Biomolecules

13 pages, 2343 KiB

Open AccessEditor’s ChoiceArticle

Receptor Interactions of Angiotensin II and Angiotensin Receptor Blockers—Relevance to COVID-19

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

Biomolecules 2021, 11(7), 979; https://doi.org/10.3390/biom11070979 - 03 Jul 2021

Cited by 15 | Viewed by 2841

Abstract

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino [...] Read more.

Angiotensin II (Ang II) may contain a charge relay system (CRS) involving Tyr/His/carboxylate, which creates a tyrosinate anion for receptor activation. Energy calculations were carried out to determine the preferred geometry for the CRS in the presence and absence of the Arg guanidino group occupying position 2 of Ang II. These findings suggest that Tyr is preferred over His for bearing the negative charge and that the CRS is stabilized by the guanidino group. Recent crystallography studies provided details of the binding of nonpeptide angiotensin receptor blockers (ARBs) to the Ang II type 1 (AT1) receptor, and these insights were applied to Ang II. A model of binding and receptor activation that explains the surmountable and insurmountable effects of Ang II analogues sarmesin and sarilesin, respectively, was developed and enabled the discovery of a new generation of ARBs called bisartans. Finally, we determined the ability of the bisartan BV6(TFA) to act as a potential ARB, demonstrating similar effects to candesartan, by reducing vasoconstriction of rabbit iliac arteries in response to cumulative doses of Ang II. Recent clinical studies have shown that Ang II receptor blockers have protective effects in hypertensive patients infected with SARS-CoV-2. Therefore, the usage of ARBS to block the AT1 receptor preventing the binding of toxic angiotensin implicated in the storm of cytokines in SARS-CoV-2 is a target treatment and opens new avenues for disease therapy. Full article

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

► Show Figures

Figure 1

20 pages, 4588 KiB

Open AccessEditor’s ChoiceArticle

Phytochemical Analysis and Anti-Inflammatory Activity of Different Ethanolic Phyto-Extracts of Artemisia annua L.

by Giulia Abate, Leilei Zhang, Mariachiara Pucci, Giulia Morbini, Eileen Mac Sweeney, Giuseppina Maccarinelli, Giovanni Ribaudo, Alessandra Gianoncelli, Daniela Uberti, Maurizio Memo, Luigi Lucini and Andrea Mastinu

Biomolecules 2021, 11(7), 975; https://doi.org/10.3390/biom11070975 - 02 Jul 2021

Cited by 54 | Viewed by 6573

Abstract

Artemisia annua L. (AA) has shown for many centuries important therapeutic virtues associated with the presence of artemisinin (ART). The aim of this study was to identify and quantify ART and other secondary metabolites in ethanolic extracts of AA and evaluate the biological [...] Read more.

Artemisia annua L. (AA) has shown for many centuries important therapeutic virtues associated with the presence of artemisinin (ART). The aim of this study was to identify and quantify ART and other secondary metabolites in ethanolic extracts of AA and evaluate the biological activity in the presence of an inflammatory stimulus. In this work, after the extraction of the aerial parts of AA with different concentrations of ethanol, ART was quantified by HPLC and HPLC-MS. In addition, anthocyanins, flavanols, flavanones, flavonols, lignans, low-molecular-weight phenolics, phenolic acids, stilbenes, and terpenes were identified and semi-quantitatively determined by UHPLC-QTOF-MS untargeted metabolomics. Finally, the viability of human neuroblastoma cells (SH-SY5Y) was evaluated in the presence of the different ethanolic extracts and in the presence of lipopolysaccharide (LPS). The results show that ART is more concentrated in AA samples extracted with 90% ethanol. Regarding the other metabolites, only the anthocyanins are more concentrated in the samples extracted with 90% ethanol. Finally, ART and all AA samples showed a protective action towards the pro-inflammatory stimulus of LPS. In particular, the anti-inflammatory effect of the leaf extract of AA with 90% ethanol was also confirmed at the molecular level since a reduction in TNF-α mRNA gene expression was observed in SH-SY5Y treated with LPS. Full article

► Show Figures

Figure 1

26 pages, 2545 KiB

Open AccessEditor’s ChoiceReview

On the Role of Paraoxonase-1 and Chemokine Ligand 2 (C-C motif) in Metabolic Alterations Linked to Inflammation and Disease. A 2021 Update

by Jordi Camps, Helena Castañé, Elisabet Rodríguez-Tomàs, Gerard Baiges-Gaya, Anna Hernández-Aguilera, Meritxell Arenas, Simona Iftimie and Jorge Joven

Biomolecules 2021, 11(7), 971; https://doi.org/10.3390/biom11070971 - 01 Jul 2021

Cited by 19 | Viewed by 3617

Abstract

Infectious and many non-infectious diseases share common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors produce [...] Read more.

Infectious and many non-infectious diseases share common molecular mechanisms. Among them, oxidative stress and the subsequent inflammatory reaction are of particular note. Metabolic disorders induced by external agents, be they bacterial or viral pathogens, excessive calorie intake, poor-quality nutrients, or environmental factors produce an imbalance between the production of free radicals and endogenous antioxidant systems; the consequence being the oxidation of lipids, proteins, and nucleic acids. Oxidation and inflammation are closely related, and whether oxidative stress and inflammation represent the causes or consequences of cellular pathology, both produce metabolic alterations that influence the pathogenesis of the disease. In this review, we highlight two key molecules in the regulation of these processes: Paraoxonase-1 (PON1) and chemokine (C-C motif) ligand 2 (CCL2). PON1 is an enzyme bound to high-density lipoproteins. It breaks down lipid peroxides in lipoproteins and cells, participates in the protection conferred by HDL against different infectious agents, and is considered part of the innate immune system. With PON1 deficiency, CCL2 production increases, inducing migration and infiltration of immune cells in target tissues and disturbing normal metabolic function. This disruption involves pathways controlling cellular homeostasis as well as metabolically-driven chronic inflammatory states. Hence, an understanding of these relationships would help improve treatments and, as well, identify new therapeutic targets. Full article

(This article belongs to the Special Issue Chemokines in Infectious and Non-infectious Diseases)

► Show Figures

Figure 1

18 pages, 5209 KiB

Open AccessEditor’s ChoiceArticle

The Protein Kinase Inhibitor Midostaurin Improves Functional Neurological Recovery and Attenuates Inflammatory Changes Following Traumatic Cervical Spinal Cord Injury

by Mohammad-Masoud Zavvarian, James Hong, Mohamad Khazaei, Jonathon Chon Teng Chio, Jian Wang, Anna Badner and Michael G. Fehlings

Biomolecules 2021, 11(7), 972; https://doi.org/10.3390/biom11070972 - 01 Jul 2021

Cited by 5 | Viewed by 4546

Abstract

Traumatic spinal cord injury (SCI) impairs neuronal function and introduces a complex cascade of secondary pathologies that limit recovery. Despite decades of preclinical and clinical research, there is a shortage of efficacious treatment options to modulate the secondary response to injury. Protein kinases [...] Read more.

Traumatic spinal cord injury (SCI) impairs neuronal function and introduces a complex cascade of secondary pathologies that limit recovery. Despite decades of preclinical and clinical research, there is a shortage of efficacious treatment options to modulate the secondary response to injury. Protein kinases are crucial signaling molecules that mediate the secondary SCI-induced cellular response and present promising therapeutic targets. The objective of this study was to examine the safety and efficacy of midostaurin—a clinically-approved multi-target protein kinase inhibitor—on cervical SCI pathogenesis. High-throughput analyses demonstrated that intraperitoneal midostaurin injection (25 mg/kg) in C6/7 injured Wistar rats altered the local inflammasome and downregulated adhesive and migratory genes at 24 h post-injury. Treated animals also exhibited enhanced recovery and restored coordination between forelimbs and hindlimbs after injury, indicating the synergistic impact of midostaurin and its dimethyl sulfoxide vehicle to improve functional recovery. Furthermore, histological analyses suggested improved tissue preservation and functionality in the treated animals during the chronic phase of injury. This study serves as a proof-of-concept experiment and demonstrates that systemic midostaurin administration is an effective strategy for mitigating cervical secondary SCI damage. Full article

► Show Figures

Figure 1

26 pages, 1376 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Transcriptomic and Epigenomic Landscape in Rett Syndrome

by Domenico Marano, Salvatore Fioriniello, Maurizio D’Esposito and Floriana Della Ragione

Biomolecules 2021, 11(7), 967; https://doi.org/10.3390/biom11070967 - 30 Jun 2021

Cited by 9 | Viewed by 4557

Abstract

Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein [...] Read more.

Rett syndrome (RTT) is an extremely invalidating, cureless, developmental disorder, and it is considered one of the leading causes of intellectual disability in female individuals. The vast majority of RTT cases are caused by de novo mutations in the X-linked Methyl-CpG binding protein 2 (MECP2) gene, which encodes a multifunctional reader of methylated DNA. MeCP2 is a master epigenetic modulator of gene expression, with a role in the organization of global chromatin architecture. Based on its interaction with multiple molecular partners and the diverse epigenetic scenario, MeCP2 triggers several downstream mechanisms, also influencing the epigenetic context, and thus leading to transcriptional activation or repression. In this frame, it is conceivable that defects in such a multifaceted factor as MeCP2 lead to large-scale alterations of the epigenome, ranging from an unbalanced deposition of epigenetic modifications to a transcriptional alteration of both protein-coding and non-coding genes, with critical consequences on multiple downstream biological processes. In this review, we provide an overview of the current knowledge concerning the transcriptomic and epigenomic alterations found in RTT patients and animal models. Full article

(This article belongs to the Collection DNA Methylation Dynamics in Health and Disease)

► Show Figures

Figure 1

15 pages, 1958 KiB

Open AccessEditor’s ChoiceArticle

Credentialing and Pharmacologically Targeting PTP4A3 Phosphatase as a Molecular Target for Ovarian Cancer

by John S. Lazo, Elizabeth R. Sharlow, Robert Cornelison, Duncan J. Hart, Danielle C. Llaneza, Anna J. Mendelson, Ettore J. Rastelli, Nikhil R. Tasker, Charles N. Landen, Jr. and Peter Wipf

Biomolecules 2021, 11(7), 969; https://doi.org/10.3390/biom11070969 - 30 Jun 2021

Cited by 5 | Viewed by 3592

Abstract

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient [...] Read more.

High grade serous ovarian cancer (OvCa) frequently becomes drug resistant and often recurs. Consequently, new drug targets and therapies are needed. Bioinformatics-based studies uncovered a relationship between high Protein Tyrosine Phosphatase of Regenerating Liver-3 (PRL3 also known as PTP4A3) expression and poor patient survival in both early and late stage OvCa. PTP4A3 mRNA levels were 5–20 fold higher in drug resistant or high grade serous OvCa cell lines compared to nonmalignant cells. JMS-053 is a potent allosteric small molecule PTP4A3 inhibitor and to explore further the role of PTP4A3 in OvCa, we synthesized and interrogated a series of JMS-053-based analogs in OvCa cell line-based phenotypic assays. While the JMS-053 analogs inhibit in vitro PTP4A3 enzyme activity, none were superior to JMS-053 in reducing high grade serous OvCa cell survival. Because PTP4A3 controls cell migration, we interrogated the effect of JMS-053 on this cancer-relevant process. Both JMS-053 and CRISPR/Cas9 PTP4A3 depletion blocked cell migration. The inhibition caused by JMS-053 required the presence of PTP4A3. JMS-053 caused additive or synergistic in vitro cytotoxicity when combined with paclitaxel and reduced in vivo OvCa dissemination. These results indicate the importance of PTP4A3 in OvCa and support further investigations of the lead inhibitor, JMS-053. Full article

(This article belongs to the Collection Feature Papers in Enzymology)

► Show Figures

Figure 1

22 pages, 2152 KiB

Open AccessEditor’s ChoiceReview

Functional Implications of the Dynamic Regulation of EpCAM during Epithelial-to-Mesenchymal Transition

by Taylor C. Brown, Narendra V. Sankpal and William E. Gillanders

Biomolecules 2021, 11(7), 956; https://doi.org/10.3390/biom11070956 - 29 Jun 2021

Cited by 34 | Viewed by 4714

Abstract

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor [...] Read more.

Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds β-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM’s role in EMT may reveal additional therapeutic opportunities. Full article

(This article belongs to the Special Issue EMT and Cancer)

► Show Figures

Figure 1

23 pages, 3912 KiB

Open AccessEditor’s ChoiceArticle

Copper Imbalance in Alzheimer’s Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants

by Rosanna Squitti, Mariacarla Ventriglia, Ilaria Simonelli, Cristian Bonvicini, Alfredo Costa, Giulia Perini, Giuliano Binetti, Luisa Benussi, Roberta Ghidoni, Giacomo Koch, Barbara Borroni, Alberto Albanese, Stefano L. Sensi and Mauro Rongioletti

Biomolecules 2021, 11(7), 960; https://doi.org/10.3390/biom11070960 - 29 Jun 2021

Cited by 32 | Viewed by 3494

Abstract

Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled [...] Read more.

Evidence indicates that patients with Alzheimer’s dementia (AD) show signs of copper (Cu) dyshomeostasis. This study aimed at evaluating the potential of Cu dysregulation as an AD susceptibility factor. We performed a meta-analysis of 56 studies investigating Cu biomarkers in brain specimens (pooled total of 182 AD and 166 healthy controls, HC) and in serum/plasma (pooled total of 2929 AD and 3547 HC). We also completed a replication study of serum Cu biomarkers in 97 AD patients and 70 HC screened for rs732774 and rs1061472 ATP7B, the gene encoding for the Cu transporter ATPase7B. Our meta-analysis showed decreased Cu in AD brain specimens, increased Cu and nonbound ceruloplasmin (Non-Cp) Cu in serum/plasma samples, and unchanged ceruloplasmin. Serum/plasma Cu excess was associated with a three to fourfold increase in the risk of having AD. Our replication study confirmed meta-analysis results and showed that carriers of the ATP7B AG haplotype were significantly more frequent in the AD group. Overall, our study shows that AD patients fail to maintain a Cu metabolic balance and reveals the presence of a percentage of AD patients carrying ATP7B AG haplotype and presenting Non-Cp Cu excess, which suggest that a subset of AD subjects is prone to Cu imbalance. This AD subtype can be the target of precision medicine-based strategies tackling Cu dysregulation. Full article

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

► Show Figures

Figure 1

15 pages, 1955 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Immunomodulatory Properties of Host Defence Peptides in Skin Wound Healing

by Marija Petkovic, Michelle Vang Mouritzen, Biljana Mojsoska and Håvard Jenssen

Biomolecules 2021, 11(7), 952; https://doi.org/10.3390/biom11070952 - 28 Jun 2021

Cited by 23 | Viewed by 5733

Abstract

Cutaneous wound healing is a vital biological process that aids skin regeneration upon injury. Wound healing failure results from persistent inflammatory conditions observed in diabetes, or autoimmune diseases like psoriasis. Chronic wounds are incurable due to factors like poor oxygenation, aberrant function of [...] Read more.

Cutaneous wound healing is a vital biological process that aids skin regeneration upon injury. Wound healing failure results from persistent inflammatory conditions observed in diabetes, or autoimmune diseases like psoriasis. Chronic wounds are incurable due to factors like poor oxygenation, aberrant function of peripheral sensory nervature, inadequate nutrients and blood tissue supply. The most significant hallmark of chronic wounds is heavily aberrant immune skin function. The immune response in humans relies on a large network of signalling molecules and their interactions. Research studies have reported on the dual role of host defence peptides (HDPs), which are also often called antimicrobial peptides (AMPs). Their duality reflects their potential for acting as antibacterial peptides, and as immunodulators that assist in modulating several biological signalling pathways related to processes such as wound healing, autoimmune disease, and others. HDPs may differentially control gene regulation and alter the behaviour of epithelial and immune cells, resulting in modulation of immune responses. In this review, we shed light on the understanding and most recent advances related to molecular mechanisms and immune modulatory features of host defence peptides in human skin wound healing. Understanding their functional role in skin immunity may further inspire topical treatments for chronic wounds. Full article

(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Wound Healing)

► Show Figures

Figure 1

23 pages, 1636 KiB

Open AccessEditor’s ChoiceReview

Ceramide Metabolism and Parkinson’s Disease—Therapeutic Targets

by Antía Custodia, Marta Aramburu-Núñez, Clara Correa-Paz, Adrián Posado-Fernández, Ana Gómez-Larrauri, José Castillo, Antonio Gómez-Muñoz, Tomás Sobrino and Alberto Ouro

Biomolecules 2021, 11(7), 945; https://doi.org/10.3390/biom11070945 - 25 Jun 2021

Cited by 32 | Viewed by 7094

Abstract

Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or [...] Read more.

Ceramide is a bioactive sphingolipid involved in numerous cellular processes. In addition to being the precursor of complex sphingolipids, ceramides can act as second messengers, especially when they are generated at the plasma membrane of cells. Its metabolic dysfunction may lead to or be a consequence of an underlying disease. Recent reports on transcriptomics and electrospray ionization mass spectrometry analysis have demonstrated the variation of specific levels of sphingolipids and enzymes involved in their metabolism in different neurodegenerative diseases. In the present review, we highlight the most relevant discoveries related to ceramide and neurodegeneration, with a special focus on Parkinson’s disease. Full article

(This article belongs to the Special Issue Involvement of Sphingolipids in the Pathogenesis of Parkinson's Disease and Parkinsonism)

► Show Figures

Figure 1

20 pages, 2344 KiB

Open AccessEditor’s ChoiceReview

α-Synuclein Strains: Does Amyloid Conformation Explain the Heterogeneity of Synucleinopathies?

by Simon Oliver Hoppe, Gamze Uzunoğlu and Carmen Nussbaum-Krammer

Biomolecules 2021, 11(7), 931; https://doi.org/10.3390/biom11070931 - 23 Jun 2021

Cited by 14 | Viewed by 3654

Abstract

Synucleinopathies are a heterogeneous group of neurodegenerative diseases with amyloid deposits that contain the α-synuclein (SNCA/α-Syn) protein as a common hallmark. It is astonishing that aggregates of a single protein are able to give rise to a whole range of different disease manifestations. [...] Read more.

Synucleinopathies are a heterogeneous group of neurodegenerative diseases with amyloid deposits that contain the α-synuclein (SNCA/α-Syn) protein as a common hallmark. It is astonishing that aggregates of a single protein are able to give rise to a whole range of different disease manifestations. The prion strain hypothesis offers a possible explanation for this conundrum. According to this hypothesis, a single protein sequence is able to misfold into distinct amyloid structures that can cause different pathologies. In fact, a growing body of evidence suggests that conformationally distinct α-Syn assemblies might be the causative agents behind different synucleinopathies. In this review, we provide an overview of research on the strain hypothesis as it applies to synucleinopathies and discuss the potential implications for diagnostic and therapeutic purposes. Full article

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

► Show Figures

Figure 1

14 pages, 2217 KiB

Open AccessEditor’s ChoiceArticle

In Vitro Compression Model for Orthodontic Tooth Movement Modulates Human Periodontal Ligament Fibroblast Proliferation, Apoptosis and Cell Cycle

by Julia Brockhaus, Rogerio B. Craveiro, Irma Azraq, Christian Niederau, Sarah K. Schröder, Ralf Weiskirchen, Joachim Jankowski and Michael Wolf

Biomolecules 2021, 11(7), 932; https://doi.org/10.3390/biom11070932 - 23 Jun 2021

Cited by 15 | Viewed by 2842

Abstract

Human Periodontal Ligament Fibroblasts (hPDLF), as part of the periodontal apparatus, modulate inflammation, regeneration and bone remodeling. Interferences are clinically manifested as attachment loss, tooth loosening and root resorption. During orthodontic tooth movement (OTM), remodeling and adaptation of the periodontium is required in [...] Read more.

Human Periodontal Ligament Fibroblasts (hPDLF), as part of the periodontal apparatus, modulate inflammation, regeneration and bone remodeling. Interferences are clinically manifested as attachment loss, tooth loosening and root resorption. During orthodontic tooth movement (OTM), remodeling and adaptation of the periodontium is required in order to enable tooth movement. hPDLF involvement in the early phase-OTM compression side was investigated for a 72-h period through a well-studied in vitro model. Changes in the morphology, cell proliferation and cell death were analyzed. Specific markers of the cell cycle were investigated by RT-qPCR and Western blot. The study showed that the morphology of hPDLF changes towards more unstructured, unsorted filaments under mechanical compression. The total cell numbers were significantly reduced with a higher cell death rate over the whole observation period. hPDLF started to recover to pretreatment conditions after 48 h. Furthermore, key molecules involved in the cell cycle were significantly reduced under compressive force at the gene expression and protein levels. These findings revealed important information for a better understanding of the preservation and remodeling processes within the periodontium through Periodontal Ligament Fibroblasts during orthodontic tooth movement. OTM initially decelerates the hPDLF cell cycle and proliferation. After adapting to environmental changes, human Periodontal Ligament Fibroblasts can regain homeostasis of the periodontium, affecting its reorganization. Full article

(This article belongs to the Special Issue Oral Regenerative Medicine: Current and Future)

► Show Figures

Figure 1

16 pages, 901 KiB

Open AccessEditor’s ChoiceReview

Leptin, Both Bad and Good Actor in Cancer

by Carlos Jiménez-Cortegana, Ana López-Saavedra, Flora Sánchez-Jiménez, Antonio Pérez-Pérez, Jesús Castiñeiras, Juan A. Virizuela-Echaburu, Luis de la de la Cruz-Merino and Víctor Sánchez-Margalet

Biomolecules 2021, 11(6), 913; https://doi.org/10.3390/biom11060913 - 20 Jun 2021

Cited by 29 | Viewed by 4783

Abstract

Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the [...] Read more.

Leptin is an important regulator of basal metabolism and food intake, with a pivotal role in obesity. Leptin exerts many different actions on various tissues and systems, including cancer, and is considered as a linkage between metabolism and the immune system. During the last decades, obesity and leptin have been associated with the initiation, proliferation and progression of many types of cancer. Obesity is also linked with complications and mortality, irrespective of the therapy used, affecting clinical outcomes. However, some evidence has suggested its beneficial role, called the “obesity paradox”, and the possible antitumoral role of leptin. Recent data regarding the immunotherapy of cancer have revealed that overweight leads to a more effective response and leptin may probably be involved in this beneficial process. Since leptin is a positive modulator of both the innate and the adaptive immune system, it may contribute to the increased immune response stimulated by immunotherapy in cancer patients and may be proposed as a good actor in cancer. Our purpose is to review this dual role of leptin in cancer, as well as trying to clarify the future perspectives of this adipokine, which further highlights its importance as a cornerstone of the immunometabolism in oncology. Full article

(This article belongs to the Special Issue Leptin and Beyond: Actors in Cancer)

► Show Figures

Figure 1

13 pages, 1794 KiB

Open AccessEditor’s ChoiceArticle

The m⁶A RNA Modification Quantity and mRNA Expression Level of RNA Methylation-Related Genes in Head and Neck Squamous Cell Carcinoma Cell Lines and Patients

by Kamila Romanowska, Agnieszka A. Rawłuszko-Wieczorek, Łukasz Marczak, Agnieszka Kosińska, Wiktoria M. Suchorska and Wojciech Golusiński

Biomolecules 2021, 11(6), 908; https://doi.org/10.3390/biom11060908 - 18 Jun 2021

Cited by 5 | Viewed by 2652

Abstract

RNA methylation at the nitrogen sixth of adenosine (m⁶A, N⁶-methyladenosine) is the most abundant RNA modification which plays a crucial role in all RNA metabolic aspects. Recently, m⁶A modification has been assigned to mediate the biological processes [...] Read more.

RNA methylation at the nitrogen sixth of adenosine (m⁶A, N⁶-methyladenosine) is the most abundant RNA modification which plays a crucial role in all RNA metabolic aspects. Recently, m⁶A modification has been assigned to mediate the biological processes of cancer cells, but their significance in HNSCC development is still poorly described. Thus, the main aim of this study was to globally quantify m⁶A modification by the mass spectrometry approach and determine the mRNA expression level of selected m⁶A RNA methyltransferase (METTL3), demethylase (FTO), and m⁶A readers (YTHDF2, YTHDC2) in 45 HNSCC patients and 4 cell lines (FaDu, Detroit 562, A-253 and SCC-15) using qPCR. In the results, we have not observed differences in the global amount of m⁶A modification and the mRNA level of the selected genes between the cancerous and paired-matched histopathologically unchanged tissues from 45 HNSCC patients. However, we have found a positive correlation between selected RNA methylation machinery genes expression and m⁶A abundance on total RNA and characterized the transcript level of those genes in the HNSCC cell lines. Moreover, the lack of global m⁶A differences between cancerous and histopathologically unchanged tissues suggests that m⁶A alterations in specific RNA sites may specifically influence HNSCC tumorigenesis. Full article

(This article belongs to the Special Issue Genetics and Molecular Biology of Head and Neck Cancer)

► Show Figures

Figure 1

19 pages, 4558 KiB

Open AccessEditor’s ChoiceReview

The Conspicuous Link between Ear, Brain and Heart–Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer’s Disease and Associated Amyloid Cardiomyopathy?

by Sergey Shityakov, Kentaro Hayashi, Stefan Störk, Verena Scheper, Thomas Lenarz and Carola Y. Förster

Biomolecules 2021, 11(6), 900; https://doi.org/10.3390/biom11060900 - 17 Jun 2021

Cited by 11 | Viewed by 4210

Abstract

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of [...] Read more.

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aβ pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain–ear–heart axis by which Aβ and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease. Full article

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

► Show Figures

Figure 1

25 pages, 2178 KiB

Open AccessEditor’s ChoiceReview

Immune Cell Modulation of the Extracellular Matrix Contributes to the Pathogenesis of Pancreatic Cancer

by Ramiz S. Ahmad, Timothy D. Eubank, Slawomir Lukomski and Brian A. Boone

Biomolecules 2021, 11(6), 901; https://doi.org/10.3390/biom11060901 - 17 Jun 2021

Cited by 19 | Viewed by 4491

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of only 9%. PDAC is characterized by a dense, fibrotic stroma composed of extracellular matrix (ECM) proteins. This desmoplastic stroma is a hallmark of PDAC, representing a significant physical barrier that is immunosuppressive and obstructs penetration of cytotoxic chemotherapy agents into the tumor microenvironment (TME). Additionally, dense ECM promotes hypoxia, making tumor cells refractive to radiation therapy and alters their metabolism, thereby supporting proliferation and survival. In this review, we outline the significant contribution of fibrosis to the pathogenesis of pancreatic cancer, with a focus on the cross talk between immune cells and pancreatic stellate cells that contribute to ECM deposition. We emphasize the cellular mechanisms by which neutrophils and macrophages, specifically, modulate the ECM in favor of PDAC-progression. Furthermore, we investigate how activated stellate cells and ECM influence immune cells and promote immunosuppression in PDAC. Finally, we summarize therapeutic strategies that target the stroma and hinder immune cell promotion of fibrogenesis, which have unfortunately led to mixed results. An enhanced understanding of the complex interactions between the pancreatic tumor ECM and immune cells may uncover novel treatment strategies that are desperately needed for this devastating disease. Full article

(This article belongs to the Special Issue The Role of Extracellular Matrix in Cancer Development and Progression)

► Show Figures

Figure 1

11 pages, 574 KiB

Open AccessEditor’s ChoiceReview

Hydrogen Sulfide (H₂S) and Polysulfide (H₂S_n) Signaling: The First 25 Years

by Hideo Kimura

Biomolecules 2021, 11(6), 896; https://doi.org/10.3390/biom11060896 - 16 Jun 2021

Cited by 75 | Viewed by 4442

Abstract

Since the first description of hydrogen sulfide (H₂S) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on H₂S have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous H₂S [...] Read more.

Since the first description of hydrogen sulfide (H₂S) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on H₂S have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous H₂S in the brain, suggesting that H₂S may have physiological roles. In 1996, we demonstrated that hydrogen sulfide (H₂S) is a potential signaling molecule, which can be produced by cystathionine β-synthase (CBS) to modify neurotransmission in the brain. Subsequently, we showed that H₂S relaxes vascular smooth muscle in synergy with nitric oxide (NO) and that cystathionine γ-lyase (CSE) is another producing enzyme. This study also opened up a new research area of a crosstalk between H₂S and NO. The cytoprotective effect, anti-inflammatory activity, energy formation, and oxygen sensing by H₂S have been subsequently demonstrated. Two additional pathways for the production of H₂S with 3-mercaptopyruvate sulfurtransferase (3MST) from l- and d-cysteine have been identified. We also discovered that hydrogen polysulfides (H₂S_n, n ≥ 2) are potential signaling molecules produced by 3MST. H₂S_n regulate the activity of ion channels and enzymes, as well as even the growth of tumors. S-Sulfuration (S-sulfhydration) proposed by Snyder is the main mechanism for H₂S/H₂S_n underlying regulation of the activity of target proteins. This mini review focuses on the key findings on H₂S/H₂S_n signaling during the first 25 years. Full article

(This article belongs to the Special Issue Hydrogen Sulfide and Polysulfides, Endogenous Mammalian Transmitters——Honorary Special Issue Commemorating the Work of Prof. Hideo Kimura)

► Show Figures

Figure 1

16 pages, 2729 KiB

Open AccessEditor’s ChoiceArticle

A Sesquiterpene Synthase from the Endophytic Fungus Serendipita indica Catalyzes Formation of Viridiflorol

by Fani Ntana, Wajid W. Bhat, Sean R. Johnson, Hans J. L. Jørgensen, David B. Collinge, Birgit Jensen and Björn Hamberger

Biomolecules 2021, 11(6), 898; https://doi.org/10.3390/biom11060898 - 16 Jun 2021

Cited by 11 | Viewed by 4286

Abstract

Interactions between plant-associated fungi and their hosts are characterized by a continuous crosstalk of chemical molecules. Specialized metabolites are often produced during these associations and play important roles in the symbiosis between the plant and the fungus, as well as in the establishment [...] Read more.

Interactions between plant-associated fungi and their hosts are characterized by a continuous crosstalk of chemical molecules. Specialized metabolites are often produced during these associations and play important roles in the symbiosis between the plant and the fungus, as well as in the establishment of additional interactions between the symbionts and other organisms present in the niche. Serendipita indica, a root endophytic fungus from the phylum Basidiomycota, is able to colonize a wide range of plant species, conferring many benefits to its hosts. The genome of S. indica possesses only few genes predicted to be involved in specialized metabolite biosynthesis, including a putative terpenoid synthase gene (SiTPS). In our experimental setup, SiTPS expression was upregulated when the fungus colonized tomato roots compared to its expression in fungal biomass growing on synthetic medium. Heterologous expression of SiTPS in Escherichia coli showed that the produced protein catalyzes the synthesis of a few sesquiterpenoids, with the alcohol viridiflorol being the main product. To investigate the role of SiTPS in the plant-endophyte interaction, an SiTPS-over-expressing mutant line was created and assessed for its ability to colonize tomato roots. Although overexpression of SiTPS did not lead to improved fungal colonization ability, an in vitro growth-inhibition assay showed that viridiflorol has antifungal properties. Addition of viridiflorol to the culture medium inhibited the germination of spores from a phytopathogenic fungus, indicating that SiTPS and its products could provide S. indica with a competitive advantage over other plant-associated fungi during root colonization. Full article

(This article belongs to the Section Chemical Biology)

► Show Figures

Figure 1

23 pages, 1795 KiB

Open AccessEditor’s ChoiceReview

Overview of Evidence-Based Chemotherapy for Oral Cancer: Focus on Drug Resistance Related to the Epithelial-Mesenchymal Transition

by Jingjing Sha, Yunpeng Bai, Huy Xuan Ngo, Tatsuo Okui and Takahiro Kanno

Biomolecules 2021, 11(6), 893; https://doi.org/10.3390/biom11060893 - 16 Jun 2021

Cited by 27 | Viewed by 3721

Abstract

The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer (OC). Epithelial-mesenchymal transition (EMT) has attracted a great deal of attention in recent years with regard to its relation to the mechanism of chemotherapy [...] Read more.

The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer (OC). Epithelial-mesenchymal transition (EMT) has attracted a great deal of attention in recent years with regard to its relation to the mechanism of chemotherapy drug resistance. EMT-activating transcription factors (EMT-ATFs), such as Snail, TWIST, and ZEB, can activate several different molecular pathways, e.g., PI3K/AKT, NF-κB, and TGF-β. In contrast, the activated oncological signal pathways provide reciprocal feedback that affects the expression of EMT-ATFs, resulting in a peritumoral extracellular environment conducive to cancer cell survival and evasion of the immune system, leading to resistance to multiple chemotherapeutic agents. We present an overview of evidence-based chemotherapy for OC treatment based on the National Comprehensive Cancer Network (NCCN) Chemotherapy Order Templates. We focus on the molecular pathways involved in drug resistance related to the EMT and highlight the signal pathways and transcription factors that may be important for EMT-regulated drug resistance. Rapid progress in antitumor regimens, together with the application of powerful techniques such as high-throughput screening and microRNA technology, will facilitate the development of therapeutic strategies to augment chemotherapy. Full article

(This article belongs to the Special Issue EMT and Cancer)

► Show Figures

Figure 1

25 pages, 9292 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Characterization of Growth and Cell Cycle Events Affected by Light Intensity in the Green Alga Parachlorella kessleri: A New Model for Cell Cycle Research

by Vilém Zachleder, Ivan N. Ivanov, Veronika Kselíková, Vitali Bialevich, Milada Vítová, Shuhei Ota, Tsuyoshi Takeshita, Shigeyuki Kawano and Kateřina Bišová

Biomolecules 2021, 11(6), 891; https://doi.org/10.3390/biom11060891 - 15 Jun 2021

Cited by 11 | Viewed by 3413

Abstract

Multiple fission is a cell cycle variation leading to the production of more than two daughter cells. Here, we used synchronized cultures of the chlorococcal green alga Parachlorella kessleri to study its growth and pattern of cell division under varying light intensities. The [...] Read more.

Multiple fission is a cell cycle variation leading to the production of more than two daughter cells. Here, we used synchronized cultures of the chlorococcal green alga Parachlorella kessleri to study its growth and pattern of cell division under varying light intensities. The time courses of DNA replication, nuclear and cellular division, cell size, total RNA, protein content, dry matter and accumulation of starch were observed at incident light intensities of 110, 250 and 500 µmol photons m⁻²s⁻¹. Furthermore, we studied the effect of deuterated water on Parachlorella kessleri growth and division, to mimic the effect of stress. We describe a novel multiple fission cell cycle pattern characterized by multiple rounds of DNA replication leading to cell polyploidization. Once completed, multiple nuclear divisions were performed with each of them, immediately followed by protoplast fission, terminated by the formation of daughter cells. The multiple fission cell cycle was represented by several consecutive doublings of growth parameters, each leading to the start of a reproductive sequence. The number of growth doublings increased with increasing light intensity and led to division into more daughter cells. This study establishes the baseline for cell cycle research at the molecular level as well as for potential biotechnological applications, particularly directed synthesis of (deuterated) starch and/or neutral lipids as carbon and energy reserves. Full article

(This article belongs to the Special Issue Cell Cycle Regulation of Algae)

► Show Figures

Figure 1

10 pages, 1277 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Towards a Better Understanding of the Relationships between Galectin-7, p53 and MMP-9 during Cancer Progression

by Yves St-Pierre

Biomolecules 2021, 11(6), 879; https://doi.org/10.3390/biom11060879 - 14 Jun 2021

Cited by 11 | Viewed by 3325

Abstract

It has been almost 25 years since the discovery of galectin-7. This member of the galectin family has attracted interest from many working in the cancer field given its highly restricted expression profile in epithelial cells and the fact that cancers of epithelial [...] Read more.

It has been almost 25 years since the discovery of galectin-7. This member of the galectin family has attracted interest from many working in the cancer field given its highly restricted expression profile in epithelial cells and the fact that cancers of epithelial origin (carcinoma) are among the most frequent and deadly cancer subtypes. Initially described as a p53-induced gene and associated with apoptosis, galectin-7 is now recognized as having a protumorigenic role in many cancer types. Several studies have indeed shown that galectin-7 is associated with aggressive behavior of cancer cells and induces expression of MMP-9, a member of the matrix metalloproteinases (MMP) family known to confer invasive behavior to cancer cells. It is therefore not surprising that many studies have examined its relationships with p53 and MMP-9. However, the relationships between galectin-7 and p53 and MMP-9 are not always clear. This is largely because p53 is often mutated in cancer cells and such mutations drastically change its functions and, consequently, its association with galectin-7. In this review, we discuss the functional relationships between galectin-7, p53 and MMP-9 and reconcile some apparently contradictory observations. A better understanding of these relationships will help to develop a working hypothesis and model that will provide the basis for further research in the hope of establishing a new paradigm for tackling the role of galectin-7 in cancer. Full article

(This article belongs to the Special Issue Cell Biology of Galectins)

► Show Figures

Figure 1

15 pages, 21732 KiB

Open AccessEditor’s ChoiceReview

Welcome to the Family: Identification of the NAD⁺ Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25

by Mathias Ziegler, Magnus Monné, Andrey Nikiforov, Gennaro Agrimi, Ines Heiland and Ferdinando Palmieri

Biomolecules 2021, 11(6), 880; https://doi.org/10.3390/biom11060880 - 14 Jun 2021

Cited by 18 | Viewed by 5132

Abstract

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective [...] Read more.

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD⁺ had long remained obscure. Only just recently, the existence of a human mitochondrial NAD⁺ carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD⁺ carrier in mammals, a long-standing mystery in NAD⁺ biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery. Full article

(This article belongs to the Special Issue Mitochondrial Transport Proteins)

► Show Figures

Figure 1

24 pages, 1529 KiB

Open AccessEditor’s ChoiceReview

Adipose-Derived Stem Cells Secretome and Its Potential Application in “Stem Cell-Free Therapy”

by Anna Trzyna and Agnieszka Banaś-Ząbczyk

Biomolecules 2021, 11(6), 878; https://doi.org/10.3390/biom11060878 - 13 Jun 2021

Cited by 80 | Viewed by 6839

Abstract

Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides [...] Read more.

Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides cytokines, proteins, and growth factors, the therapeutic effect of secretome is hidden in non-coding RNAs such as miR-21, miR-24, and miR-26 carried via exosomes secreted by adequate cells. The whole secretome, including ASC-derived exosomes (ASC-exos) has been proven in many studies to have immunomodulatory, proangiogenic, neurotrophic, and epithelization activity and can potentially be used for neurodegenerative, cardiovascular, respiratory, inflammatory, and autoimmune diseases as well as wound healing treatment. Due to limitations in the use of stem cells in cell-based therapy, its secretome with emphasis on exosomes seems to be a reasonable and safer alternative with increased effectiveness and fewer side effects. Moreover, the great advantage of cell-free therapy is the possibility of biobanking the ASCs secretome. In this review, we focus on the current state of knowledge on the use of the ASCs secretome in stem cell-free therapy. Full article

(This article belongs to the Special Issue Recent Advances in Translational Adipose-Derived Stem Cell Biology)

► Show Figures

Figure 1

23 pages, 3286 KiB

Open AccessEditor’s ChoiceReview

Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk

by Sara Chiappalupi, Laura Salvadori, Rosario Donato, Francesca Riuzzi and Guglielmo Sorci

Biomolecules 2021, 11(6), 876; https://doi.org/10.3390/biom11060876 - 12 Jun 2021

Cited by 21 | Viewed by 3726

Abstract

The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential [...] Read more.

The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential to the deleterious effects of the renin–angiotensin system (RAS), which participates in infection and multiorgan injury in COVID-19 patients. Thus, RAGE might be a major player in severe COVID-19, and appears to be a useful therapeutic molecular target in infections by SARS-CoV-2. The role of RAGE gene polymorphisms in predisposing patients to severe COVID-19 is discussed. Full article

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

► Show Figures

Figure 1

18 pages, 3245 KiB

Open AccessEditor’s ChoiceArticle

HK2 Mediated Glycolytic Metabolism in Mouse Photoreceptors Is Not Required to Cause Late Stage Age-Related Macular Degeneration-Like Pathologies

by Shun-Yun Cheng, Anneliese Malachi, Joris Cipi, Shan Ma, Richard S. Brush, Martin-Paul Agbaga and Claudio Punzo

Biomolecules 2021, 11(6), 871; https://doi.org/10.3390/biom11060871 - 11 Jun 2021

Cited by 5 | Viewed by 3942

Abstract

Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein [...] Read more.

Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein TSC1. Here, we confirm our previous findings by deletion of the other complex protein, namely TSC2, in rod photoreceptors. Similar to deletion of Tsc1, mice with deletion of Tsc2 in rods develop AMD-like pathologies, including accumulation of apolipoproteins, migration of microglia, geographic atrophy, and neovascular pathologies. Subtle differences between the two mouse models, such as a significant increase in microglia activation with loss of Tsc2, were seen as well. To investigate the role of altered glucose metabolism in disease pathogenesis, we generated mice with simulation deletions of Tsc2 and hexokinase-2 (Hk2) in rods. Although retinal lactate levels returned to normal in mice with Tsc2-Hk2 deletion, AMD-like pathologies still developed. The data suggest that the metabolic adaptations in PRs that cause AMD-like pathologies are independent of HK2-mediated aerobic glycolysis. Full article

(This article belongs to the Special Issue Ocular Diseases and Therapeutics)

► Show Figures

Figure 1

25 pages, 12270 KiB

Open AccessEditor’s ChoiceReview

Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling

by Christopher L. Cioffi

Biomolecules 2021, 11(6), 864; https://doi.org/10.3390/biom11060864 - 10 Jun 2021

Cited by 8 | Viewed by 3788

Abstract

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal [...] Read more.

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na⁺/Cl⁻-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain. Full article

(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)

► Show Figures

Graphical abstract

16 pages, 3919 KiB

Open AccessEditor’s ChoiceArticle

Bioinstructive Layer-by-Layer-Coated Customizable 3D Printed Perfusable Microchannels Embedded in Photocrosslinkable Hydrogels for Vascular Tissue Engineering

by Cristiana F. V. Sousa, Catarina A. Saraiva, Tiago R. Correia, Tamagno Pesqueira, Sónia G. Patrício, Maria Isabel Rial-Hermida, João Borges and João F. Mano

Biomolecules 2021, 11(6), 863; https://doi.org/10.3390/biom11060863 - 10 Jun 2021

Cited by 25 | Viewed by 4187

Abstract

The development of complex and large 3D vascularized tissue constructs remains the major goal of tissue engineering and regenerative medicine (TERM). To date, several strategies have been proposed to build functional and perfusable vascular networks in 3D tissue-engineered constructs to ensure the long-term [...] Read more.

The development of complex and large 3D vascularized tissue constructs remains the major goal of tissue engineering and regenerative medicine (TERM). To date, several strategies have been proposed to build functional and perfusable vascular networks in 3D tissue-engineered constructs to ensure the long-term cell survival and the functionality of the assembled tissues after implantation. However, none of them have been entirely successful in attaining a fully functional vascular network. Herein, we report an alternative approach to bioengineer 3D vascularized constructs by embedding bioinstructive 3D multilayered microchannels, developed by combining 3D printing with the layer-by-layer (LbL) assembly technology, in photopolymerizable hydrogels. Alginate (ALG) was chosen as the ink to produce customizable 3D sacrificial microstructures owing to its biocompatibility and structural similarity to the extracellular matrices of native tissues. ALG structures were further LbL coated with bioinstructive chitosan and arginine–glycine–aspartic acid-coupled ALG multilayers, embedded in shear-thinning photocrosslinkable xanthan gum hydrogels and exposed to a calcium-chelating solution to form perfusable multilayered microchannels, mimicking the biological barriers, such as the basement membrane, in which the endothelial cells were seeded, denoting an enhanced cell adhesion. The 3D constructs hold great promise for engineering a wide array of large-scale 3D vascularized tissue constructs for modular TERM strategies. Full article

(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)

► Show Figures

Figure 1

18 pages, 4133 KiB

Open AccessEditor’s ChoiceArticle

Polystyrene Nanoplastics as Carriers of Metals. Interactions of Polystyrene Nanoparticles with Silver Nanoparticles and Silver Nitrate, and Their Effects on Human Intestinal Caco-2 Cells

by Josefa Domenech, Constanza Cortés, Lourdes Vela, Ricard Marcos and Alba Hernández

Biomolecules 2021, 11(6), 859; https://doi.org/10.3390/biom11060859 - 09 Jun 2021

Cited by 28 | Viewed by 4414

Abstract

Environmental plastic wastes are continuously degraded to their micro and nanoforms. Since in the environment they coexist with other pollutants, it has been suggested that they could act as vectors transporting different toxic trace elements, such as metals. To confirm this, we have [...] Read more.

Environmental plastic wastes are continuously degraded to their micro and nanoforms. Since in the environment they coexist with other pollutants, it has been suggested that they could act as vectors transporting different toxic trace elements, such as metals. To confirm this, we have assessed the potential interactions between nanopolystyrene, as a model of nanoplastic debris, and silver compounds (silver nanoparticles and silver nitrate), as models of metal contaminant. Using TEM-EDX methodological approaches, we have been able to demonstrate metal sorption by nanopolystyrene. Furthermore, using Caco-2 cells and confocal microscopy, we have observed the co-localization of nanopolystyrene/nanosilver in different cellular compartments, including the cell nucleus. Although the internalization of these complexes showed no exacerbated cytotoxic effects, compared to the effects of each compound alone, the silver/nanopolystyrene complexes modulate the cell’s uptake of silver and slightly modify some harmful cellular effects of silver, such as the ability to induce genotoxic and oxidative DNA damage. Full article

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

► Show Figures

Figure 1

13 pages, 2234 KiB

Open AccessEditor’s ChoiceArticle

JMJ Histone Demethylases Balance H3K27me3 and H3K4me3 Levels at the HSP21 Locus during Heat Acclimation in Arabidopsis

by Nobutoshi Yamaguchi and Toshiro Ito

Biomolecules 2021, 11(6), 852; https://doi.org/10.3390/biom11060852 - 07 Jun 2021

Cited by 12 | Viewed by 3695

Abstract

Exposure to moderately high temperature enables plants to acquire thermotolerance to high temperatures that might otherwise be lethal. In Arabidopsis thaliana, histone H3 lysine 27 trimethylation (H3K27me3) at the heat shock protein 17.6C (HSP17.6C) and HSP22 loci is removed by [...] Read more.

Exposure to moderately high temperature enables plants to acquire thermotolerance to high temperatures that might otherwise be lethal. In Arabidopsis thaliana, histone H3 lysine 27 trimethylation (H3K27me3) at the heat shock protein 17.6C (HSP17.6C) and HSP22 loci is removed by Jumonji C domain-containing protein (JMJ) histone demethylases, thus allowing the plant to ‘remember’ the heat experience. Other heat memory genes, such as HSP21, are downregulated in acclimatized jmj quadruple mutants compared to the wild type, but how those genes are regulated remains uncharacterized. Here, we show that histone H3 lysine 4 trimethylation (H3K4me3) at HSP21 was maintained at high levels for at least three days in response to heat. This heat-dependent H3K4me3 accumulation was compromised in the acclimatized jmj quadruple mutant as compared to the acclimatized wild type. JMJ30 directly bound to the HSP21 locus in response to heat and coordinated H3K27me3 and H3K4me3 levels under standard and fluctuating conditions. Our results suggest that JMJs mediate the balance between H3K27me3 and H3K4me3 at the HSP21 locus through proper maintenance of H3K27me3 removal during heat acclimation. Full article

(This article belongs to the Special Issue Recent Advances and Applications of Biostimulants for Plant Growth Promotion and Environmental Stress Adaptation)

► Show Figures

Figure 1

47 pages, 14889 KiB

Open AccessEditor’s ChoiceReview

Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development

by Bodo C. Melnik, Wolfgang Stremmel, Ralf Weiskirchen, Swen Malte John and Gerd Schmitz

Biomolecules 2021, 11(6), 851; https://doi.org/10.3390/biom11060851 - 07 Jun 2021

Cited by 78 | Viewed by 8789

Abstract

Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing [...] Read more.

Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing infant, the majority of recent studies report on the MEV subfraction of milk exosomes (MEX) and their miRNA cargo, which are in the focus of this review. MEX and the dominant miRNA-148a play a key role in intestinal maturation, barrier function and suppression of nuclear factor-κB (NF-κB) signaling and may thus be helpful for the prevention and treatment of necrotizing enterocolitis. MEX and their miRNAs reach the systemic circulation and may impact epigenetic programming of various organs including the liver, thymus, brain, pancreatic islets, beige, brown and white adipose tissue as well as bones. Translational evidence indicates that MEX and their miRNAs control the expression of global cellular regulators such as DNA methyltransferase 1—which is important for the up-regulation of developmental genes including insulin, insulin-like growth factor-1, α-synuclein and forkhead box P3—and receptor-interacting protein 140, which is important for the regulation of multiple nuclear receptors. MEX-derived miRNA-148a and miRNA-30b may stimulate the expression of uncoupling protein 1, the key inducer of thermogenesis converting white into beige/brown adipose tissue. MEX have to be considered as signalosomes derived from the maternal lactation genome emitted to promote growth, maturation, immunological and metabolic programming of the offspring. Deeper insights into milk’s molecular biology allow the conclusion that infants are both “breast-fed” and “breast-programmed”. In this regard, MEX miRNA-deficient artificial formula is not an adequate substitute for breastfeeding, the birthright of all mammals. Full article

(This article belongs to the Special Issue Breast Milk-Derived Biomolecules in Human Health)

► Show Figures

Figure 1

13 pages, 3688 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Glycine Receptors in Spinal Nociceptive Control—An Update

by Hanns Ulrich Zeilhofer, Karolina Werynska, Jacinthe Gingras and Gonzalo E. Yévenes

Biomolecules 2021, 11(6), 846; https://doi.org/10.3390/biom11060846 - 06 Jun 2021

Cited by 21 | Viewed by 4663

Abstract

Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid [...] Read more.

Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid deleterious side effects such as sedation, addiction, or impaired motor control, which would arise from wide-range facilitation of inhibition. Specific targeting of glycinergic inhibition, which dominates in the spinal cord and parts of the hindbrain, may help reduce these side effects. Selective targeting of the α3 subtype of glycine receptors (GlyRs), which is highly enriched in the superficial layers of the spinal dorsal horn, a key site of nociceptive processing, may help to further narrow down pharmacological intervention on the nociceptive system and increase tolerability. This review provides an update on the physiological properties and functions of α3 subtype GlyRs and on the present state of related drug discovery programs. Full article

(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)

► Show Figures

Figure 1

12 pages, 478 KiB

Open AccessEditor’s ChoiceArticle

Exploring the Connection between Porphyromonas gingivalis and Neurodegenerative Diseases: A Pilot Quantitative Study on the Bacterium Abundance in Oral Cavity and the Amount of Antibodies in Serum

by Raffaella Franciotti, Pamela Pignatelli, Claudia Carrarini, Federica Maria Romei, Martina Mastrippolito, Antonella Gentile, Rosa Mancinelli, Stefania Fulle, Adriano Piattelli, Marco Onofrj and Maria Cristina Curia

Biomolecules 2021, 11(6), 845; https://doi.org/10.3390/biom11060845 - 06 Jun 2021

Cited by 13 | Viewed by 4383

Abstract

Recent studies support the hypothesis that microbes can seed some Alzheimer’s disease (AD) cases, leading to inflammation and overproduction of amyloid peptides. Porphyromonas gingivalis (Pg) is a keystone pathogen of chronic periodontitis and has been identified as risk factor for the development and [...] Read more.

Recent studies support the hypothesis that microbes can seed some Alzheimer’s disease (AD) cases, leading to inflammation and overproduction of amyloid peptides. Porphyromonas gingivalis (Pg) is a keystone pathogen of chronic periodontitis and has been identified as risk factor for the development and progression of AD. The present preliminary study aimed to quantify Pg abundance in neurodegenerative disease (ND) patients compared with neurologic patients without neurodegenerative disorders (no-ND) and healthy controls (HC) to determine possible association between Pg abundance and neurodegenerative process. Pg was quantified on DNA extracted from the oral samples of 49 patients and 29 HC by quantitative polymerase chain reaction (qPCR). Anti-Pg antibodies were also detected on patient serum samples by enzyme-linked immunosorbent assays (ELISA). The Pg abundance in the oral cavity was significantly different among groups (p = 0.004). It was higher in ND than no-ND (p = 0.010) and HC (p = 0.008). The Pg abundance was correlated with the antibodies (p = 0.001) with different slopes between ND and no-ND (p = 0.037). Pg abundance was not correlated with oral indices and comorbidities. These results extend our understanding of the association between oral pathogens and AD to other neurodegenerative processes, confirming the hypothesis that oral pathogens can induce an antibody systemic response, influencing the progression of the disease. Full article

(This article belongs to the Collection Natural and Synthetic Compounds in Neurodegenerative Disorders)

► Show Figures

Graphical abstract

23 pages, 3522 KiB

Open AccessEditor’s ChoiceReview

Folding and Stability of Ankyrin Repeats Control Biological Protein Function

by Amit Kumar and Jochen Balbach

Biomolecules 2021, 11(6), 840; https://doi.org/10.3390/biom11060840 - 05 Jun 2021

Cited by 16 | Viewed by 5410

Abstract

Ankyrin repeat proteins are found in all three kingdoms of life. Fundamentally, these proteins are involved in protein-protein interaction in order to activate or suppress biological processes. The basic architecture of these proteins comprises repeating modules forming elongated structures. Due to the lack [...] Read more.

Ankyrin repeat proteins are found in all three kingdoms of life. Fundamentally, these proteins are involved in protein-protein interaction in order to activate or suppress biological processes. The basic architecture of these proteins comprises repeating modules forming elongated structures. Due to the lack of long-range interactions, a graded stability among the repeats is the generic properties of this protein family determining both protein folding and biological function. Protein folding intermediates were frequently found to be key for the biological functions of repeat proteins. In this review, we discuss most recent findings addressing this close relation for ankyrin repeat proteins including DARPins, Notch receptor ankyrin repeat domain, IκBα inhibitor of NFκB, and CDK inhibitor p19^INK4d. The role of local folding and unfolding and gradual stability of individual repeats will be discussed during protein folding, protein-protein interactions, and post-translational modifications. The conformational changes of these repeats function as molecular switches for biological regulation, a versatile property for modern drug discovery. Full article

(This article belongs to the Special Issue Protein Folding Stability and Dynamics: Commemorative Issue in Honor of Professor Sir Christopher Dobson (1949–2019))

► Show Figures

Figure 1

17 pages, 360 KiB

Open AccessEditor’s ChoiceReview

MicroRNA as a Novel Biomarker in the Diagnosis of Head and Neck Cancer

by Jacek Kabzinski, Monika Maczynska and Ireneusz Majsterek

Biomolecules 2021, 11(6), 844; https://doi.org/10.3390/biom11060844 - 05 Jun 2021

Cited by 25 | Viewed by 4362

Abstract

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018, and although the survival statistics for some patient groups are improving, there is still an urgent need to find a fast [...] Read more.

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018, and although the survival statistics for some patient groups are improving, there is still an urgent need to find a fast and reliable biomarker that allows early diagnosis. This niche can be filled by microRNA, small single-stranded non-coding RNA molecules, which are expressed in response to specific events in the body. This article presents the potential use of microRNAs in the diagnosis of HNSCC, compares the advances in this field to other diseases, especially other cancers, and discusses the detailed use of miRNA as a biomarker in profiling and predicting the treatment outcome with radiotherapy and immunotherapy. Potential problems and difficulties related to the development of this promising technology, and areas on which future research should be focused in order to overcome these difficulties, were also indicated. Full article

(This article belongs to the Special Issue Genetics and Molecular Biology of Head and Neck Cancer)

9 pages, 6289 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

SARS-CoV-2 and Skin: The Pathologist’s Point of View

by Gerardo Cazzato, Giulia Mazzia, Antonietta Cimmino, Anna Colagrande, Sara Sablone, Teresa Lettini, Roberta Rossi, Nadia Santarella, Rossella Elia, Eleonora Nacchiero, Michele Maruccia, Andrea Marzullo, Eugenio Maiorano, Giuseppe Giudice, Giuseppe Ingravallo and Leonardo Resta

Biomolecules 2021, 11(6), 838; https://doi.org/10.3390/biom11060838 - 04 Jun 2021

Cited by 12 | Viewed by 2799

Abstract

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million [...] Read more.

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million cases worldwide. Although the lung is the most frequently affected organ, the skin has also resulted in being a target body district, so much so as to suggest it may be a real “sentinel” of COVID-19 disease. Here we present 17 cases of skin manifestations studied and analyzed in recent months in our Department; immunohistochemical investigations were carried out on samples for the S1 spike-protein of SARS-CoV-2, as well as electron microscopy investigations showing evidence of virions within the constituent cells of the eccrine sweat glands and the endothelium of small blood vessels. Finally, we conduct a brief review of the COVID-related skin manifestations, confirmed by immunohistochemistry and/or electron microscopy, described in the literature. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

► Show Figures

Figure 1

18 pages, 5209 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Parallel and Sequential Pathways of Molecular Recognition of a Tandem-Repeat Protein and Its Intrinsically Disordered Binding Partner

by Ben M. Smith, Pamela J. E. Rowling, Christopher M. Dobson and Laura S. Itzhaki

Biomolecules 2021, 11(6), 827; https://doi.org/10.3390/biom11060827 - 01 Jun 2021

Cited by 3 | Viewed by 3337

Abstract

The Wnt signalling pathway plays an important role in cell proliferation, differentiation, and fate decisions in embryonic development and the maintenance of adult tissues. The twelve armadillo (ARM) repeat-containing protein β-catenin acts as the signal transducer in this pathway. Here, we investigated the [...] Read more.

The Wnt signalling pathway plays an important role in cell proliferation, differentiation, and fate decisions in embryonic development and the maintenance of adult tissues. The twelve armadillo (ARM) repeat-containing protein β-catenin acts as the signal transducer in this pathway. Here, we investigated the interaction between β-catenin and the intrinsically disordered transcription factor TCF7L2, comprising a very long nanomolar-affinity interface of approximately 4800 Å² that spans ten of the twelve ARM repeats of β-catenin. First, a fluorescence reporter system for the interaction was engineered and used to determine the kinetic rate constants for the association and dissociation. The association kinetics of TCF7L2 and β-catenin were monophasic and rapid (7.3 ± 0.1 × 10⁷ M⁻¹·s⁻¹), whereas dissociation was biphasic and slow (5.7 ± 0.4 × 10⁻⁴ s⁻¹, 15.2 ± 2.8 × 10⁻⁴ s⁻¹). This reporter system was then combined with site-directed mutagenesis to investigate the striking variability in the conformation adopted by TCF7L2 in the three different crystal structures of the TCF7L2–β-catenin complex. We found that the mutation had very little effect on the association kinetics, indicating that most interactions form after the rate-limiting barrier for association. Mutations of the N- and C-terminal subdomains of TCF7L2 that adopt relatively fixed conformations in the crystal structures had large effects on the dissociation kinetics, whereas the mutation of the labile sub-domain connecting them had negligible effect. These results point to a two-site avidity mechanism of binding with the linker region forming a “fuzzy” complex involving transient contacts that are not site-specific. Strikingly, the two mutations in the N-terminal subdomain that had the largest effects on the dissociation kinetics showed two additional phases, indicating partial flux through an alternative dissociation pathway that is inaccessible to the wild type. The results presented here provide insights into the kinetics of the molecular recognition of a long intrinsically disordered region with an elongated repeat-protein surface, a process found to involve parallel routes with sequential steps in each. Full article

(This article belongs to the Special Issue Protein Folding Stability and Dynamics: Commemorative Issue in Honor of Professor Sir Christopher Dobson (1949–2019))

► Show Figures

Figure 1

18 pages, 693 KiB

Open AccessEditor’s ChoiceReview

Sustainable Agriculture Systems in Vegetable Production Using Chitin and Chitosan as Plant Biostimulants

by Mohamad Hesam Shahrajabian, Christina Chaski, Nikolaos Polyzos, Nikolaos Tzortzakis and Spyridon A. Petropoulos

Biomolecules 2021, 11(6), 819; https://doi.org/10.3390/biom11060819 - 31 May 2021

Cited by 89 | Viewed by 8811

Abstract

Chitin and chitosan are natural compounds that are biodegradable and nontoxic and have gained noticeable attention due to their effective contribution to increased yield and agro-environmental sustainability. Several effects have been reported for chitosan application in plants. Particularly, it can be used in [...] Read more.

Chitin and chitosan are natural compounds that are biodegradable and nontoxic and have gained noticeable attention due to their effective contribution to increased yield and agro-environmental sustainability. Several effects have been reported for chitosan application in plants. Particularly, it can be used in plant defense systems against biological and environmental stress conditions and as a plant growth promoter—it can increase stomatal conductance and reduce transpiration or be applied as a coating material in seeds. Moreover, it can be effective in promoting chitinolytic microorganisms and prolonging storage life through post-harvest treatments, or benefit nutrient delivery to plants since it may prevent leaching and improve slow release of nutrients in fertilizers. Finally, it can remediate polluted soils through the removal of cationic and anionic heavy metals and the improvement of soil properties. On the other hand, chitin also has many beneficial effects such as plant growth promotion, improved plant nutrition and ability to modulate and improve plants’ resistance to abiotic and biotic stressors. The present review presents a literature overview regarding the effects of chitin, chitosan and derivatives on horticultural crops, highlighting their important role in modern sustainable crop production; the main limitations as well as the future prospects of applications of this particular biostimulant category are also presented. Full article

(This article belongs to the Special Issue Recent Advances and Applications of Biostimulants for Plant Growth Promotion and Environmental Stress Adaptation)

► Show Figures

Figure 1

22 pages, 871 KiB

Open AccessEditor’s ChoiceReview

Effects of Anthocyanins on Vascular Health

by Ioana Mozos, Corina Flangea, Daliborca C. Vlad, Cristina Gug, Costin Mozos, Dana Stoian, Constantin T. Luca, Jarosław O. Horbańczuk, Olaf K. Horbańczuk and Atanas G. Atanasov

Biomolecules 2021, 11(6), 811; https://doi.org/10.3390/biom11060811 - 30 May 2021

Cited by 41 | Viewed by 6335

Abstract

Cardiovascular disorders are leading mortality causes worldwide, often with a latent evolution. Vascular health depends on endothelial function, arterial stiffness, and the presence of atherosclerotic plaques. Preventive medicine deserves special attention, focusing on modifiable cardiovascular risk factors, including diet. A diet rich in [...] Read more.

Cardiovascular disorders are leading mortality causes worldwide, often with a latent evolution. Vascular health depends on endothelial function, arterial stiffness, and the presence of atherosclerotic plaques. Preventive medicine deserves special attention, focusing on modifiable cardiovascular risk factors, including diet. A diet rich in fruits and vegetables has well-known health benefits, especially due to its polyphenolic components. Anthocyanins, water-soluble flavonoid species, responsible for the red-blue color in plants and commonly found in berries, exert favorable effects on the endothelial function, oxidative stress, inhibit COX-1, and COX-2 enzymes, exert antiatherogenic, antihypertensive, antiglycation, antithrombotic, and anti-inflammatory activity, ameliorate dyslipidemia and arterial stiffness. The present review aims to give a current overview of the mechanisms involved in the vascular protective effect of anthocyanins from the human diet, considering epidemiological data, in vitro and in vivo preclinical research, clinical observational, retrospective, intervention and randomized studies, dietary and biomarker studies, and discussing preventive benefits of anthocyanins and future research directions. Full article

► Show Figures

Figure 1

22 pages, 921 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease

by Emma C. Tovey Crutchfield, Sarah E. Garnish and Joanne M. Hildebrand

Biomolecules 2021, 11(6), 803; https://doi.org/10.3390/biom11060803 - 28 May 2021

Cited by 14 | Viewed by 3647

Abstract

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that [...] Read more.

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that inhibit necroptosis by targeting the kinase activity of RIPK1, one of the main upstream conduits to MLKL activation, have shown promise in several murine models of non-infectious disease and in phase II human clinical trials. This has triggered in excess of one billion dollars (USD) in investment into the emerging class of necroptosis blocking drugs, and the potential utility of targeting the terminal effector is being closely scrutinised. Here we review murine models of disease, both genetic deletion and mutation, that investigate the role of MLKL. We summarize a series of examples from several broad disease categories including ischemia reperfusion injury, sterile inflammation, pathogen infection and hematological stress. Elucidating MLKL’s contribution to mouse models of disease is an important first step to identify human indications that stand to benefit most from MLKL-targeted drug therapies. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

► Show Figures

Figure 1

16 pages, 2936 KiB

Open AccessEditor’s ChoiceArticle

Lower Gene Expression of Angiotensin Converting Enzyme 2 Receptor in Lung Tissues of Smokers with COVID-19 Pneumonia

by Francesca Lunardi, Francesco Fortarezza, Luca Vedovelli, Federica Pezzuto, Annalisa Boscolo, Marco Rossato, Roberto Vettor, Anna Maria Cattelan, Claudia Del Vecchio, Andrea Crisanti, Paolo Navalesi, Dario Gregori and Fiorella Calabrese

Biomolecules 2021, 11(6), 796; https://doi.org/10.3390/biom11060796 - 26 May 2021

Cited by 2 | Viewed by 2493

Abstract

Angiotensin-converting enzyme 2 (ACE-2) is the main cell entry receptor for severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), thus playing a critical role in causing Coronavirus disease 2019 (COVID-19). The role of smoking habit in the susceptibility to infection is still controversial. In this study [...] Read more.

Angiotensin-converting enzyme 2 (ACE-2) is the main cell entry receptor for severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), thus playing a critical role in causing Coronavirus disease 2019 (COVID-19). The role of smoking habit in the susceptibility to infection is still controversial. In this study we correlated lung ACE-2 gene expression with several clinical/pathological data to explore susceptibility to infection. This is a retrospective observational study on 29 consecutive COVID-19 autopsies. SARS-CoV-2 genome and ACE-2 mRNA expression were evaluated by real-time polymerase chain reaction in lung tissue samples and correlated with several data with focus on smoking habit. Smoking was less frequent in high than low ACE-2 expressors (p = 0.014). A Bayesian regression also including age, gender, hypertension, and virus quantity confirmed that smoking was the most probable risk factor associated with low ACE-2 expression in the model. A direct relation was found between viral quantity and ACE-2 expression (p = 0.028). Finally, high ACE-2 expressors more frequently showed a prevalent pattern of vascular injury than low expressors (p = 0.049). In conclusion, ACE-2 levels were decreased in the lung tissue of smokers with severe COVID-19 pneumonia. These results point out complex biological interactions between SARS-CoV-2 and ACE-2 particularly concerning the aspect of smoking habit and need larger prospective case series and translational studies. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

► Show Figures

Figure 1

33 pages, 2611 KiB

Open AccessEditor’s ChoiceReview

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

by Igor A. Schepetkin, Mark B. Plotnikov, Andrei I. Khlebnikov, Tatiana M. Plotnikova and Mark T. Quinn

Biomolecules 2021, 11(6), 777; https://doi.org/10.3390/biom11060777 - 22 May 2021

Cited by 35 | Viewed by 5394

Abstract

Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are [...] Read more.

Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed. Full article

(This article belongs to the Collection Feature Papers in Biochemistry)

► Show Figures

Figure 1

22 pages, 2069 KiB

Open AccessEditor’s ChoiceReview

Mechanisms That Activate 26S Proteasomes and Enhance Protein Degradation

by Alfred L. Goldberg, Hyoung Tae Kim, Donghoon Lee and Galen Andrew Collins

Biomolecules 2021, 11(6), 779; https://doi.org/10.3390/biom11060779 - 22 May 2021

Cited by 18 | Viewed by 5908

Abstract

Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin–proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become [...] Read more.

Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin–proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become activated by a two-step mechanism requiring an association of the ubiquitin chain with Usp14 and then a loosely folded protein domain with the ATPases. The initial activation step is signaled by Usp14’s UBL domain, and many UBL-domain-containing proteins (e.g., Rad23, Parkin) also activate the proteasome. ZFAND5 is a distinct type of activator that binds ubiquitin conjugates and the proteasome and stimulates proteolysis during muscle atrophy. The proteasome’s activities are also regulated through subunit phosphorylation. Agents that raise cAMP and activate PKA stimulate within minutes Rpn6 phosphorylation and enhance the selective degradation of short-lived proteins. Likewise, hormones, fasting, and exercise, which raise cAMP, activate proteasomes and proteolysis in target tissues. Agents that raise cGMP and activate PKG also stimulate 26S activities but modify different subunit(s) and stimulate also the degradation of long-lived cell proteins. Both kinases enhance the selective degradation of aggregation-prone proteins that cause neurodegenerative diseases. These new mechanisms regulating proteolysis thus have clear physiological importance and therapeutic potential. Full article

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

► Show Figures

Figure 1

21 pages, 1770 KiB

Open AccessEditor’s ChoiceReview

DEER Analysis of GPCR Conformational Heterogeneity

by Matthias Elgeti and Wayne L. Hubbell

Biomolecules 2021, 11(6), 778; https://doi.org/10.3390/biom11060778 - 22 May 2021

Cited by 21 | Viewed by 4558

Abstract

G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor [...] Read more.

G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor basal activity, ligand affinity, intrinsic efficacy and signal bias. These parameters are encoded in characteristic receptor conformations existing in equilibrium and their populations, which are thus of paramount interest for the understanding of receptor (mal-)functions and rational design of improved therapeutics. To this end, the combination of site-directed spin labeling and EPR spectroscopy, in particular double electron–electron resonance (DEER), is exceedingly valuable as it has access to sub-Angstrom spatial resolution and provides a detailed picture of the number and populations of conformations in equilibrium. This review gives an overview of existing DEER studies on GPCRs with a focus on the delineation of structure/function frameworks, highlighting recent developments in data analysis and visualization. We introduce “conformational efficacy” as a parameter to describe ligand-specific shifts in the conformational equilibrium, taking into account the loose coupling between receptor segments observed for different GPCRs using DEER. Full article

(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)

► Show Figures

Figure 1

12 pages, 493 KiB

Open AccessEditor’s ChoiceReview

Can Cannabidiol Affect the Efficacy of Chemotherapy and Epigenetic Treatments in Cancer?

by Courtney Griffiths, James Aikins, David Warshal and Olga Ostrovsky

Biomolecules 2021, 11(5), 766; https://doi.org/10.3390/biom11050766 - 20 May 2021

Cited by 13 | Viewed by 4549

Abstract

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. [...] Read more.

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound’s response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications. Full article

(This article belongs to the Special Issue Novel Indications of Epigenetic Therapy in Cancer)

► Show Figures

Figure 1

18 pages, 3807 KiB

Open AccessEditor’s ChoiceArticle

Proton Detected Solid-State NMR of Membrane Proteins at 28 Tesla (1.2 GHz) and 100 kHz Magic-Angle Spinning

by Evgeny Nimerovsky, Kumar Tekwani Movellan, Xizhou Cecily Zhang, Marcel C. Forster, Eszter Najbauer, Kai Xue, Rıza Dervişoǧlu, Karin Giller, Christian Griesinger, Stefan Becker and Loren B. Andreas

Biomolecules 2021, 11(5), 752; https://doi.org/10.3390/biom11050752 - 18 May 2021

Cited by 37 | Viewed by 4676

Abstract

The available magnetic field strength for high resolution NMR in persistent superconducting magnets has recently improved from 23.5 to 28 Tesla, increasing the proton resonance frequency from 1 to 1.2 GHz. For magic-angle spinning (MAS) NMR, this is expected to improve resolution, provided [...] Read more.

The available magnetic field strength for high resolution NMR in persistent superconducting magnets has recently improved from 23.5 to 28 Tesla, increasing the proton resonance frequency from 1 to 1.2 GHz. For magic-angle spinning (MAS) NMR, this is expected to improve resolution, provided the sample preparation results in homogeneous broadening. We compare two-dimensional (2D) proton detected MAS NMR spectra of four membrane proteins at 950 and 1200 MHz. We find a consistent improvement in resolution that scales superlinearly with the increase in magnetic field for three of the four examples. In 3D and 4D spectra, which are now routinely acquired, this improvement indicates the ability to resolve at least 2 and 2.5 times as many signals, respectively. Full article

(This article belongs to the Special Issue Advances in Membrane Proteins 2021)

► Show Figures

Figure 1

10 pages, 999 KiB

Open AccessEditor’s ChoiceArticle

Plasma Extracellular Vesicle α-Synuclein Level in Patients with Parkinson’s Disease

by Chen-Chih Chung, Lung Chan, Jia-Hung Chen, Yi-Chieh Hung and Chien-Tai Hong

Biomolecules 2021, 11(5), 744; https://doi.org/10.3390/biom11050744 - 17 May 2021

Cited by 13 | Viewed by 2790

Abstract

Background: The most established pathognomonic protein of Parkinson’s disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) [...] Read more.

Background: The most established pathognomonic protein of Parkinson’s disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) secreted from cells and present in blood transport molecules are novel platforms for biomarker identification. In blood EVs, α-synuclein originates predominantly from the brain without the interference of the blood–brain barrier. The present study investigated the role of plasma EV-borne α-synuclein as a biomarker of PD. Methods: Patients with mild to moderate stages of PD (n = 116) and individuals without PD (n = 46) were recruited to serve as the PD study group and the control group, respectively. Plasma EVs were isolated, and immunomagnetic reduction–based immunoassay was used to assess EV α-synuclein levels. Conventional statistical analysis was performed using SPSS 25.0, and p < 0.05 was considered significant. Results: Compared with controls, we observed significantly lower plasma EV α-synuclein levels in the patients with PD (PD: 56.0 ± 3.7 fg/mL vs. control: 74.5 ± 4.3 fg/mL, p = 0.009), and the significance remained after adjustment for age and sex. Plasma EV α-synuclein levels in the patients with PD did not correlate with age, disease duration, Part I and II scores of the Unified Parkinson’s Disease Rating Scale (UPDRS), or the Mini-Mental State Examination scores. However, such levels were significantly correlated with UPDRS Part III score, which assesses motor dysfunction. Furthermore, the severity of akinetic-rigidity symptoms, but not tremor, was inversely associated with plasma EV α-synuclein level. Conclusion: Plasma EV α-synuclein was significantly different between the control and PD group and was associated with akinetic-rigidity symptom severity in patients with PD. This study corroborates the possible diagnostic and subtyping roles of plasma EV α-synuclein in patients with PD, and it further provides a basis for this protein’s clinical relevance and feasibility as a PD biomarker. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

► Show Figures

Figure 1

20 pages, 4523 KiB

Open AccessEditor’s ChoiceArticle

Beneficial Modulation of Lipid Mediator Biosynthesis in Innate Immune Cells by Antirheumatic Tripterygium wilfordii Glycosides

by Kehong Zhang, Simona Pace, Paul M. Jordan, Lukas K. Peltner, Alexander Weber, Dagmar Fischer, Robert K. Hofstetter, Xinchun Chen and Oliver Werz

Biomolecules 2021, 11(5), 746; https://doi.org/10.3390/biom11050746 - 17 May 2021

Cited by 9 | Viewed by 2901

Abstract

Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation [...] Read more.

Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation and immune responses and are strongly linked to RA. The mechanism by which TWG affects LM networks in RA treatment remains elusive. Employing LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed striking modulation of LM pathways by TWG in human monocyte-derived macrophage (MDM) phenotypes. In inflammatory M1-MDM, TWG (30 µg/mL) potently suppressed agonist-induced formation of 5-LOX products which was confirmed in human PMNL and traced back to direct inhibition of 5-LOX (IC₅₀ = 2.9 µg/mL). TWG also efficiently blocked thromboxane formation in M1-MDM without inhibiting other prostanoids and COX enzymes. Importantly, in anti-inflammatory M2-MDM, TWG (30 µg/mL) induced pronounced formation of specialized pro-resolving mediators (SPM) and related 12/15-LOX-derived SPM precursors, without COX and 5-LOX activation. During MDM polarization, TWG (1 µg/mL) decreased the capacity to generate pro-inflammatory 5-LOX and COX products, cytokines and markers for M1 phenotypes. Together, suppression of pro-inflammatory LM but SPM induction may contribute to the antirheumatic properties of TWG. Full article

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

► Show Figures

Figure 1

22 pages, 5131 KiB

Open AccessEditor’s ChoiceReview

A Bittersweet Computational Journey among Glycosaminoglycans

by Giulia Paiardi, Maria Milanesi, Rebecca C. Wade, Pasqualina D’Ursi and Marco Rusnati

Biomolecules 2021, 11(5), 739; https://doi.org/10.3390/biom11050739 - 15 May 2021

Cited by 10 | Viewed by 3687

Abstract

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of [...] Read more.

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of a wide array of physiological and pathological processes by binding to different proteins, thus modulating their structure and function, and their concentration and availability in the microenvironment. Unfortunately, the enormous structural diversity of GAGs/PGs has hampered the development of dedicated analytical technologies and experimental models. Similarly, computational approaches (in particular, molecular modeling, docking and dynamics simulations) have not been fully exploited in glycobiology, despite their potential to demystify the complexity of GAGs/PGs at a structural and functional level. Here, we review the state-of-the art of computational approaches to studying GAGs/PGs with the aim of pointing out the “bitter” and “sweet” aspects of this field of research. Furthermore, we attempt to bridge the gap between bioinformatics and glycobiology, which have so far been kept apart by conceptual and technical differences. For this purpose, we provide computational scientists and glycobiologists with the fundamentals of these two fields of research, with the aim of creating opportunities for their combined exploitation, and thereby contributing to a substantial improvement in scientific knowledge. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

► Show Figures

Figure 1

27 pages, 4242 KiB

Open AccessEditor’s ChoiceReview

Phototheranostics Using Erythrocyte-Based Particles

by Taylor Hanley, Raviraj Vankayala, Chi-Hua Lee, Jack C. Tang, Joshua M. Burns and Bahman Anvari

Biomolecules 2021, 11(5), 729; https://doi.org/10.3390/biom11050729 - 13 May 2021

Cited by 13 | Viewed by 3652

Abstract

There has been a recent increase in the development of delivery systems based on red blood cells (RBCs) for light-mediated imaging and therapeutic applications. These constructs are able to take advantage of the immune evasion properties of the RBC, while the addition of [...] Read more.

There has been a recent increase in the development of delivery systems based on red blood cells (RBCs) for light-mediated imaging and therapeutic applications. These constructs are able to take advantage of the immune evasion properties of the RBC, while the addition of an optical cargo allows the particles to be activated by light for a number of promising applications. Here, we review some of the common fabrication methods to engineer these constructs. We also present some of the current light-based applications with potential for clinical translation, and offer some insight into future directions in this exciting field. Full article

(This article belongs to the Special Issue Bioinspired and Biomimicking Materials for Biomedical Applications)

► Show Figures

Figure 1

20 pages, 1093 KiB

Open AccessEditor’s ChoiceReview

The Pentose Phosphate Pathway in Yeasts–More Than a Poor Cousin of Glycolysis

by Laura-Katharina Bertels, Lucía Fernández Murillo and Jürgen J. Heinisch

Biomolecules 2021, 11(5), 725; https://doi.org/10.3390/biom11050725 - 12 May 2021

Cited by 44 | Viewed by 11667

Abstract

The pentose phosphate pathway (PPP) is a route that can work in parallel to glycolysis in glucose degradation in most living cells. It has a unidirectional oxidative part with glucose-6-phosphate dehydrogenase as a key enzyme generating NADPH, and a non-oxidative part involving the [...] Read more.

The pentose phosphate pathway (PPP) is a route that can work in parallel to glycolysis in glucose degradation in most living cells. It has a unidirectional oxidative part with glucose-6-phosphate dehydrogenase as a key enzyme generating NADPH, and a non-oxidative part involving the reversible transketolase and transaldolase reactions, which interchange PPP metabolites with glycolysis. While the oxidative branch is vital to cope with oxidative stress, the non-oxidative branch provides precursors for the synthesis of nucleic, fatty and aromatic amino acids. For glucose catabolism in the baker’s yeast Saccharomyces cerevisiae, where its components were first discovered and extensively studied, the PPP plays only a minor role. In contrast, PPP and glycolysis contribute almost equally to glucose degradation in other yeasts. We here summarize the data available for the PPP enzymes focusing on S. cerevisiae and Kluyveromyces lactis, and describe the phenotypes of gene deletions and the benefits of their overproduction and modification. Reference to other yeasts and to the importance of the PPP in their biotechnological and medical applications is briefly being included. We propose future studies on the PPP in K. lactis to be of special interest for basic science and as a host for the expression of human disease genes. Full article

(This article belongs to the Special Issue Fungal Metabolism - Enzymes and Bioactive Compounds)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI