapeutic approaches. Full article
(This article belongs to the Special Issue Immunotherapy and Cancer)
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13 pages, 1002 KiB  
Review
Nicotinamide N-Methyltransferase as Promising Tool for Management of Gastrointestinal Neoplasms
by Valentina Pozzi, Roberto Campagna, Davide Sartini and Monica Emanuelli
Biomolecules 2022, 12(9), 1173; https://doi.org/10.3390/biom12091173 - 24 Aug 2022
Cited by 15 | Viewed by 2286
Abstract
Gastrointestinal (GI) neoplasms include esophageal, gastric, colorectal, hepatic, and pancreatic cancers. They are characterized by asymptomatic behavior, being responsible for diagnostic delay. Substantial refractoriness to chemo- and radiotherapy, exhibited by late-stage tumors, contribute to determine poor patient outcome. Therefore, it is of outmost [...] Read more.
Gastrointestinal (GI) neoplasms include esophageal, gastric, colorectal, hepatic, and pancreatic cancers. They are characterized by asymptomatic behavior, being responsible for diagnostic delay. Substantial refractoriness to chemo- and radiotherapy, exhibited by late-stage tumors, contribute to determine poor patient outcome. Therefore, it is of outmost importance to identify new molecular targets for the development of effective therapeutic strategies. In this study, we focused on the enzyme nicotinamide N-methyltransferase (NNMT), which catalyzes the N-methylation reaction of nicotinamide and whose overexpression has been reported in numerous neoplasms, including GI cancers. The aim of this review was to report data illustrating NNMT involvement in these tumors, highlighting its contribution to tumor cell phenotype. Cited works clearly demonstrate the interesting potential use of enzyme level determination for both diagnostic and prognostic purposes. NNMT was also found to positively affect cell viability, proliferation, migration, and invasiveness, contributing to sustain in vitro and in vivo tumor growth and metastatic spread. Moreover, enzyme upregulation featuring tumor cells was significantly associated with enhancement of resistance to treatment with chemotherapeutic drugs. Taken together, these results strongly suggest the possibility to target NNMT for setup of molecular-based strategies to effectively treat GI cancers. Full article
(This article belongs to the Special Issue Biomarkers and Therapeutical Targets in Precision Medicine)
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22 pages, 819 KiB  
Review
Cytosolic Hsp90 Isoform-Specific Functions and Clinical Significance
by Samarpan Maiti and Didier Picard
Biomolecules 2022, 12(9), 1166; https://doi.org/10.3390/biom12091166 - 23 Aug 2022
Cited by 23 | Viewed by 3891
Abstract
The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two cytosolic Hsp90 isoforms: Hsp90α and Hsp90β. These two isoforms are 85% identical and encoded by two [...] Read more.
The heat shock protein 90 (Hsp90) is a molecular chaperone and a key regulator of proteostasis under both physiological and stress conditions. In mammals, there are two cytosolic Hsp90 isoforms: Hsp90α and Hsp90β. These two isoforms are 85% identical and encoded by two different genes. Hsp90β is constitutively expressed and essential for early mouse development, while Hsp90α is stress-inducible and not necessary for survivability. These two isoforms are known to have largely overlapping functions and to interact with a large fraction of the proteome. To what extent there are isoform-specific functions at the protein level has only relatively recently begun to emerge. There are studies indicating that one isoform is more involved in the functionality of a specific tissue or cell type. Moreover, in many diseases, functionally altered cells appear to be more dependent on one particular isoform. This leaves space for designing therapeutic strategies in an isoform-specific way, which may overcome the unfavorable outcome of pan-Hsp90 inhibition encountered in previous clinical trials. For this to succeed, isoform-specific functions must be understood in more detail. In this review, we summarize the available information on isoform-specific functions of mammalian Hsp90 and connect it to possible clinical applications. Full article
(This article belongs to the Special Issue Hsp90 Structure, Mechanism and Disease)
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16 pages, 1196 KiB  
Review
Synaptic Effects of Palmitoylethanolamide in Neurodegenerative Disorders
by Martina Assogna, Francesco Di Lorenzo, Alessandro Martorana and Giacomo Koch
Biomolecules 2022, 12(8), 1161; https://doi.org/10.3390/biom12081161 - 22 Aug 2022
Cited by 10 | Viewed by 3456
Abstract
Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and [...] Read more.
Increasing evidence strongly supports the key role of neuroinflammation in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease, frontotemporal dementia, and amyotrophic lateral sclerosis. Neuroinflammation may alter synaptic transmission contributing to the progression of neurodegeneration, as largely documented in animal models and in patients’ studies. In the last few years, palmitoylethanolamide (PEA), an endogenous lipid mediator, and its new composite, which is a formulation constituted of PEA and the well-recognized antioxidant flavonoid luteolin (Lut) subjected to an ultra-micronization process (co-ultraPEALut), has been identified as a potential therapeutic agent in different disorders by exerting potential beneficial effects on neurodegeneration and neuroinflammation by modulating synaptic transmission. In this review, we will show the potential therapeutic effects of PEA in animal models and in patients affected by neurodegenerative disorders. Full article
(This article belongs to the Special Issue To Go Where Nature Leads: Focus on Palmitoylethanolamide and Related ALIAmides As Innovative Approach to Neuroinflammatory and Pain-Related Disease States in Honor of Doctor Francesco Della Valle)
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16 pages, 1196 KiB  
Review
Heat Shock Protein 90 (Hsp90) and Hsp70 as Potential Therapeutic Targets in Autoimmune Skin Diseases
by Stefan Tukaj and Krzysztof Sitko
Biomolecules 2022, 12(8), 1153; https://doi.org/10.3390/biom12081153 - 20 Aug 2022
Cited by 18 | Viewed by 4058
Abstract
Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to one-fifth of the world’s population suffers from chronic, noninfectious inflammatory skin diseases, the development [...] Read more.
Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to one-fifth of the world’s population suffers from chronic, noninfectious inflammatory skin diseases, the development of which is significantly influenced by an autoimmune response. One of the hallmarks of autoimmune diseases is the loss of immune tolerance, which leads to the formation of autoreactive lymphocytes or autoantibodies and, consequently, to chronic inflammation and tissue damage. The treatment of autoimmune skin diseases mainly focuses on immunosuppression (using, e.g., corticosteroids) but almost never leads to the development of permanent mechanisms of immune tolerance. In addition, current therapies and their long-term administration may cause serious adverse effects. Hence, safer and more effective therapies that bring sustained balance between pro- and anti-inflammatory responses are still desired. Both intra- and extracellular heat shock proteins (Hsps), specifically well-characterized inducible Hsp90 and Hsp70 chaperones, have been highlighted as therapeutic targets for autoimmune diseases. This review presents preclinical data on the involvement of Hsp90 and Hsp70 in modulating the immune response, specifically in the context of the treatment of selected autoimmune skin diseases with emphasis on autoimmune bullous skin diseases and psoriasis. Full article
(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)
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15 pages, 1605 KiB  
Review
STIM Proteins and Regulation of SOCE in ER-PM Junctions
by Moaz Ahmad, Sasirekha Narayanasamy, Hwei Ling Ong and Indu Ambudkar
Biomolecules 2022, 12(8), 1152; https://doi.org/10.3390/biom12081152 - 20 Aug 2022
Cited by 6 | Viewed by 2584
Abstract
ER-PM junctions are membrane contact sites formed by the endoplasmic reticulum (ER) and plasma membrane (PM) in close apposition together. The formation and stability of these junctions are dependent on constitutive and dynamic enrichment of proteins, which either contribute to junctional stability or [...] Read more.
ER-PM junctions are membrane contact sites formed by the endoplasmic reticulum (ER) and plasma membrane (PM) in close apposition together. The formation and stability of these junctions are dependent on constitutive and dynamic enrichment of proteins, which either contribute to junctional stability or modulate the lipid levels of both ER and plasma membranes. The ER-PM junctions have come under much scrutiny recently as they serve as hubs for assembling the Ca2+ signaling complexes. This review summarizes: (1) key findings that underlie the abilities of STIM proteins to accumulate in ER-PM junctions; (2) the modulation of Orai/STIM complexes by other components found within the same junction; and (3) how Orai1 channel activation is coordinated and coupled with downstream signaling pathways. Full article
(This article belongs to the Special Issue Lipid-Gating and Lipid-Protein Interactions in Ion Channels)
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23 pages, 1100 KiB  
Review
Race for the Cure: From the Oldest to the Newest Monoclonal Antibodies for Multiple Myeloma Treatment
by Gianfranco Lapietra, Francesca Fazio and Maria Teresa Petrucci
Biomolecules 2022, 12(8), 1146; https://doi.org/10.3390/biom12081146 - 19 Aug 2022
Cited by 4 | Viewed by 2895
Abstract
Multiple myeloma is characterized by a wide clinical heterogeneity due to an intricate network of interactions between bone marrow-resident clonal plasma cells and the microenvironment. Over the last years, dramatic improvement in the understanding of these pathways led to the introduction of novel [...] Read more.
Multiple myeloma is characterized by a wide clinical heterogeneity due to an intricate network of interactions between bone marrow-resident clonal plasma cells and the microenvironment. Over the last years, dramatic improvement in the understanding of these pathways led to the introduction of novel drugs with immune-mediated mechanisms of action. Some of these compounds, such as the anti-cd38 daratumumab and isatuximab, the anti-slamf-7 elotuzumab, and the antibody-drug conjugate belantamab-mafodotin, have been tested in large clinical trials and have now fully entered the real-life management. The bispecific T-cell engagers are under investigation with promising results, and other satisfactory data is expected from the application of nanotechnologies. The perfect timing to introduce these drugs in the sequence of treatment and their adverse events represent new challenges to be addressed, and further experience is required to improve their use. Full article
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16 pages, 1724 KiB  
Review
A Review of Biomarkers of Cardiac Allograft Rejection: Toward an Integrated Diagnosis of Rejection
by Guillaume Coutance, Eva Desiré and Jean-Paul Duong Van Huyen
Biomolecules 2022, 12(8), 1135; https://doi.org/10.3390/biom12081135 - 18 Aug 2022
Cited by 5 | Viewed by 2235
Abstract
Despite major advances in immunosuppression, allograft rejection remains an important complication after heart transplantation, and it is associated with increased morbidity and mortality. The gold standard invasive strategy to monitor and diagnose cardiac allograft rejection, based on the pathologic evaluation of endomyocardial biopsies, [...] Read more.
Despite major advances in immunosuppression, allograft rejection remains an important complication after heart transplantation, and it is associated with increased morbidity and mortality. The gold standard invasive strategy to monitor and diagnose cardiac allograft rejection, based on the pathologic evaluation of endomyocardial biopsies, suffers from many limitations including the low prevalence of rejection, sample bias, high inter-observer variability, and international working formulations based on arbitrary cut-offs that simplify the landscape of rejection. The development of innovative diagnostic and prognostic strategies—integrating conventional histology, molecular profiling of allograft biopsy, and the discovery of new tissue or circulating biomarkers—is one of the major challenges of translational medicine in solid organ transplantation, and particularly in heart transplantation. Major advances in the field of biomarkers of rejection have paved the way for a paradigm shift in the monitoring and diagnosis of cardiac allograft rejection. We review the recent developments in the field, including non-invasive biomarkers to minimize the number of protocol endomyocardial biopsies and tissue biomarkers as companion tools of pathology to refine the diagnosis of cardiac rejection. Finally, we discuss the potential role of these biomarkers to provide an integrated bio-histomolecular diagnosis of cardiac allograft rejection. Full article
(This article belongs to the Special Issue New Biomarkers in Solid Organ Transplantation)
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19 pages, 1935 KiB  
Review
In Vitro Modeling of the Blood–Brain Barrier for the Study of Physiological Conditions and Alzheimer’s Disease
by Thomas Gabriel Schreiner, Ioana Creangă-Murariu, Bogdan Ionel Tamba, Nicolae Lucanu and Bogdan Ovidiu Popescu
Biomolecules 2022, 12(8), 1136; https://doi.org/10.3390/biom12081136 - 18 Aug 2022
Cited by 12 | Viewed by 3230
Abstract
The blood–brain barrier (BBB) is an essential structure for the maintenance of brain homeostasis. Alterations to the BBB are linked with a myriad of pathological conditions and play a significant role in the onset and evolution of neurodegenerative diseases, including Alzheimer’s disease. Thus, [...] Read more.
The blood–brain barrier (BBB) is an essential structure for the maintenance of brain homeostasis. Alterations to the BBB are linked with a myriad of pathological conditions and play a significant role in the onset and evolution of neurodegenerative diseases, including Alzheimer’s disease. Thus, a deeper understanding of the BBB’s structure and function is mandatory for a better knowledge of neurodegenerative disorders and the development of effective therapies. Because studying the BBB in vivo imposes overwhelming difficulties, the in vitro approach remains the main possible way of research. With many in vitro BBB models having been developed over the last years, the main aim of this review is to systematically present the most relevant designs used in neurological research. In the first part of the article, the physiological and structural–functional parameters of the human BBB are detailed. Subsequently, available BBB models are presented in a comparative approach, highlighting their advantages and limitations. Finally, the new perspectives related to the study of Alzheimer’s disease with the help of novel devices that mimic the in vivo human BBB milieu gives the paper significant originality. Full article
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15 pages, 1047 KiB  
Review
Advancing Our Understanding of the Chronically Denervated Schwann Cell: A Potential Therapeutic Target?
by Liam A. McMorrow, Adrian Kosalko, Daniel Robinson, Alberto Saiani and Adam J. Reid
Biomolecules 2022, 12(8), 1128; https://doi.org/10.3390/biom12081128 - 17 Aug 2022
Cited by 6 | Viewed by 2456
Abstract
Outcomes for patients following major peripheral nerve injury are extremely poor. Despite advanced microsurgical techniques, the recovery of function is limited by an inherently slow rate of axonal regeneration. In particular, a time-dependent deterioration in the ability of the distal stump to support [...] Read more.
Outcomes for patients following major peripheral nerve injury are extremely poor. Despite advanced microsurgical techniques, the recovery of function is limited by an inherently slow rate of axonal regeneration. In particular, a time-dependent deterioration in the ability of the distal stump to support axonal growth is a major determinant to the failure of reinnervation. Schwann cells (SC) are crucial in the orchestration of nerve regeneration; their plasticity permits the adoption of a repair phenotype following nerve injury. The repair SC modulates the initial immune response, directs myelin clearance, provides neurotrophic support and remodels the distal nerve. These functions are critical for regeneration; yet the repair phenotype is unstable in the setting of chronic denervation. This phenotypic instability accounts for the deteriorating regenerative support offered by the distal nerve stump. Over the past 10 years, our understanding of the cellular machinery behind this repair phenotype, in particular the role of c-Jun, has increased exponentially, creating opportunities for therapeutic intervention. This review will cover the activation of the repair phenotype in SC, the effects of chronic denervation on SC and current strategies to ‘hack’ these cellular pathways toward supporting more prolonged periods of neural regeneration. Full article
(This article belongs to the Special Issue Recent Advances in Schwann Cells)
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25 pages, 1657 KiB  
Review
Minor Phytocannabinoids: A Misleading Name but a Promising Opportunity for Biomedical Research
by Diego Caprioglio, Hawraz Ibrahim M. Amin, Orazio Taglialatela-Scafati, Eduardo Muñoz and Giovanni Appendino
Biomolecules 2022, 12(8), 1084; https://doi.org/10.3390/biom12081084 - 6 Aug 2022
Cited by 10 | Viewed by 2982
Abstract
Despite the very large number of phytocannabinoids isolated from Cannabis (Cannabis sativa L.), bioactivity studies have long remained focused on the so called “Big Four” [Δ9-THC (1), CBD (2), CBG (3) and CBC ( [...] Read more.
Despite the very large number of phytocannabinoids isolated from Cannabis (Cannabis sativa L.), bioactivity studies have long remained focused on the so called “Big Four” [Δ9-THC (1), CBD (2), CBG (3) and CBC (4)] because of their earlier characterization and relatively easy availability via isolation and/or synthesis. Bioactivity information on the chemical space associated with the remaining part of the cannabinome, a set of ca 150 compounds traditionally referred to as “minor phytocannabinoids”, is scarce and patchy, yet promising in terms of pharmacological potential. According to their advancement stage, we sorted the bioactivity data available on these compounds, better referred to as the “dark cannabinome”, into categories: discovery (in vitro phenotypical and biochemical assays), preclinical (animal models), and clinical. Strategies to overcome the availability issues associated with minor phytocannabinoids are discussed, as well as the still unmet challenges facing their development as mainstream drugs. Full article
(This article belongs to the Special Issue Chemistry, Biosynthesis and Biological Activity of Natural Substances: A Themed Issue Dedicated to Professor Evidente)
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39 pages, 15358 KiB  
Review
Detergent-Free Isolation of Membrane Proteins and Strategies to Study Them in a Near-Native Membrane Environment
by Bankala Krishnarjuna and Ayyalusamy Ramamoorthy
Biomolecules 2022, 12(8), 1076; https://doi.org/10.3390/biom12081076 - 4 Aug 2022
Cited by 17 | Viewed by 7867
Abstract
Atomic-resolution structural studies of membrane-associated proteins and peptides in a membrane environment are important to fully understand their biological function and the roles played by them in the pathology of many diseases. However, the complexity of the cell membrane has severely limited the [...] Read more.
Atomic-resolution structural studies of membrane-associated proteins and peptides in a membrane environment are important to fully understand their biological function and the roles played by them in the pathology of many diseases. However, the complexity of the cell membrane has severely limited the application of commonly used biophysical and biochemical techniques. Recent advancements in NMR spectroscopy and cryoEM approaches and the development of novel membrane mimetics have overcome some of the major challenges in this area. For example, the development of a variety of lipid-nanodiscs has enabled stable reconstitution and structural and functional studies of membrane proteins. In particular, the ability of synthetic amphipathic polymers to isolate membrane proteins directly from the cell membrane, along with the associated membrane components such as lipids, without the use of a detergent, has opened new avenues to study the structure and function of membrane proteins using a variety of biophysical and biological approaches. This review article is focused on covering the various polymers and approaches developed and their applications for the functional reconstitution and structural investigation of membrane proteins. The unique advantages and limitations of the use of synthetic polymers are also discussed. Full article
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19 pages, 820 KiB  
Review
Viral Complexity
by Frank O. Aylward and Mohammad Moniruzzaman
Biomolecules 2022, 12(8), 1061; https://doi.org/10.3390/biom12081061 - 30 Jul 2022
Cited by 6 | Viewed by 5094
Abstract
Although traditionally viewed as streamlined and simple, discoveries over the last century have revealed that viruses can exhibit surprisingly complex physical structures, genomic organization, ecological interactions, and evolutionary histories. Viruses can have physical dimensions and genome lengths that exceed many cellular lineages, and [...] Read more.
Although traditionally viewed as streamlined and simple, discoveries over the last century have revealed that viruses can exhibit surprisingly complex physical structures, genomic organization, ecological interactions, and evolutionary histories. Viruses can have physical dimensions and genome lengths that exceed many cellular lineages, and their infection strategies can involve a remarkable level of physiological remodeling of their host cells. Virus–virus communication and widespread forms of hyperparasitism have been shown to be common in the virosphere, demonstrating that dynamic ecological interactions often shape their success. And the evolutionary histories of viruses are often fraught with complexities, with chimeric genomes including genes derived from numerous distinct sources or evolved de novo. Here we will discuss many aspects of this viral complexity, with particular emphasis on large DNA viruses, and provide an outlook for future research. 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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22 pages, 2265 KiB  
Review
Targeting Oxidative Stress Involved in Endometriosis and Its Pain
by Lauren Clower, Taylor Fleshman, Werner J. Geldenhuys and Nalini Santanam
Biomolecules 2022, 12(8), 1055; https://doi.org/10.3390/biom12081055 - 29 Jul 2022
Cited by 28 | Viewed by 6254
Abstract
Endometriosis is a common gynecological disorder seen in women and is characterized by chronic pelvic pain and infertility. This disorder is becoming more prevalent with increased morbidity. The etiology of endometriosis remains to be fully elucidated, which will lead to improved therapeutic options. [...] Read more.
Endometriosis is a common gynecological disorder seen in women and is characterized by chronic pelvic pain and infertility. This disorder is becoming more prevalent with increased morbidity. The etiology of endometriosis remains to be fully elucidated, which will lead to improved therapeutic options. In this review, we will evaluate the biochemical mechanisms leading to oxidative stress and their implication in the pathophysiology of endometriosis, as well as potential treatments that target these processes. A comprehensive exploration of previous research revealed that endometriosis is associated with elevated reactive oxygen species and oxidation products, decreased antioxidants and detoxification enzymes, and dysregulated iron metabolism. High levels of oxidative stress contributed to inflammation, extracellular matrix degradation, angiogenesis, and cell proliferation, which may explain its role in endometriosis. Endometriosis-associated pain was attributed to neurogenic inflammation and a feed-forward mechanism involving macrophages, pro-inflammatory cytokines, and pain-inducing prostaglandins. N-acetylcysteine, curcumin, melatonin, and combined vitamin C and E supplementation displayed promising results for the treatment of endometriosis, but further research is needed for their use in this population. Full article
(This article belongs to the Special Issue Focusing on Free Radicals in Oxidative Stress-Related Human Diseases: Perspectives and Therapeutical Approaches)
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15 pages, 532 KiB  
Review
Dostarlimab: A Review
by Bárbara Costa and Nuno Vale
Biomolecules 2022, 12(8), 1031; https://doi.org/10.3390/biom12081031 - 26 Jul 2022
Cited by 32 | Viewed by 7885
Abstract
Dostarlimab (JEMPERLI) is a PD-1 monoclonal antibody for the treatment of adult patients, with mismatch repair deficient (dMMR), recurrent or advanced endometrial cancer that has progressed on or following prior therapy with a platinum-containing regimen. As determined by an FDA-approved test this indication [...] Read more.
Dostarlimab (JEMPERLI) is a PD-1 monoclonal antibody for the treatment of adult patients, with mismatch repair deficient (dMMR), recurrent or advanced endometrial cancer that has progressed on or following prior therapy with a platinum-containing regimen. As determined by an FDA-approved test this indication was granted rapid approval based on the rate of tumor response and the duration of the response. Continued approval for this indication is conditioned on further confirmatory trials demonstrating and documenting clinical benefit. In June 2022, the clinical trial NCT04165772 reported a 100% remission rate for rectal cancer. This clinical trial brought proof that we can match a tumor and the genetics of what is driving it, with therapy. This clinical trial continues to enroll patient and is currently enrolling patients with gastric, prostate, and pancreatic cancers. Dostarlamib is being recommended for rectal cancer. The focus of this review is to summarize the existing knowledge regarding Dostarlimab and explore the possibilities of mono- and combination therapies. Full article
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19 pages, 1868 KiB  
Review
Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease
by Ewan Douglas Fowler and Spyros Zissimopoulos
Biomolecules 2022, 12(8), 1030; https://doi.org/10.3390/biom12081030 - 26 Jul 2022
Cited by 11 | Viewed by 3347
Abstract
The ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary [...] Read more.
The ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca2+ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca2+ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca2+ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na+/Ca2+ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level. Full article
(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)
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25 pages, 8303 KiB  
Review
Degradation of Exogenous Fatty Acids in Escherichia coli
by Viola Pavoncello, Frédéric Barras and Emmanuelle Bouveret
Biomolecules 2022, 12(8), 1019; https://doi.org/10.3390/biom12081019 - 22 Jul 2022
Cited by 14 | Viewed by 4258
Abstract
Many bacteria possess all the machineries required to grow on fatty acids (FA) as a unique source of carbon and energy. FA degradation proceeds through the β-oxidation cycle that produces acetyl-CoA and reduced NADH and FADH cofactors. In addition to all the enzymes [...] Read more.
Many bacteria possess all the machineries required to grow on fatty acids (FA) as a unique source of carbon and energy. FA degradation proceeds through the β-oxidation cycle that produces acetyl-CoA and reduced NADH and FADH cofactors. In addition to all the enzymes required for β-oxidation, FA degradation also depends on sophisticated systems for its genetic regulation and for FA transport. The fact that these machineries are conserved in bacteria suggests a crucial role in environmental conditions, especially for enterobacteria. Bacteria also possess specific enzymes required for the degradation of FAs from their environment, again showing the importance of this metabolism for bacterial adaptation. In this review, we mainly describe FA degradation in the Escherichia coli model, and along the way, we highlight and discuss important aspects of this metabolism that are still unclear. We do not detail exhaustively the diversity of the machineries found in other bacteria, but we mention them if they bring additional information or enlightenment on specific aspects. Full article
(This article belongs to the Special Issue Theme Issue Honoring Scientist Louis Pasteur on His 200th Birthday)
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15 pages, 1892 KiB  
Review
Comparison of Tau and Amyloid-β Targeted Immunotherapy Nanoparticles for Alzheimer’s Disease
by Yara Mashal, Hosam Abdelhady and Arun K. Iyer
Biomolecules 2022, 12(7), 1001; https://doi.org/10.3390/biom12071001 - 18 Jul 2022
Cited by 9 | Viewed by 3320
Abstract
Alzheimer’s disease (AD) is a rapidly growing global concern associated with the accumulation of amyloid-β plaques and intracellular neurofibrillary tangles in the brain combined with a high acetylcholinesterase activity. AD diagnosis is usually made too late, when patients have an extensive neuronal death, [...] Read more.
Alzheimer’s disease (AD) is a rapidly growing global concern associated with the accumulation of amyloid-β plaques and intracellular neurofibrillary tangles in the brain combined with a high acetylcholinesterase activity. AD diagnosis is usually made too late, when patients have an extensive neuronal death, and brain damage is irreversible. Several therapeutic targets have been defined mainly related to two hypotheses of AD: the tau hypothesis and the amyloid-β hypothesis. Here, we intend to investigate and to compare different therapeutic approaches for AD, mainly based on nanoparticles (NPs) targeted at the brain and at the pathological hallmarks of the disease. We analyzed preclinical trials that have successfully improved drug bioavailability in the brain by using targeted nanocarriers towards either tau, amyloid-β, or both. We then compared these trials to find out which protein is more efficient in therapeutic targeting. We found that the search for a cure was mostly based on the amyloid-β hypothesis, with Aβ dysplasia emerging as the most confirmed and convincing therapeutic target. Targeted NPs have proven useful to enhance both the bioavailability and the performance of therapies against AD in animal models. A better understanding of AD mechanisms will help the successful application of targeted NPs for combined therapies. Full article
(This article belongs to the Special Issue Development of Peptide-Based Drugs for Alzheimer’s Disease)
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13 pages, 951 KiB  
Review
The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases
by Knut Hestad, Jan Alexander, Helge Rootwelt and Jan O. Aaseth
Biomolecules 2022, 12(7), 998; https://doi.org/10.3390/biom12070998 - 18 Jul 2022
Cited by 52 | Viewed by 5772
Abstract
Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan [...] Read more.
Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role in pathogenesis, is one of several competing pathways of tryptophan metabolism. The present article is a narrative review of tryptophan metabolism, neuroinflammation, depression, and neurodegeneration. A disturbed tryptophan metabolism with increased activity of the kynurenine pathway and production of quinolinic acid may result in deficiencies in tryptophan and derived neurotransmitters. Quinolinic acid is an N-methyl-D-aspartate receptor agonist, and raised levels in CSF, together with increased levels of inflammatory cytokines, have been reported in mood disorders. Increased quinolinic acid has also been observed in neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis, and HIV-related cognitive decline. Oxidative stress in connection with increased indole-dioxygenase (IDO) activity and kynurenine formation may contribute to inflammatory responses and the production of cytokines. Increased formation of quinolinic acid may occur at the expense of kynurenic acid and neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions on tryptophan metabolism, adequate protein intake with appropriate amounts of tryptophan and antioxidants may offer protection against oxidative stress and provide a balanced set of physiological receptor ligands. Full article
(This article belongs to the Special Issue Biochemistry in Medicine—Honorary Special Issue Commemorating Research and Work of Professors Jan O. Aaseth and Jan Alexander)
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20 pages, 1173 KiB  
Review
Epigenetic Reprogramming of the Inflammatory Response in Obesity and Type 2 Diabetes
by Federica Zatterale, Gregory Alexander Raciti, Immacolata Prevenzano, Alessia Leone, Michele Campitelli, Veronica De Rosa, Francesco Beguinot and Luca Parrillo
Biomolecules 2022, 12(7), 982; https://doi.org/10.3390/biom12070982 - 14 Jul 2022
Cited by 12 | Viewed by 3005
Abstract
For the past several decades, the prevalence of obesity and type 2 diabetes (T2D) has continued to rise on a global level. The risk contributing to this pandemic implicates both genetic and environmental factors, which are functionally integrated by epigenetic mechanisms. While these [...] Read more.
For the past several decades, the prevalence of obesity and type 2 diabetes (T2D) has continued to rise on a global level. The risk contributing to this pandemic implicates both genetic and environmental factors, which are functionally integrated by epigenetic mechanisms. While these conditions are accompanied by major abnormalities in fuel metabolism, evidence indicates that altered immune cell functions also play an important role in shaping of obesity and T2D phenotypes. Interestingly, these events have been shown to be determined by epigenetic mechanisms. Consistently, recent epigenome-wide association studies have demonstrated that immune cells from obese and T2D individuals feature specific epigenetic profiles when compared to those from healthy subjects. In this work, we have reviewed recent literature reporting epigenetic changes affecting the immune cell phenotype and function in obesity and T2D. We will further discuss therapeutic strategies targeting epigenetic marks for treating obesity and T2D-associated inflammation. Full article
(This article belongs to the Special Issue Advances in Immunogenetic Markers of Human Multifactorial Diseases)
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14 pages, 538 KiB  
Review
Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment
by Mariangela Succoio, Rosa Sacchettini, Alessandro Rossi, Giancarlo Parenti and Margherita Ruoppolo
Biomolecules 2022, 12(7), 968; https://doi.org/10.3390/biom12070968 - 11 Jul 2022
Cited by 24 | Viewed by 14998
Abstract
Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of [...] Read more.
Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented. Full article
(This article belongs to the Special Issue Rare Diseases: From Molecular Pathways to Therapeutic Strategies)
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22 pages, 3630 KiB  
Review
Understanding How Heart Metabolic Derangement Shows Differential Stage Specificity for Heart Failure with Preserved and Reduced Ejection Fraction
by Federico Ferro, Renza Spelat, Camilla Valente and Paolo Contessotto
Biomolecules 2022, 12(7), 969; https://doi.org/10.3390/biom12070969 - 11 Jul 2022
Cited by 10 | Viewed by 3333
Abstract
Heart failure (HF) is a clinical condition defined by structural and functional abnormalities in the heart that gradually result in reduced cardiac output (HFrEF) and/or increased cardiac pressures at rest and under stress (HFpEF). The presence of asymptomatic individuals hampers HF identification, resulting [...] Read more.
Heart failure (HF) is a clinical condition defined by structural and functional abnormalities in the heart that gradually result in reduced cardiac output (HFrEF) and/or increased cardiac pressures at rest and under stress (HFpEF). The presence of asymptomatic individuals hampers HF identification, resulting in delays in recognizing patients until heart dysfunction is manifested, thus increasing the chance of poor prognosis. Given the recent advances in metabolomics, in this review we dissect the main alterations occurring in the metabolic pathways behind the decrease in cardiac function caused by HF. Indeed, relevant preclinical and clinical research has been conducted on the metabolite connections and differences between HFpEF and HFrEF. Despite these promising results, it is crucial to note that, in addition to identifying single markers and reliable threshold levels within the healthy population, the introduction of composite panels would strongly help in the identification of those individuals with an increased HF risk. That said, additional research in the field is required to overcome the current drawbacks and shed light on the pathophysiological changes that lead to HF. Finally, greater collaborative data sharing, as well as standardization of procedures and approaches, would enhance this research field to fulfil its potential. Full article
(This article belongs to the Special Issue Recent Advances in Cellular and Molecular Mechanisms of Cardiovascular and Metabolic Diseases)
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21 pages, 1201 KiB  
Review
Exosomes in Alpha-Synucleinopathies: Propagators of Pathology or Potential Candidates for Nanotherapeutics?
by Panagiota Mavroeidi, Maria Vetsi, Dimitra Dionysopoulou and Maria Xilouri
Biomolecules 2022, 12(7), 957; https://doi.org/10.3390/biom12070957 - 8 Jul 2022
Cited by 12 | Viewed by 3199
Abstract
The pathological accumulation of alpha-synuclein governs the pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed alpha-synucleinopathies. Alpha-synuclein can be released in the extracellular space, partly via exosomes, and this extracellular protein pool may [...] Read more.
The pathological accumulation of alpha-synuclein governs the pathogenesis of neurodegenerative disorders, such as Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy, collectively termed alpha-synucleinopathies. Alpha-synuclein can be released in the extracellular space, partly via exosomes, and this extracellular protein pool may contribute to disease progression by facilitating the spread of pathological alpha-synuclein or activating immune cells. The content of exosomes depends on their origin and includes specific proteins, lipids, functional mRNAs and various non-coding RNAs. Given their ability to mediate intercellular communication via the transport of multilevel information, exosomes are considered to be transporters of toxic agents. Beyond neurons, glial cells also release exosomes, which may contain inflammatory molecules and this glia-to-neuron or neuron-to-glia transmission of exosomal alpha-synuclein may contribute to the propagation of pathology and neuroinflammation throughout the brain. In addition, as their content varies as per their originating and recipient cells, these vesicles can be utilized as a diagnostic biomarker for early disease detection, whereas targeted exosomes may be used as scaffolds to deliver therapeutic agents into the brain. This review summarizes the current knowledge regarding the role of exosomes in the progression of alpha-synuclein-related pathology and their potential use as biomarkers and nanotherapeutics in alpha-synucleinopathies. Full article
(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)
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13 pages, 636 KiB  
Review
Metal-Based Compounds in Antiviral Therapy
by Chiara Abate, Federica Carnamucio, Ottavia Giuffrè and Claudia Foti
Biomolecules 2022, 12(7), 933; https://doi.org/10.3390/biom12070933 - 3 Jul 2022
Cited by 20 | Viewed by 2865
Abstract
In recent years, the study of metal complexes and metal-based nanomaterials has aroused particular interest, leading to the promotion of new effective systems for the abatement of various viral diseases. Starting from the analysis of chemical properties, this review focuses on the employment [...] Read more.
In recent years, the study of metal complexes and metal-based nanomaterials has aroused particular interest, leading to the promotion of new effective systems for the abatement of various viral diseases. Starting from the analysis of chemical properties, this review focuses on the employment of metal-based nanoparticles as antiviral drugs and how this interaction leads to a substantial enhancement in antiviral activity. The use of metal-based antiviral drugs has also spread for the formulation of antiviral vaccines, thanks especially to the remarkable adjuvant activities of some of the metal complexes. In particular, the small size and inert nature of Au- and Ag-based nanoparticles have been exploited for the design of systems for antiviral drug delivery, leading to the development of specific and safe therapies that lead to a decrease in side effects. Full article
(This article belongs to the Special Issue State-of-the-Art Highlighting Antiviral Therapy and Viral Diseases Diagnosis in Italy 2020–2021)
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