Biomolecules

12 pages, 2764 KiB

Open AccessEditor’s ChoiceArticle

O-methylated N-glycans Distinguish Mosses from Vascular Plants

by David Stenitzer, Réka Mócsai, Harald Zechmeister, Ralf Reski, Eva L. Decker and Friedrich Altmann

Biomolecules 2022, 12(1), 136; https://doi.org/10.3390/biom12010136 - 15 Jan 2022

Cited by 8 | Viewed by 2704

Abstract

In the animal kingdom, a stunning variety of N-glycan structures have emerged with phylogenetic specificities of various kinds. In the plant kingdom, however, N-glycosylation appears to be strictly conservative and uniform. From mosses to all kinds of gymno- and angiosperms, land plants mainly [...] Read more.

In the animal kingdom, a stunning variety of N-glycan structures have emerged with phylogenetic specificities of various kinds. In the plant kingdom, however, N-glycosylation appears to be strictly conservative and uniform. From mosses to all kinds of gymno- and angiosperms, land plants mainly express structures with the common pentasaccharide core substituted with xylose, core α1,3-fucose, maybe terminal GlcNAc residues and Lewis A determinants. In contrast, green algae biosynthesise unique and unusual N-glycan structures with uncommon monosaccharides, a plethora of different structures and various kinds of O-methylation. Mosses, a group of plants that are separated by at least 400 million years of evolution from vascular plants, have hitherto been seen as harbouring an N-glycosylation machinery identical to that of vascular plants. To challenge this view, we analysed the N-glycomes of several moss species using MALDI-TOF/TOF, PGC-MS/MS and GC-MS. While all species contained the plant-typical heptasaccharide with no, one or two terminal GlcNAc residues (MMXF, MGnXF and GnGnXF, respectively), many species exhibited MS signals with 14.02 Da increments as characteristic for O-methylation. Throughout all analysed moss N-glycans, the level of methylation differed strongly even within the same family. In some species, methylated glycans dominated, while others had no methylation at all. GC-MS revealed the main glycan from Funaria hygrometrica to contain 2,6-O-methylated terminal mannose. Some mosses additionally presented very large, likewise methylated complex-type N-glycans. This first finding of the methylation of N-glycans in land plants mirrors the presumable phylogenetic relation of mosses to green algae, where the O-methylation of mannose and many other monosaccharides is a common trait. Full article

(This article belongs to the Special Issue Glycosylation—The Most Diverse Post-Translational Modification)

► Show Figures

Graphical abstract

10 pages, 1938 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Pathophysiology and Therapeutics of Thoracic Aortic Aneurysm in Marfan Syndrome

by Keiichi Asano, Anna Cantalupo, Lauriane Sedes and Francesco Ramirez

Biomolecules 2022, 12(1), 128; https://doi.org/10.3390/biom12010128 - 14 Jan 2022

Cited by 18 | Viewed by 5494

Abstract

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein [...] Read more.

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder. Full article

(This article belongs to the Special Issue Aortic Aneurysm and Dissection: Heterogeneity and Molecular Mechanisms)

► Show Figures

Figure 1

34 pages, 1491 KiB

Open AccessEditor’s ChoiceReview

Mechanistic Link between Vitamin B12 and Alzheimer’s Disease

by Anna Andrea Lauer, Heike Sabine Grimm, Birgit Apel, Nataliya Golobrodska, Lara Kruse, Elina Ratanski, Noemi Schulten, Laura Schwarze, Thomas Slawik, Saskia Sperlich, Antonia Vohla and Marcus Otto Walter Grimm

Biomolecules 2022, 12(1), 129; https://doi.org/10.3390/biom12010129 - 14 Jan 2022

Cited by 35 | Viewed by 16232

Abstract

Alzheimer’s disease (AD) is the most common form of dementia in the elderly population, affecting over 55 million people worldwide. Histopathological hallmarks of this multifactorial disease are an increased plaque burden and tangles in the brains of affected individuals. Several lines of evidence [...] Read more.

Alzheimer’s disease (AD) is the most common form of dementia in the elderly population, affecting over 55 million people worldwide. Histopathological hallmarks of this multifactorial disease are an increased plaque burden and tangles in the brains of affected individuals. Several lines of evidence indicate that B12 hypovitaminosis is linked to AD. In this review, the biochemical pathways involved in AD that are affected by vitamin B12, focusing on APP processing, Aβ fibrillization, Aβ-induced oxidative damage as well as tau hyperphosphorylation and tau aggregation, are summarized. Besides the mechanistic link, an overview of clinical studies utilizing vitamin B supplementation are given, and a potential link between diseases and medication resulting in a reduced vitamin B12 level and AD are discussed. Besides the disease-mediated B12 hypovitaminosis, the reduction in vitamin B12 levels caused by an increasing change in dietary preferences has been gaining in relevance. In particular, vegetarian and vegan diets are associated with vitamin B12 deficiency, and therefore might have potential implications for AD. In conclusion, our review emphasizes the important role of vitamin B12 in AD, which is particularly important, as even in industrialized countries a large proportion of the population might not be sufficiently supplied with vitamin B12. Full article

► Show Figures

Graphical abstract

9 pages, 1512 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of COA6 in the Mitochondrial Copper Delivery Pathway to Cytochrome c Oxidase

by Abhinav B. Swaminathan and Vishal M. Gohil

Biomolecules 2022, 12(1), 125; https://doi.org/10.3390/biom12010125 - 13 Jan 2022

Cited by 19 | Viewed by 3582

Abstract

Copper is essential for the stability and activity of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Copper is bound to COX1 and COX2, two core subunits of CcO, forming the Cu_B and Cu_A sites, respectively. Biogenesis [...] Read more.

Copper is essential for the stability and activity of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Copper is bound to COX1 and COX2, two core subunits of CcO, forming the Cu_B and Cu_A sites, respectively. Biogenesis of these two copper sites of CcO occurs separately and requires a number of evolutionarily conserved proteins that form the mitochondrial copper delivery pathway. Pathogenic mutations in some of the proteins of the copper delivery pathway, such as SCO1, SCO2, and COA6, have been shown to cause fatal infantile human disorders, highlighting the biomedical significance of understanding copper delivery mechanisms to CcO. While two decades of studies have provided a clearer picture regarding the biochemical roles of SCO1 and SCO2 proteins, some discrepancy exists regarding the function of COA6, the new member of this pathway. Initial genetic and biochemical studies have linked COA6 with copper delivery to COX2 and follow-up structural and functional studies have shown that it is specifically required for the biogenesis of the Cu_A site by acting as a disulfide reductase of SCO and COX2 proteins. Its role as a copper metallochaperone has also been proposed. Here, we critically review the recent literature regarding the molecular function of COA6 in Cu_A biogenesis. Full article

(This article belongs to the Special Issue Insights in the Structure and Functions of Mitochondrial Proteins and Metalloproteins)

► Show Figures

Figure 1

14 pages, 1494 KiB

Open AccessEditor’s ChoiceReview

The Builders of the Junction: Roles of Junctophilin1 and Junctophilin2 in the Assembly of the Sarcoplasmic Reticulum–Plasma Membrane Junctions in Striated Muscle

by Stefano Perni

Biomolecules 2022, 12(1), 109; https://doi.org/10.3390/biom12010109 - 10 Jan 2022

Cited by 9 | Viewed by 3381

Abstract

Contraction of striated muscle is triggered by a massive release of calcium from the sarcoplasmic reticulum (SR) into the cytoplasm. This intracellular calcium release is initiated by membrane depolarization, which is sensed by voltage-gated calcium channels Ca_V1.1 (in skeletal muscle) and [...] Read more.

Contraction of striated muscle is triggered by a massive release of calcium from the sarcoplasmic reticulum (SR) into the cytoplasm. This intracellular calcium release is initiated by membrane depolarization, which is sensed by voltage-gated calcium channels Ca_V1.1 (in skeletal muscle) and Ca_V1.2 (in cardiac muscle) in the plasma membrane (PM), which in turn activate the calcium-releasing channel ryanodine receptor (RyR) embedded in the SR membrane. This cross-communication between channels in the PM and in the SR happens at specialized regions, the SR-PM junctions, where these two compartments come in close proximity. Junctophilin1 and Junctophilin2 are responsible for the formation and stabilization of SR-PM junctions in striated muscle and actively participate in the recruitment of the two essential players in intracellular calcium release, Ca_V and RyR. This short review focuses on the roles of junctophilins1 and 2 in the formation and organization of SR-PM junctions in skeletal and cardiac muscle and on the functional consequences of the absence or malfunction of these proteins in striated muscle in light of recently published data and recent advancements in protein structure prediction. Full article

(This article belongs to the Special Issue State-of-the-Art of Myology in Italy 2020–2021)

► Show Figures

Figure 1

20 pages, 6389 KiB

Open AccessEditor’s ChoiceReview

Sex Hormone-Specific Neuroanatomy of Takotsubo Syndrome: Is the Insular Cortex a Moderator?

by Michiaki Nagai, Carola Yvette Förster and Keigo Dote

Biomolecules 2022, 12(1), 110; https://doi.org/10.3390/biom12010110 - 10 Jan 2022

Cited by 11 | Viewed by 4204

Abstract

Takotsubo syndrome (TTS), a transient form of dysfunction in the heart’s left ventricle, occurs predominantly in postmenopausal women who have emotional stress. Earlier studies support the concept that the human circulatory system is modulated by a cortical network (consisting of the anterior cingulate [...] Read more.

Takotsubo syndrome (TTS), a transient form of dysfunction in the heart’s left ventricle, occurs predominantly in postmenopausal women who have emotional stress. Earlier studies support the concept that the human circulatory system is modulated by a cortical network (consisting of the anterior cingulate gyrus, amygdala, and insular cortex (Ic)) that plays a pivotal role in the central autonomic nervous system in relation to emotional stressors. The Ic plays a crucial role in the sympathovagal balance, and decreased levels of female sex hormones have been speculated to change functional cerebral asymmetry, with a possible link to autonomic instability. In this review, we focus on the Ic as an important moderator of the human brain–heart axis in association with sex hormones. We also summarize the current knowledge regarding the sex-specific neuroanatomy in TTS. Full article

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

► Show Figures

Figure 1

14 pages, 7816 KiB

Open AccessEditor’s ChoiceArticle

The Mucolipin TRPML2 Channel Enhances the Sensitivity of Multiple Myeloma Cell Lines to Ibrutinib and/or Bortezomib Treatment

by Giorgio Santoni, Consuelo Amantini, Federica Maggi, Oliviero Marinelli, Matteo Santoni and Maria Beatrice Morelli

Biomolecules 2022, 12(1), 107; https://doi.org/10.3390/biom12010107 - 9 Jan 2022

Cited by 5 | Viewed by 2113

Abstract

Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells and their accumulation in the bone marrow. The aim of the present study is the evaluation of biological effects of Ibrutinib in human MM cell lines alone [...] Read more.

Multiple myeloma (MM) is a haematological B cell malignancy characterised by clonal proliferation of plasma cells and their accumulation in the bone marrow. The aim of the present study is the evaluation of biological effects of Ibrutinib in human MM cell lines alone or in combination with different doses of Bortezomib. In addition, the relationship between the expression of TRPML2 channels and chemosensitivity of different MM cell lines to Ibrutinib administered alone or in combination with Bortezomib has been evaluated. By RT-PCR and Western blot analysis, we found that the Ibrutinib-resistant U266 cells showed lower TRPML2 expression, whereas higher TRPML2 mRNA and protein levels were evidenced in RPMI cells. Moreover, TRPML2 gene silencing in RPMI cells markedly reverted the effects induced by Ibrutinib alone or in combination with Bortezomib suggesting that the sensitivity to Ibrutinib is TRPML2 mediated. In conclusion, this study suggests that the expression of TRPML2 in MM cells increases the sensitivity to Ibrutinib treatment, suggesting for a potential stratification of Ibrutinib sensitivity of MM patients on the basis of the TRPML2 expression. Furthermore, studies in vitro and in vivo should still be necessary to completely address the molecular mechanisms and the potential role of TRPML2 channels in therapy and prognosis of MM patients. Full article

(This article belongs to the Special Issue Transient Receptor Potential (TRP) Channels: Markers and Therapeutic Targets for Cancer?)

► Show Figures

Figure 1

15 pages, 1521 KiB

Open AccessEditor’s ChoiceReview

Multi-Organ Crosstalk with Endocrine Pancreas: A Focus on How Gut Microbiota Shapes Pancreatic Beta-Cells

by Elisa Fernández-Millán and Carlos Guillén

Biomolecules 2022, 12(1), 104; https://doi.org/10.3390/biom12010104 - 8 Jan 2022

Cited by 15 | Viewed by 5550

Abstract

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells [...] Read more.

Type 2 diabetes (T2D) results from impaired beta-cell function and insufficient beta-cell mass compensation in the setting of insulin resistance. Current therapeutic strategies focus their efforts on promoting the maintenance of functional beta-cell mass to ensure appropriate glycemic control. Thus, understanding how beta-cells communicate with metabolic and non-metabolic tissues provides a novel area for investigation and implicates the importance of inter-organ communication in the pathology of metabolic diseases such as T2D. In this review, we provide an overview of secreted factors from diverse organs and tissues that have been shown to impact beta-cell biology. Specifically, we discuss experimental and clinical evidence in support for a role of gut to beta-cell crosstalk, paying particular attention to bacteria-derived factors including short-chain fatty acids, lipopolysaccharide, and factors contained within extracellular vesicles that influence the function and/or the survival of beta cells under normal or diabetogenic conditions. Full article

(This article belongs to the Special Issue The Pancreatic Beta Cell)

► Show Figures

Figure 1

29 pages, 1962 KiB

Open AccessEditor’s ChoiceReview

Anti-Planktonic and Anti-Biofilm Properties of Pentacyclic Triterpenes—Asiatic Acid and Ursolic Acid as Promising Antibacterial Future Pharmaceuticals

by Zuzanna Sycz, Dorota Tichaczek-Goska and Dorota Wojnicz

Biomolecules 2022, 12(1), 98; https://doi.org/10.3390/biom12010098 - 7 Jan 2022

Cited by 38 | Viewed by 3553

Abstract

Due to the ever-increasing number of multidrug-resistant bacteria, research concerning plant-derived compounds with antimicrobial mechanisms of action has been conducted. Pentacyclic triterpenes, which have a broad spectrum of medicinal properties, are one of such groups. Asiatic acid (AA) and ursolic acid (UA), which [...] Read more.

Due to the ever-increasing number of multidrug-resistant bacteria, research concerning plant-derived compounds with antimicrobial mechanisms of action has been conducted. Pentacyclic triterpenes, which have a broad spectrum of medicinal properties, are one of such groups. Asiatic acid (AA) and ursolic acid (UA), which belong to this group, exhibit diverse biological activities that include antioxidant, anti-inflammatory, diuretic, and immunostimulatory. Some of these articles usually contain only a short section describing the antibacterial effects of AA or UA. Therefore, our review article aims to provide the reader with a broader understanding of the activity of these acids against pathogenic bacteria. The bacteria in the human body can live in the planktonic form and create a biofilm structure. Therefore, we found it valuable to present the action of AA and UA on both planktonic and biofilm cultures. The article also presents mechanisms of the biological activity of these substances against microorganisms. Full article

(This article belongs to the Collection Feature Papers in Synthetic Biology and Bioengineering)

► Show Figures

Figure 1

19 pages, 1191 KiB

Open AccessEditor’s ChoiceReview

The Role of miRNA in Regulating the Fate of Monocytes in Health and Cancer

by Anna Alwani, Aneta Andreasik, Rafał Szatanek, Maciej Siedlar and Monika Baj-Krzyworzeka

Biomolecules 2022, 12(1), 100; https://doi.org/10.3390/biom12010100 - 7 Jan 2022

Cited by 9 | Viewed by 3262

Abstract

Monocytes represent a heterogeneous population of blood cells that provide a link between innate and adaptive immunity. The unique potential of monocytes as both precursors (e.g., of macrophages) and effector cells (as phagocytes or cytotoxic cells) makes them an interesting research and therapeutic [...] Read more.

Monocytes represent a heterogeneous population of blood cells that provide a link between innate and adaptive immunity. The unique potential of monocytes as both precursors (e.g., of macrophages) and effector cells (as phagocytes or cytotoxic cells) makes them an interesting research and therapeutic target. At the site of a tumor, monocytes/macrophages constitute a major population of infiltrating leukocytes and, depending on the type of tumor, may play a dual role as either a bad or good indicator for cancer recovery. The functional activity of monocytes and macrophages derived from them is tightly regulated at the transcriptional and post-transcriptional level. This review summarizes the current understanding of the role of small regulatory miRNA in monocyte formation, maturation and function in health and cancer development. Additionally, signatures of miRNA-based monocyte subsets and the influence of exogenous miRNA generated in the tumor environment on the function of monocytes are discussed. Full article

(This article belongs to the Special Issue MicroRNAs - Small Molecules with Great Potential in Tumorigenesis)

► Show Figures

Figure 1

18 pages, 2669 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Role of Fibroblasts and Myofibroblasts on the Pathogenesis and Treatment of Pelvic Organ Prolapse

by Zeliha Guler and Jan Paul Roovers

Biomolecules 2022, 12(1), 94; https://doi.org/10.3390/biom12010094 - 6 Jan 2022

Cited by 36 | Viewed by 8218

Abstract

Pelvic organ prolapse (POP) is a multifactorial connective tissue disorder caused by damage to the supportive structures of the pelvic floor, leading to the descent of pelvic organs in the vagina. In women with POP, fibroblast function is disturbed or altered, which causes [...] Read more.

Pelvic organ prolapse (POP) is a multifactorial connective tissue disorder caused by damage to the supportive structures of the pelvic floor, leading to the descent of pelvic organs in the vagina. In women with POP, fibroblast function is disturbed or altered, which causes impaired collagen metabolism that affects the mechanical properties of the tissue. Ideal surgical repair, either native tissue repair or POP surgery using an implant, aims to create a functional pelvic floor that is load-bearing, activating fibroblasts to regulate collagen metabolism without creating fibrotic tissue. Fibroblast function plays a crucial role in the pathophysiology of POP by directly affecting the connective tissue quality. On the other hand, fibroblasts determine the success of the POP treatment, as the fibroblast-to-(myo)fibroblast transition is the key event during wound healing and tissue repair. In this review, we aim to resolve the question of “cause and result” for the fibroblasts in the development and treatment of POP. This review may contribute to preventing the development and progress of anatomical abnormalities involved in POP and to optimizing surgical outcomes. Full article

(This article belongs to the Special Issue Biology of Fibroblasts and Myofibroblasts)

► Show Figures

Figure 1

12 pages, 2324 KiB

Open AccessEditor’s ChoiceArticle

Characterization and Modification of Light-Sensitive Phosphodiesterases from Choanoflagellates

by Yuehui Tian, Shang Yang, Georg Nagel and Shiqiang Gao

Biomolecules 2022, 12(1), 88; https://doi.org/10.3390/biom12010088 - 6 Jan 2022

Cited by 5 | Viewed by 3432

Abstract

Enzyme rhodopsins, including cyclase opsins (Cyclops) and rhodopsin phosphodiesterases (RhoPDEs), were recently discovered in fungi, algae and protists. In contrast to the well-developed light-gated guanylyl/adenylyl cyclases as optogenetic tools, ideal light-regulated phosphodiesterases are still in demand. Here, we investigated and engineered the RhoPDEs [...] Read more.

Enzyme rhodopsins, including cyclase opsins (Cyclops) and rhodopsin phosphodiesterases (RhoPDEs), were recently discovered in fungi, algae and protists. In contrast to the well-developed light-gated guanylyl/adenylyl cyclases as optogenetic tools, ideal light-regulated phosphodiesterases are still in demand. Here, we investigated and engineered the RhoPDEs from Salpingoeca rosetta, Choanoeca flexa and three other protists. All the RhoPDEs (fused with a cytosolic N-terminal YFP tag) can be expressed in Xenopus oocytes, except the AsRhoPDE that lacks the retinal-binding lysine residue in the last (8th) transmembrane helix. An N296K mutation of YFP::AsRhoPDE enabled its expression in oocytes, but this mutant still has no cGMP hydrolysis activity. Among the RhoPDEs tested, SrRhoPDE, CfRhoPDE1, 4 and MrRhoPDE exhibited light-enhanced cGMP hydrolysis activity. Engineering SrRhoPDE, we obtained two single point mutants, L623F and E657Q, in the C-terminal catalytic domain, which showed ~40 times decreased cGMP hydrolysis activity without affecting the light activation ratio. The molecular characterization and modification will aid in developing ideal light-regulated phosphodiesterase tools in the future. Full article

(This article belongs to the Special Issue State-of-Art in Protein Engineering)

► Show Figures

Figure 1

17 pages, 2500 KiB

Open AccessEditor’s ChoiceReview

Breast Cancer Treatment: The Case of Gold(I)-Based Compounds as a Promising Class of Bioactive Molecules

by Rossana Galassi, Lorenzo Luciani, Junbiao Wang, Silvia Vincenzetti, Lishan Cui, Augusto Amici, Stefania Pucciarelli and Cristina Marchini

Biomolecules 2022, 12(1), 80; https://doi.org/10.3390/biom12010080 - 5 Jan 2022

Cited by 11 | Viewed by 2923

Abstract

Breast cancers (BCs) may present dramatic diagnoses, both for ineffective therapies and for the limited outcomes in terms of lifespan. For these types of tumors, the search for new drugs is a primary necessity. It is widely recognized that gold compounds are highly [...] Read more.

Breast cancers (BCs) may present dramatic diagnoses, both for ineffective therapies and for the limited outcomes in terms of lifespan. For these types of tumors, the search for new drugs is a primary necessity. It is widely recognized that gold compounds are highly active and extremely potent as anticancer agents against many cancer cell lines. The presence of the metal plays an essential role in the activation of the cytotoxicity of these coordination compounds, whose activity, if restricted to the ligands alone, would be non-existent. On the other hand, gold exhibits a complex biochemistry, substantially variable depending on the chemical environments around the central metal. In this review, the scientific findings of the last 6–7 years on two classes of gold(I) compounds, containing phosphane or carbene ligands, are reviewed. In addition to this class of Au(I) compounds, the recent developments in the application of Auranofin in regards to BCs are reported. Auranofin is a triethylphosphine-thiosugar compound that, being a drug approved by the FDA—therefore extensively studied—is an interesting lead gold compound and a good comparison to understand the activities of structurally related Au(I) compounds. Full article

(This article belongs to the Special Issue Bioactive Molecules: Structures, Functions, and Potential Uses for Cancer Prevention and Targeted Therapies)

► Show Figures

Figure 1

9 pages, 249 KiB

Open AccessEditor’s ChoiceArticle

Association between Soluble α-Klotho Protein and Metabolic Syndrome in the Adult Population

by Yung-Wen Cheng, Chun-Chi Hung, Wen-Hui Fang and Wei-Liang Chen

Biomolecules 2022, 12(1), 70; https://doi.org/10.3390/biom12010070 - 4 Jan 2022

Cited by 18 | Viewed by 3137

Abstract

Klotho protein is an anti-aging protein and plays multiple roles in ion-regulation, anti-oxidative stress, and energy metabolism through various pathways. Metabolic syndrome is a combination of multiple conditions that compose of multiple risk factors of cardiovascular disease and type 2 diabetes. Gene regulation [...] Read more.

Klotho protein is an anti-aging protein and plays multiple roles in ion-regulation, anti-oxidative stress, and energy metabolism through various pathways. Metabolic syndrome is a combination of multiple conditions that compose of multiple risk factors of cardiovascular disease and type 2 diabetes. Gene regulation and protein expression are discovered associated with metabolic syndrome. We aimed to figure out the correlation between Klotho protein and metabolic syndrome in generally healthy adults. A cross-sectional study of 9976 respondents ≥ 18 years old from the US National Health and Nutrition Examination Survey (2007–2012) by utilizing their soluble Klotho protein concentrations. Multivariate linear regression models were used to analyze the effect of soluble Klotho protein on the prevalence of metabolic syndrome. Soluble Klotho protein concentration was inversely correlated with the presence of metabolic syndromes (p = 0.013) and numbers of components that met the definition of metabolic syndrome (p < 0.05). The concentration of Soluble Klotho protein was negatively associated with abdominal obesity and high triglyceride (TG) in the adjusted model (p < 0.05). Soluble Klotho protein is correlated with changing metabolic syndrome components in adults, especially central obesity and high TG levels. Despite conventional function as co-factor with fibroblast growth factor-23 (FGF23) that regulates phosphate and vitamin D homeostasis, FGF23-independent soluble Klotho protein may act on multiple signal pathways in different organs and tissue in roles of anti-aging and protection from metabolic syndrome. Full article

10 pages, 2527 KiB

Open AccessEditor’s ChoiceArticle

Acetyltransferases GCN5 and PCAF Are Required for B Lymphocyte Maturation in Mice

by Valentyn Oksenych, Dan Su and Jeremy A. Daniel

Biomolecules 2022, 12(1), 61; https://doi.org/10.3390/biom12010061 - 31 Dec 2021

Cited by 4 | Viewed by 3153

Abstract

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region, and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for the successful maturation of [...] Read more.

B lymphocyte development has two DNA recombination processes: V(D)J recombination of the immunoglobulin (Igh) gene variable region, and class switching of the Igh constant regions from IgM to IgG, IgA, or IgE. V(D)J recombination is required for the successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. CSR occurs outside of the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an open chromatin state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated a mouse model that lacked both GCN5 and PCAF in B cells. Double-deficient mice possessed low levels of mature B cells in the bone marrow and peripheral organs, an accumulation of pro-B cells in bone marrow, and reduced CSR levels. We concluded that both GCN5 and PCAF are required for B-cell development in vivo. Full article

(This article belongs to the Collection DNA Repair and Immune Response)

► Show Figures

Figure 1

21 pages, 3531 KiB

Open AccessEditor’s ChoiceReview

Site-Specific Proteasome Inhibitors

by Alexei F. Kisselev

Biomolecules 2022, 12(1), 54; https://doi.org/10.3390/biom12010054 - 31 Dec 2021

Cited by 33 | Viewed by 4380

Abstract

Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, [...] Read more.

Proteasome is a multi-subunit protein degradation machine, which plays a key role in the maintenance of protein homeostasis and, through degradation of regulatory proteins, in the regulation of numerous cell functions. Proteasome inhibitors are essential tools for biomedical research. Three proteasome inhibitors, bortezomib, carfilzomib, and ixazomib are approved by the FDA for the treatment of multiple myeloma; another inhibitor, marizomib, is undergoing clinical trials. The proteolytic core of the proteasome has three pairs of active sites, β5, β2, and β1. All clinical inhibitors and inhibitors that are widely used as research tools (e.g., epoxomicin, MG-132) inhibit multiple active sites and have been extensively reviewed in the past. In the past decade, highly specific inhibitors of individual active sites and the distinct active sites of the lymphoid tissue-specific immunoproteasome have been developed. Here, we provide a comprehensive review of these site-specific inhibitors of mammalian proteasomes and describe their utilization in the studies of the biology of the active sites and their roles as drug targets for the treatment of different diseases. Full article

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

► Show Figures

Graphical abstract

26 pages, 5586 KiB

Open AccessEditor’s ChoiceArticle

The Functional Differences between the GroEL Chaperonin of Escherichia coli and the HtpB Chaperonin of Legionella pneumophila Can Be Mapped to Specific Amino Acid Residues

by Karla N. Valenzuela-Valderas, Gabriel Moreno-Hagelsieb, John R. Rohde and Rafael A. Garduño

Biomolecules 2022, 12(1), 59; https://doi.org/10.3390/biom12010059 - 31 Dec 2021

Cited by 3 | Viewed by 2299

Abstract

Group I chaperonins are a highly conserved family of essential proteins that self-assemble into molecular nanoboxes that mediate the folding of cytoplasmic proteins in bacteria and organelles. GroEL, the chaperonin of Escherichia coli, is the archetype of the family. Protein folding-independent functions [...] Read more.

Group I chaperonins are a highly conserved family of essential proteins that self-assemble into molecular nanoboxes that mediate the folding of cytoplasmic proteins in bacteria and organelles. GroEL, the chaperonin of Escherichia coli, is the archetype of the family. Protein folding-independent functions have been described for numerous chaperonins, including HtpB, the chaperonin of the bacterial pathogen Legionella pneumophila. Several protein folding-independent functions attributed to HtpB are not shared by GroEL, suggesting that differences in the amino acid (aa) sequence between these two proteins could correlate with functional differences. GroEL and HtpB differ in 137 scattered aa positions. Using the Evolutionary Trace (ET) bioinformatics method, site-directed mutagenesis, and a functional reporter test based upon a yeast-two-hybrid interaction with the eukaryotic protein ECM29, it was determined that out of those 137 aa, ten (M68, M212, S236, K298, N507 and the cluster AEHKD in positions 471-475) were involved in the interaction of HtpB with ECM29. GroEL was completely unable to interact with ECM29, but when GroEL was modified at those 10 aa positions, to display the HtpB aa, it acquired a weak ability to interact with ECM29. This constitutes proof of concept that the unique functional abilities of HtpB can be mapped to specific aa positions. Full article

(This article belongs to the Special Issue Biomolecules of Legionella – Tiny Parts Building the Virulence Machinery)

► Show Figures

Figure 1

17 pages, 1305 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Adipose Triglyceride Lipase in Hepatic Physiology and Pathophysiology

by Tianjiao Li, Wei Guo and Zhanxiang Zhou

Biomolecules 2022, 12(1), 57; https://doi.org/10.3390/biom12010057 - 31 Dec 2021

Cited by 26 | Viewed by 4825

Abstract

The liver is extremely active in oxidizing triglycerides (TG) for energy production. An imbalance between TG synthesis and hydrolysis leads to metabolic disorders in the liver, including excessive lipid accumulation, oxidative stress, and ultimately liver damage. Adipose triglyceride lipase (ATGL) is the rate-limiting [...] Read more.

The liver is extremely active in oxidizing triglycerides (TG) for energy production. An imbalance between TG synthesis and hydrolysis leads to metabolic disorders in the liver, including excessive lipid accumulation, oxidative stress, and ultimately liver damage. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme that catalyzes the first step of TG breakdown to glycerol and fatty acids. Although its role in controlling lipid homeostasis has been relatively well-studied in the adipose tissue, heart, and skeletal muscle, it remains largely unknown how and to what extent ATGL is regulated in the liver, responds to stimuli and regulators, and mediates disease progression. Therefore, in this review, we describe the current understanding of the structure–function relationship of ATGL, the molecular mechanisms of ATGL regulation at translational and post-translational levels, and—most importantly—its role in lipid and glucose homeostasis in health and disease with a focus on the liver. Advances in understanding the molecular mechanisms underlying hepatic lipid accumulation are crucial to the development of targeted therapies for treating hepatic metabolic disorders. Full article

(This article belongs to the Special Issue Lipid and Glucose Metabolism in Liver Diseases)

► Show Figures

Figure 1

14 pages, 2437 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway

by Chen-Chi Liu, Hsin-Hsien Li, Jiun-Han Lin, Ming-Chen Chiang, Tien-Wei Hsu, Anna Fen-Yau Li, David Hung-Tsang Yen, Han-Shui Hsu and Shih-Chieh Hung

Biomolecules 2022, 12(1), 48; https://doi.org/10.3390/biom12010048 - 29 Dec 2021

Cited by 18 | Viewed by 3598

Abstract

Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we [...] Read more.

Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma. Full article

(This article belongs to the Special Issue Advances in Molecular Characterization and Therapeutic Targeting of Cancer Stem Cells)

► Show Figures

Graphical abstract

23 pages, 4457 KiB

Open AccessEditor’s ChoiceArticle

Secondary Metabolites Coordinately Protect Grapes from Excessive Light and Sunburn Damage during Development

by Joanna M. Gambetta, Valentina Romat, Leigh M. Schmidtke and Bruno P. Holzapfel

Biomolecules 2022, 12(1), 42; https://doi.org/10.3390/biom12010042 - 28 Dec 2021

Cited by 12 | Viewed by 3010

Abstract

Sunburn is a physiological disorder that reduces grape quality and vineyard yield. It is the result of excessive sunlight and high temperatures. As climate change continues to increase air temperatures, reports of sunburn damage in vineyards worldwide are becoming more frequent. Grapes produce [...] Read more.

Sunburn is a physiological disorder that reduces grape quality and vineyard yield. It is the result of excessive sunlight and high temperatures. As climate change continues to increase air temperatures, reports of sunburn damage in vineyards worldwide are becoming more frequent. Grapes produce secondary metabolites (carotenoids, polyphenols and aroma compounds) to counter photooxidative stress and acclimate to higher radiation environments. This study evaluated changes in these compounds in during ripening when grapes were exposed post-flowering (ED) and at véraison (LD), and compared them to a nondefoliated control (ND). ND contained more α-terpineol and violaxanthin, and the defoliated treatments contained more zeaxanthin, β-carotene, C₆ compounds and flavonoids. ED berries adapted better to higher-light environments, displayed larger changes in secondary metabolite concentrations and lower levels of sunburn damage than LD berries did. The composition of berries with increasing sunburn damage was evaluated for the first time. Berries with no damage had the lowest concentrations of flavonoids and oxidized glutathione, and the highest concentrations of chlorophyll and α-terpineol. As damage increased, destruction of photosynthetic pigments, increase in polyphenols and loss of aroma compounds were evidenced. A significant effect of temperature and developmental stage on grape composition was also observed. This study provides a holistic overview of changes in secondary metabolites experienced by grape berries when exposed to excessive light, how these vary along development and how they affect sunburn incidence. Full article

(This article belongs to the Special Issue Climate Change and Grape and Wine Biomolecules: Effect and Solutions)

► Show Figures

Graphical abstract

12 pages, 2806 KiB

Open AccessEditor’s ChoiceArticle

A Rapid Method for Postmortem Vitreous Chemistry—Deadside Analysis

by Brita Zilg, Kanar Alkass, Robert Kronstrand, Sören Berg and Henrik Druid

Biomolecules 2022, 12(1), 32; https://doi.org/10.3390/biom12010032 - 27 Dec 2021

Cited by 6 | Viewed by 3571

Abstract

Vitreous fluid is commonly collected for toxicological analysis during forensic postmortem investigations. Vitreous fluid is also often analyzed for potassium, sodium, chloride and glucose for estimation of time since death, and for the evaluation of electrolyte imbalances and hyperglycemia, respectively. Obtaining such results [...] Read more.

Vitreous fluid is commonly collected for toxicological analysis during forensic postmortem investigations. Vitreous fluid is also often analyzed for potassium, sodium, chloride and glucose for estimation of time since death, and for the evaluation of electrolyte imbalances and hyperglycemia, respectively. Obtaining such results in the early phase of a death investigation is desirable both in regard to assisting the police and in the decision-making prior to the autopsy. We analyzed vitreous fluid with blood gas instruments to evaluate/examine the possible impact of different sampling and pre-analytical treatment. We found that samples from the right and left eye, the center of the eye as well as whole vitreous samples gave similar results. We also found imprecision to be very low and that centrifugation and dilution were not necessary when analyzing vitreous samples with blood gas instruments. Similar results were obtained when analyzing the same samples with a regular multi-analysis instrument, but we found that such instruments could require dilution of samples with high viscosity, and that such dilution might impact measurement accuracy. In conclusion, using a blood gas instrument, the analysis of postmortem vitreous fluid for electrolytes and glucose without sample pretreatment produces rapid and reliable results. Full article

(This article belongs to the Special Issue Postmortem Biochemistry-When Death Matters)

► Show Figures

Figure 1

12 pages, 588 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Automatic Activity Arising in Cardiac Muscle Sleeves of the Pulmonary Vein

by Pierre Bredeloux, Come Pasqualin, Romain Bordy, Veronique Maupoil and Ian Findlay

Biomolecules 2022, 12(1), 23; https://doi.org/10.3390/biom12010023 - 24 Dec 2021

Cited by 7 | Viewed by 3234

Abstract

Ectopic activity in the pulmonary vein cardiac muscle sleeves can both induce and maintain human atrial fibrillation. A central issue in any study of the pulmonary veins is their difference from the left atrial cardiac muscle. Here, we attempt to summarize the physiological [...] Read more.

Ectopic activity in the pulmonary vein cardiac muscle sleeves can both induce and maintain human atrial fibrillation. A central issue in any study of the pulmonary veins is their difference from the left atrial cardiac muscle. Here, we attempt to summarize the physiological phenomena underlying the occurrence of ectopic electrical activity in animal pulmonary veins. We emphasize that the activation of multiple signaling pathways influencing not only myocyte electrophysiology but also the means of excitation–contraction coupling may be required for the initiation of triggered or automatic activity. We also gather information regarding not only the large-scale structure of cardiac muscle sleeves but also recent studies suggesting that cellular heterogeneity may contribute to the generation of arrythmogenic phenomena and to the distinction between pulmonary vein and left atrial heart muscle. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

14 pages, 1909 KiB

Open AccessEditor’s ChoiceReview

Lipoprotein(a)—The Crossroads of Atherosclerosis, Atherothrombosis and Inflammation

by Sabina Ugovšek and Miran Šebeštjen

Biomolecules 2022, 12(1), 26; https://doi.org/10.3390/biom12010026 - 24 Dec 2021

Cited by 42 | Viewed by 6216

Abstract

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations [...] Read more.

Increased lipoprotein(a) (Lp(a)) levels are an independent predictor of coronary artery disease (CAD), degenerative aortic stenosis (DAS), and heart failure independent of CAD and DAS. Lp(a) levels are genetically determinated in an autosomal dominant mode, with great intra- and inter-ethnic diversity. Most variations in Lp(a) levels arise from genetic variations of the gene that encodes the apolipoprotein(a) component of Lp(a), the LPA gene. LPA is located on the long arm of chromosome 6, within region 6q2.6–2.7. Lp(a) levels increase cardiovascular risk through several unrelated mechanisms. Lp(a) quantitatively carries all of the atherogenic risk of low-density lipoprotein cholesterol, although it is even more prone to oxidation and penetration through endothelia to promote the production of foam cells. The thrombogenic properties of Lp(a) result from the homology between apolipoprotein(a) and plasminogen, which compete for the same binding sites on endothelial cells to inhibit fibrinolysis and promote intravascular thrombosis. LPA has up to 70% homology with the human plasminogen gene. Oxidized phospholipids promote differentiation of pro-inflammatory macrophages that secrete pro-inflammatory cytokines (e. g., interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α). The aim of this review is to define which of these mechanisms of Lp(a) is predominant in different groups of patients. Full article

(This article belongs to the Special Issue Emerging Circulating Biomarkers in Atherosclerosis: From Molecular Mechanisms to Therapeutic Strategies)

► Show Figures

Figure 1

15 pages, 784 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Do Epstein–Barr Virus Mutations and Natural Genome Sequence Variations Contribute to Disease?

by Paul J. Farrell and Robert E. White

Biomolecules 2022, 12(1), 17; https://doi.org/10.3390/biom12010017 - 23 Dec 2021

Cited by 19 | Viewed by 4780

Abstract

Most of the world’s population is infected by the Epstein–Barr virus (EBV), but the incidence of the diseases associated with EBV infection differs greatly in different parts of the world. Many factors may determine those differences, but variation in the virus genome is [...] Read more.

Most of the world’s population is infected by the Epstein–Barr virus (EBV), but the incidence of the diseases associated with EBV infection differs greatly in different parts of the world. Many factors may determine those differences, but variation in the virus genome is likely to be a contributing factor for some of the diseases. Here, we describe the main forms of EBV genome sequence variation, and the mechanisms by which variations in the virus genome are likely to contribute to disease. EBV genome deletions or polymorphisms can also provide useful markers for monitoring disease. If some EBV strains prove to be more pathogenic than others, this suggests the possible value of immunising people against infection by those pathogenic strains. Full article

(This article belongs to the Special Issue Immunity and Pathogenesis of Epstein-Barr Virus Infection)

► Show Figures

Figure 1

18 pages, 4861 KiB

Open AccessEditor’s ChoiceArticle

Shock-Induced Damage Mechanism of Perineuronal Nets

by Khandakar Abu Hasan Al Mahmud, Fuad Hasan, Md Ishak Khan and Ashfaq Adnan

Biomolecules 2022, 12(1), 10; https://doi.org/10.3390/biom12010010 - 22 Dec 2021

Cited by 6 | Viewed by 3614

Abstract

The perineuronal net (PNN) region of the brain’s extracellular matrix (ECM) surrounds the neural networks within the brain tissue. The PNN is a protective net-like structure regulating neuronal activity such as neurotransmission, charge balance, and action potential generation. Shock-induced damage of this essential [...] Read more.

The perineuronal net (PNN) region of the brain’s extracellular matrix (ECM) surrounds the neural networks within the brain tissue. The PNN is a protective net-like structure regulating neuronal activity such as neurotransmission, charge balance, and action potential generation. Shock-induced damage of this essential component may lead to neuronal cell death and neurodegenerations. The shock generated during a vehicle accident, fall, or improvised device explosion may produce sufficient energy to damage the structure of the PNN. The goal is to investigate the mechanics of the PNN in reaction to shock loading and to understand the mechanical properties of different PNN components such as glycan, GAG, and protein. In this study, we evaluated the mechanical strength of PNN molecules and the interfacial strength between the PNN components. Afterward, we assessed the PNN molecules’ damage efficiency under various conditions such as shock speed, preexisting bubble, and boundary conditions. The secondary structure altercation of the protein molecules of the PNN was analyzed to evaluate damage intensity under varying shock speeds. At a higher shock speed, damage intensity is more elevated, and hyaluronan (glycan molecule) is most likely to break at the rigid junction. The primary structure of the protein molecules is least likely to fail. Instead, the molecules’ secondary bonds will be altered. Our study suggests that the number of hydrogen bonds during the shock wave propagation is reduced, which leads to the change in protein conformations and damage within the PNN structure. As such, we found a direct connection between shock wave intensity and PNN damage. Full article

► Show Figures

Figure 1

21 pages, 3971 KiB

Open AccessEditor’s ChoiceArticle

Connexin 43 Gene Ablation Does Not Alter Human Pluripotent Stem Cell Germ Lineage Specification

by Grace A. Christopher, Rebecca J. Noort and Jessica L. Esseltine

Biomolecules 2022, 12(1), 15; https://doi.org/10.3390/biom12010015 - 22 Dec 2021

Cited by 1 | Viewed by 3021

Abstract

During embryonic germ layer development, cells communicate with each other and their environment to ensure proper lineage specification and tissue development. Connexin (Cx) proteins facilitate direct cell–cell communication through gap junction channels. While previous reports suggest that gap junctional intercellular communication may contribute [...] Read more.

During embryonic germ layer development, cells communicate with each other and their environment to ensure proper lineage specification and tissue development. Connexin (Cx) proteins facilitate direct cell–cell communication through gap junction channels. While previous reports suggest that gap junctional intercellular communication may contribute to germ layer formation, there have been limited comprehensive expression analyses or genetic ablation studies on Cxs during human pluripotent stem cell (PSC) germ lineage specification. We screened the mRNA profile and protein expression patterns of select human Cx isoforms in undifferentiated human induced pluripotent stem cells (iPSCs), and after directed differentiation into the three embryonic germ lineages: ectoderm, definitive endoderm, and mesoderm. Transcript analyses by qPCR revealed upregulation of Cx45 and Cx62 in iPSC-derived ectoderm; Cx45 in mesoderm; and Cx30.3, Cx31, Cx32, Cx36, Cx37, and Cx40 in endoderm relative to control human iPSCs. Generated Cx43 (GJA1) CRISPR-Cas9 knockout iPSCs successfully differentiated into cells of all three germ layers, suggesting that Cx43 is dispensable during directed iPSC lineage specification. Furthermore, qPCR screening of select Cx transcripts in our GJA1-/- iPSCs showed no significant Cx upregulation in response to the loss of Cx43 protein. Future studies will reveal possible compensation by additional Cxs, suggesting targets for future CRISPR-Cas9 ablation studies in human iPSC lineage specification. Full article

(This article belongs to the Section Chemical Biology)

► Show Figures

Figure 1

14 pages, 1097 KiB

Open AccessEditor’s ChoiceReview

Diagnostic and Therapeutic Values of Angiogenic Factors in Endometrial Cancer

by Luka Roškar, Irena Roškar, Tea Lanišnik Rižner and Špela Smrkolj

Biomolecules 2022, 12(1), 7; https://doi.org/10.3390/biom12010007 - 21 Dec 2021

Cited by 12 | Viewed by 4467

Abstract

Endometrial cancer (EC) is the most frequent gynecological malignancy in developed countries and requires a relatively invasive diagnostic evaluation and operative therapy as the primary therapeutic approach. Angiogenesis is one of the main processes needed for cancer growth and spread. The production of [...] Read more.

Endometrial cancer (EC) is the most frequent gynecological malignancy in developed countries and requires a relatively invasive diagnostic evaluation and operative therapy as the primary therapeutic approach. Angiogenesis is one of the main processes needed for cancer growth and spread. The production of angiogenic factors (AFs) appears early in the process of carcinogenesis. The detection of AFs in plasma and tissue and a better understanding of the angiogenic properties of EC may contribute not only to earlier but also more specific diagnosis and consequently tailored and individual therapeutic approaches. AFs and their receptors also have high potential as binding sites for targeted cancer therapy. In this review, we discuss angiogenesis in EC and the characteristics of the AFs that most contribute to angiogenesis in EC. We also highlight therapeutic strategies that target angiogenesis as potential EC therapy. Full article

(This article belongs to the Special Issue Risk Prediction Tools and Biomarkers in Gynaecological Cancer)

► Show Figures

Figure 1

19 pages, 1064 KiB

Open AccessEditor’s ChoiceReview

The Cross Marks the Spot: The Emerging Role of JmjC Domain-Containing Proteins in Myeloid Malignancies

by Hans Felix Staehle, Heike Luise Pahl and Jonas Samuel Jutzi

Biomolecules 2021, 11(12), 1911; https://doi.org/10.3390/biom11121911 - 20 Dec 2021

Cited by 6 | Viewed by 3673

Abstract

Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone [...] Read more.

Histone methylation tightly regulates chromatin accessibility, transcription, proliferation, and cell differentiation, and its perturbation contributes to oncogenic reprogramming of cells. In particular, many myeloid malignancies show evidence of epigenetic dysregulation. Jumonji C (JmjC) domain-containing proteins comprise a large and diverse group of histone demethylases (KDMs), which remove methyl groups from lysines in histone tails and other proteins. Cumulating evidence suggests an emerging role for these demethylases in myeloid malignancies, rendering them attractive targets for drug interventions. In this review, we summarize the known functions of Jumonji C (JmjC) domain-containing proteins in myeloid malignancies. We highlight challenges in understanding the context-dependent mechanisms of these proteins and explore potential future pharmacological targeting. Full article

(This article belongs to the Special Issue Jumonji Domain-Containing Proteins in Cancer Progression)

► Show Figures

Figure 1

16 pages, 1435 KiB

Open AccessEditor’s ChoiceArticle

Sedimentary Cobalt Protoporphyrin as a Potential Precursor of Prosthetic Heme Group for Bacteria Inhabiting Fossil Organic Matter-Rich Shale Rock

by Robert Stasiuk and Renata Matlakowska

Biomolecules 2021, 11(12), 1913; https://doi.org/10.3390/biom11121913 - 20 Dec 2021

Cited by 1 | Viewed by 2354

Abstract

This study hypothesizes that bacteria inhabiting shale rock affect the content of the sedimentary cobalt protoporphyrin present in it and can use it as a precursor for heme synthesis. To verify this hypothesis, we conducted qualitative and quantitative comparative analyses of cobalt protoporphyrin [...] Read more.

This study hypothesizes that bacteria inhabiting shale rock affect the content of the sedimentary cobalt protoporphyrin present in it and can use it as a precursor for heme synthesis. To verify this hypothesis, we conducted qualitative and quantitative comparative analyses of cobalt protoporphyrin as well as heme, and heme iron in shale rock that were (i) inhabited by bacteria in the field, (ii) treated with bacteria in the laboratory, and with (iii) bacterial culture on synthetic cobalt protoporphyrin. Additionally, we examined the above-mentioned samples for the presence of enzymes involved in the heme biosynthesis and uptake as well as hemoproteins. We found depletion of cobalt protoporphyrin and a much higher heme concentration in the shale rock inhabited by bacteria in the field as well as the shale rock treated with bacteria in the laboratory. Similarly, we observed the accumulation of protoporphyrin in bacterial cells grown on synthetic cobalt protoporphyrin. We detected numerous hemoproteins in metaproteome of bacteria inhabited shale rock in the field and in proteomes of bacteria inhabited shale rock and synthetic cobalt protoporhyrin in the laboratory, but none of them had all the enzymes involved in the heme biosynthesis. However, proteins responsible for heme uptake, ferrochelatase and sirohydrochlorin cobaltochelatase/sirohydrochlorin cobalt-lyase were detected in all studied samples. Full article

► Show Figures

Figure 1

14 pages, 2955 KiB

Open AccessEditor’s ChoiceArticle

Prototype Foamy Virus Integrase Displays Unique Biochemical Activities among Retroviral Integrases

by Anthony J. Rabe, Yow Yong Tan, Ross C. Larue and Kristine E. Yoder

Biomolecules 2021, 11(12), 1910; https://doi.org/10.3390/biom11121910 - 20 Dec 2021

Cited by 2 | Viewed by 2765

Abstract

Integrases of different retroviruses assemble as functional complexes with varying multimers of the protein. Retroviral integrases require a divalent metal cation to perform one-step transesterification catalysis. Tetrameric prototype foamy virus (PFV) intasomes assembled from purified integrase and viral DNA oligonucleotides were characterized for [...] Read more.

Integrases of different retroviruses assemble as functional complexes with varying multimers of the protein. Retroviral integrases require a divalent metal cation to perform one-step transesterification catalysis. Tetrameric prototype foamy virus (PFV) intasomes assembled from purified integrase and viral DNA oligonucleotides were characterized for their activity in the presence of different cations. While most retroviral integrases are inactive in calcium, PFV intasomes appear to be uniquely capable of catalysis in calcium. The PFV intasomes also contrast with other retroviral integrases by displaying an inverse correlation of activity with increasing manganese beginning at relatively low concentrations. The intasomes were found to be significantly more active in the presence of chloride co-ions compared to acetate. While HIV-1 integrase appears to commit to a target DNA within 20 s, PFV intasomes do not commit to target DNA during their reaction lifetime. Together, these data highlight the unique biochemical activities of PFV integrase compared to other retroviral integrases. Full article

(This article belongs to the Section Enzymology)

► Show Figures

Figure 1

14 pages, 1347 KiB

Open AccessEditor’s ChoiceArticle

Dexamethasone for Inner Ear Therapy: Biocompatibility and Bio-Efficacy of Different Dexamethasone Formulations In Vitro

by Ziwen Gao, Jana Schwieger, Farnaz Matin-Mann, Peter Behrens, Thomas Lenarz and Verena Scheper

Biomolecules 2021, 11(12), 1896; https://doi.org/10.3390/biom11121896 - 17 Dec 2021

Cited by 13 | Viewed by 3762

Abstract

Dexamethasone is widely used in preclinical studies and clinical trials to treat inner ear disorders. The results of those studies vary widely, maybe due to the different dexamethasone formulations used. Laboratory (lab) and medical grade (med) dexamethasone (DEX, C₂₂H₂₉FO [...] Read more.

Dexamethasone is widely used in preclinical studies and clinical trials to treat inner ear disorders. The results of those studies vary widely, maybe due to the different dexamethasone formulations used. Laboratory (lab) and medical grade (med) dexamethasone (DEX, C₂₂H₂₉FO₅) and dexamethasone dihydrogen phosphate-disodium (DPS, C₂₂H₂₈FNa₂O₈P) were investigated for biocompatibility and bio-efficacy in vitro. The biocompatibility of each dexamethasone formulation in concentrations from 0.03 to 10,000 µM was evaluated using an MTT assay. The concentrations resulting in the highest cell viability were selected to perform a bio-efficiency test using a TNFα-reduction assay. All dexamethasone formulations up to 900 µM are biocompatible in vitro. DPS-lab becomes toxic at 1000 µM and DPS-med at 2000 µM, while DEX-lab and DEX-med become toxic at 4000 µM. Bio-efficacy was evaluated for DEX-lab and DPS-med at 300 µM, for DEX-med at 60 µM, and DPS-lab at 150 µM, resulting in significantly reduced expression of TNFα, with DPS-lab having the highest effect. Different dexamethasone formulations need to be applied in different concentration ranges to be biocompatible. The concentration to be applied in future studies should carefully be chosen based on the respective dexamethasone form, application route and duration to ensure biocompatibility and bio-efficacy. Full article

(This article belongs to the Special Issue Inner Ear Therapeutics)

► Show Figures

Figure 1

18 pages, 14701 KiB

Open AccessEditor’s ChoiceReview

Insulin-Responsive Transcription Factors

by Gerald Thiel, Lisbeth A. Guethlein and Oliver G. Rössler

Biomolecules 2021, 11(12), 1886; https://doi.org/10.3390/biom11121886 - 15 Dec 2021

Cited by 15 | Viewed by 5473

Abstract

The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor [...] Read more.

The hormone insulin executes its function via binding and activating of the insulin receptor, a receptor tyrosine kinase that is mainly expressed in skeletal muscle, adipocytes, liver, pancreatic β-cells, and in some areas of the central nervous system. Stimulation of the insulin receptor activates intracellular signaling cascades involving the enzymes extracellular signal-regulated protein kinase-1/2 (ERK1/2), phosphatidylinositol 3-kinase, protein kinase B/Akt, and phospholipase Cγ as signal transducers. Insulin receptor stimulation is correlated with multiple physiological and biochemical functions, including glucose transport, glucose homeostasis, food intake, proliferation, glycolysis, and lipogenesis. This review article focuses on the activation of gene transcription as a result of insulin receptor stimulation. Signal transducers such as protein kinases or the GLUT4-induced influx of glucose connect insulin receptor stimulation with transcription. We discuss insulin-responsive transcription factors that respond to insulin receptor activation and generate a transcriptional network executing the metabolic functions of insulin. Importantly, insulin receptor stimulation induces transcription of genes encoding essential enzymes of glycolysis and lipogenesis and inhibits genes encoding essential enzymes of gluconeogenesis. Overall, the activation or inhibition of insulin-responsive transcription factors is an essential aspect of orchestrating a wide range of insulin-induced changes in the biochemistry and physiology of insulin-responsive tissues. Full article

(This article belongs to the Special Issue Obesity, Diabetes, and Cancer: The Role of the Insulin/IGF Axis; Mechanisms and Clinical Implications)

► Show Figures

Figure 1

13 pages, 1829 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

A System-Level Mechanism of Anmyungambi Decoction for Obesity: A Network Pharmacological Approach

by Dongyeop Jang, Hayeong Jeong, Chang-Eop Kim and Jungtae Leem

Biomolecules 2021, 11(12), 1881; https://doi.org/10.3390/biom11121881 - 15 Dec 2021

Cited by 4 | Viewed by 3301

Abstract

Obesity is a low-grade systemic inflammatory disease involving adipocytokines. As though Anmyungambi decoction (AMGB) showed significant improvement on obesity in a clinical trial, the molecular mechanism of AMGB in obesity remains unknown. Therefore, we explored the potential mechanisms of action of AMGB on [...] Read more.

Obesity is a low-grade systemic inflammatory disease involving adipocytokines. As though Anmyungambi decoction (AMGB) showed significant improvement on obesity in a clinical trial, the molecular mechanism of AMGB in obesity remains unknown. Therefore, we explored the potential mechanisms of action of AMGB on obesity through network pharmacological approaches. We revealed that targets of AMGB are significantly associated with obesity-related and adipocyte-elevated genes. Evodiamine, berberine, genipin, palmitic acid, genistein, and quercetin were shown to regulate adipocytokine signaling pathway proteins which mainly involved tumor necrosis factor receptor 1, leptin receptor. In terms of the regulatory pathway of lipolysis in adipocytes, norephedrine, pseudoephedrine, quercetin, and limonin were shown to affect adrenergic receptor-beta, protein kinase A, etc. We also found that AMGB has the potentials to enhance the insulin signaling pathway thereby preventing type II diabetes mellitus. Additionally, AMGB was discovered to be able to control not only insulin-related proteins but also inflammatory mediators and apoptotic regulators and caspases, hence reducing hepatocyte injury in nonalcoholic fatty liver disease. Our findings help develop a better understanding of how AMGB controls obesity. Full article

(This article belongs to the Special Issue Phytochemical Constituents of Medicinal Plants for the Treatment of Inflammatory Disease 2021)

► Show Figures

Figure 1

14 pages, 1176 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Physiological and Pathophysiological Roles of Mitochondrial Na⁺-Ca²⁺ Exchanger, NCLX, in Hearts

by Ayako Takeuchi and Satoshi Matsuoka

Biomolecules 2021, 11(12), 1876; https://doi.org/10.3390/biom11121876 - 14 Dec 2021

Cited by 14 | Viewed by 3219

Abstract

It has been over 10 years since SLC24A6/SLC8B1, coding the Na⁺/Ca²⁺/Li⁺ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na⁺-Ca²⁺ exchange, a major Ca²⁺ efflux system in cardiac mitochondria. This molecular [...] Read more.

It has been over 10 years since SLC24A6/SLC8B1, coding the Na⁺/Ca²⁺/Li⁺ exchanger (NCLX), was identified as the gene responsible for mitochondrial Na⁺-Ca²⁺ exchange, a major Ca²⁺ efflux system in cardiac mitochondria. This molecular identification enabled us to determine structure–function relationships, as well as physiological/pathophysiological contributions, and our understandings have dramatically increased. In this review, we provide an overview of the recent achievements in relation to NCLX, focusing especially on its heart-specific characteristics, biophysical properties, and spatial distribution in cardiomyocytes, as well as in cardiac mitochondria. In addition, we discuss the roles of NCLX in cardiac functions under physiological and pathophysiological conditions—the generation of rhythmicity, the energy metabolism, the production of reactive oxygen species, and the opening of mitochondrial permeability transition pores. Full article

(This article belongs to the Special Issue Molecular Pathogenesis of Cardiac Arrhythmia)

► Show Figures

Figure 1

13 pages, 1295 KiB

Open AccessEditor’s ChoiceArticle

New Variants of the Cytochrome P450 2R1 (CYP2R1) Gene in Individuals with Severe Vitamin D-Activating Enzyme 25(OH)D Deficiency

by Martyna Fronczek, Joanna Katarzyna Strzelczyk, Krzysztof Biernacki, Silvia Salatino, Tadeusz Osadnik and Zofia Ostrowska

Biomolecules 2021, 11(12), 1867; https://doi.org/10.3390/biom11121867 - 12 Dec 2021

Cited by 8 | Viewed by 3065

Abstract

Background: Vitamin D is a fat-soluble cholesterol derivative found in two forms, vitamin D2, and vitamin D3. Cytochrome P450 2R1 (CYP2R1) encoded by the CYP2R1 gene is the major hydroxylase that activates vitamin D by catalyzing the formation of 25-hydroxyvitamin D (25(OH)D). Methods: [...] Read more.

Background: Vitamin D is a fat-soluble cholesterol derivative found in two forms, vitamin D2, and vitamin D3. Cytochrome P450 2R1 (CYP2R1) encoded by the CYP2R1 gene is the major hydroxylase that activates vitamin D by catalyzing the formation of 25-hydroxyvitamin D (25(OH)D). Methods: We collected 89 (100%) subjects, 46 of which (51.69%) had a documented severe deficiency of 25(OH)D (<10 ng/mL) and 43 (48.31%) in the control group with documented optimum levels of 25(OH)D (>30 ng/mL). We performed Sanger sequencing of three selected fragments of the CYP2R1 gene (Ch11: 14878000–14878499; Ch11: 14880058–14880883 and Ch11: 14885321–14886113) that affect the binding of substrates to this enzyme and analyzed the possible involvement of genetic variation in these regions with an increased risk of vitamin D deficiency in healthy Polish individuals. Results: Two substitutions were found within the three fragments. Bioinformatic analysis suggested that one of these (NC_000011.10: g.14878291G>A) may influence the structure and function of CYP2R1. Conclusions: Variant NC_000011.10: g.14878291G>A may have a perturbing effect on heme binding in the active site of CYP2R1 and on the function of 25-hydroxylase and probably affects the concentration of 25(OH)D in vivo. We intend to perform functional verification in a larger patient population to confirm and extend these results. Full article

(This article belongs to the Special Issue Biochemistry and Molecular Biology of Vitamin D and Its Analog)

► Show Figures

Figure 1

16 pages, 15180 KiB

Open AccessEditor’s ChoiceArticle

Structural Characterization of Rat Galectin-5, an N-Tailed Monomeric Proto-Type-like Galectin

by Federico M. Ruiz, Francisco J. Medrano, Anna-Kristin Ludwig, Herbert Kaltner, Nadezhda V. Shilova, Nicolai V. Bovin, Hans-Joachim Gabius and Antonio Romero

Biomolecules 2021, 11(12), 1854; https://doi.org/10.3390/biom11121854 - 9 Dec 2021

Cited by 1 | Viewed by 2550

Abstract

Galectins are multi-purpose effectors acting via interactions with distinct counterreceptors based on protein-glycan/protein recognition. These processes are emerging to involve several regions on the protein so that the availability of a detailed structural characterization of a full-length galectin is essential. We report here [...] Read more.

Galectins are multi-purpose effectors acting via interactions with distinct counterreceptors based on protein-glycan/protein recognition. These processes are emerging to involve several regions on the protein so that the availability of a detailed structural characterization of a full-length galectin is essential. We report here the first crystallographic information on the N-terminal extension of the carbohydrate recognition domain of rat galectin-5, which is precisely described as an N-tailed proto-type-like galectin. In the ligand-free protein, the three amino-acid stretch from Ser2 to Ser5 is revealed to form an extra β-strand (F0), and the residues from Thr6 to Asn12 are part of a loop protruding from strands S1 and F0. In the ligand-bound structure, amino acids Ser2–Tyr10 switch position and are aligned to the edge of the β-sandwich. Interestingly, the signal profile in our glycan array screening shows the sugar-binding site to preferentially accommodate the histo-blood-group B (type 2) tetrasaccharide and N-acetyllactosamine-based di- and oligomers. The crystal structures revealed the characteristically preformed structural organization around the central Trp77 of the CRD with involvement of the sequence signature’s amino acids in binding. Ligand binding was also characterized calorimetrically. The presented data shows that the N-terminal extension can adopt an ordered structure and shapes the hypothesis that a ligand-induced shift in the equilibrium between flexible and ordered conformers potentially acts as a molecular switch, enabling new contacts in this region. Full article

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

► Show Figures

Figure 1

23 pages, 5766 KiB

Open AccessEditor’s ChoiceArticle

Cyclic Tetra-Adenylate (cA₄) Recognition by Csa3; Implications for an Integrated Class 1 CRISPR-Cas Immune Response in Saccharolobus solfataricus

by Alexander A. Charbonneau, Debra M. Eckert, Colin C. Gauvin, Nathanael G. Lintner and C. Martin Lawrence

Biomolecules 2021, 11(12), 1852; https://doi.org/10.3390/biom11121852 - 9 Dec 2021

Cited by 9 | Viewed by 3226

Abstract

Csa3 family transcription factors are ancillary CRISPR-associated proteins composed of N-terminal CARF domains and C-terminal winged helix-turn-helix domains. The activity of Csa3 transcription factors is thought to be controlled by cyclic oligoadenyate (cOA) second messengers produced by type III CRISPR-Cas surveillance complexes. Here [...] Read more.

Csa3 family transcription factors are ancillary CRISPR-associated proteins composed of N-terminal CARF domains and C-terminal winged helix-turn-helix domains. The activity of Csa3 transcription factors is thought to be controlled by cyclic oligoadenyate (cOA) second messengers produced by type III CRISPR-Cas surveillance complexes. Here we show that Saccharolobus solfataricus Csa3a recognizes cyclic tetra-adenylate (cA₄) and that Csa3a lacks self-regulating “ring nuclease” activity present in some other CARF domain proteins. The crystal structure of the Csa3a/cA4 complex was also determined and the structural and thermodynamic basis for cA₄ recognition are described, as are conformational changes in Csa3a associated with cA₄ binding. We also characterized the effect of cA₄ on recognition of putative DNA binding sites. Csa3a binds to putative promoter sequences in a nonspecific, cooperative and cA₄-independent manner, suggesting a more complex mode of transcriptional regulation. We conclude the Csa3a/cA₄ interaction represents a nexus between the type I and type III CRISPR-Cas systems present in S. solfataricus, and discuss the role of the Csa3/cA₄ interaction in coordinating different arms of this integrated class 1 immune system to mount a synergistic, highly orchestrated immune response. Full article

(This article belongs to the Collection Molecular Biology: Feature Papers)

► Show Figures

Figure 1

17 pages, 1386 KiB

Open AccessEditor’s ChoiceReview

Role of Epithelium-Derived Cytokines in Atopic Dermatitis and Psoriasis: Evidence and Therapeutic Perspectives

by Francesco Borgia, Paolo Custurone, Lucia Peterle, Giovanni Pioggia and Sebastiano Gangemi

Biomolecules 2021, 11(12), 1843; https://doi.org/10.3390/biom11121843 - 7 Dec 2021

Cited by 13 | Viewed by 3654

Abstract

Atopic dermatitis and psoriasis are two of the most common chronic skin conditions. Current target therapies represent viable and safe solutions for the most severe cases of these two dermatoses but, presently, several limitations exist in terms of efficacy and side effects. A [...] Read more.

Atopic dermatitis and psoriasis are two of the most common chronic skin conditions. Current target therapies represent viable and safe solutions for the most severe cases of these two dermatoses but, presently, several limitations exist in terms of efficacy and side effects. A new class of products, epithelium-derived cytokines (TSLP, IL-25, IL-33), show an increasing potential for use in target therapy for these patients, and demonstrate a direct link between a generalized inflammatory and oxidative stress status and the human skin. A review was conducted to better understand their role in the aforementioned conditions. Of these three molecules, TSLP led has been most often considered in studies regarding target therapies, and most of the results in the literature are related to this cytokine. These three cytokines share common stimuli and are linked to each other in both acute and chronic phases of these diseases, and have been challenged as target therapies or biomarkers of disease activity. The results lead to the conclusion that epithelium-derived cytokines could represent a therapeutic opportunity for these patients, especially in itch control. Furthermore, they might work better when paired together with currently available therapies or in combination with in-development treatments. Further studies are needed in order to verify the efficacy and safety of the biologic treatments currently under development. Full article

► Show Figures

Figure 1

23 pages, 1422 KiB

Open AccessEditor’s ChoiceReview

Effects of Metformin in Heart Failure: From Pathophysiological Rationale to Clinical Evidence

by Teresa Salvatore, Raffaele Galiero, Alfredo Caturano, Erica Vetrano, Luca Rinaldi, Francesca Coviello, Anna Di Martino, Gaetana Albanese, Raffaele Marfella, Celestino Sardu and Ferdinando Carlo Sasso

Biomolecules 2021, 11(12), 1834; https://doi.org/10.3390/biom11121834 - 4 Dec 2021

Cited by 58 | Viewed by 9335

Abstract

Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the [...] Read more.

Type 2 diabetes mellitus (T2DM) is a worldwide major health burden and heart failure (HF) is the most common cardiovascular (CV) complication in affected patients. Therefore, identifying the best pharmacological approach for glycemic control, which is also useful to prevent and ameliorate the prognosis of HF, represents a crucial issue. Currently, the choice is between the new drugs sodium/glucose co-transporter 2 inhibitors that have consistently shown in large CV outcome trials (CVOTs) to reduce the risk of HF-related outcomes in T2DM, and metformin, an old medicament that might end up relegated to the background while exerting interesting protective effects on multiple organs among which include heart failure. When compared with other antihyperglycemic medications, metformin has been demonstrated to be safe and to lower morbidity and mortality for HF, even if these results are difficult to interpret as they emerged mainly from observational studies. Meta-analyses of randomized controlled clinical trials have not produced positive results on the risk or clinical course of HF and sadly, large CV outcome trials are lacking. The point of force of metformin with respect to new diabetic drugs is the amount of data from experimental investigations that, for more than twenty years, still continues to provide mechanistic explanations of the several favorable actions in heart failure such as, the improvement of the myocardial energy metabolic status by modulation of glucose and lipid metabolism, the attenuation of oxidative stress and inflammation, and the inhibition of myocardial cell apoptosis, leading to reduced cardiac remodeling and preserved left ventricular function. In the hope that specific large-scale trials will be carried out to definitively establish the metformin benefit in terms of HF failure outcomes, we reviewed the literature in this field, summarizing the available evidence from experimental and clinical studies reporting on effects in heart metabolism, function, and structure, and the prominent pathophysiological mechanisms involved. Full article

(This article belongs to the Special Issue Pharmacology of Cardiovascular Disease)

► Show Figures

Figure 1

15 pages, 2992 KiB

Open AccessEditor’s ChoiceReview

Diet Impact on Obesity beyond Calories and Trefoil Factor Family 2 (TFF2) as an Illustration: Metabolic Implications and Potential Applications

by Abdelaziz Ghanemi, Mayumi Yoshioka and Jonny St-Amand

Biomolecules 2021, 11(12), 1830; https://doi.org/10.3390/biom11121830 - 4 Dec 2021

Cited by 5 | Viewed by 3062

Abstract

Obesity is a health problem with increasing impacts on public health, economy and even social life. In order to reestablish the energy balance, obesity management focuses mainly on two pillars; exercise and diet. Beyond the contribution to the caloric intake, the diet nutrients [...] Read more.

Obesity is a health problem with increasing impacts on public health, economy and even social life. In order to reestablish the energy balance, obesity management focuses mainly on two pillars; exercise and diet. Beyond the contribution to the caloric intake, the diet nutrients and composition govern a variety of properties. This includes the energy balance-independent properties and the indirect metabolic effects. Whereas the energy balance-independent properties are close to “pharmacological” effects and include effects such as antioxidant and anti-inflammatory, the indirect metabolic effects represent the contribution a diet can have on energy metabolism beyond the caloric contribution itself, which include the food intake control and metabolic changes. As an illustration, we also described the metabolic implication and hypothetical pathways of the high-fat diet-induced gene Trefoil Factor Family 2. The properties the diet has can have a variety of applications mainly in pharmacology and nutrition and further explore the “pharmacologically” active food towards potential therapeutic applications. Full article

(This article belongs to the Special Issue Molecular Mechanisms Underlying Eating Disorders and Obesity)

► Show Figures

Figure 1

17 pages, 6521 KiB

Open AccessEditor’s ChoiceReview

Hyperbaric Oxygen Treatment: Effects on Mitochondrial Function and Oxidative Stress

by Nofar Schottlender, Irit Gottfried and Uri Ashery

Biomolecules 2021, 11(12), 1827; https://doi.org/10.3390/biom11121827 - 3 Dec 2021

Cited by 56 | Viewed by 8253

Abstract

Hyperbaric oxygen treatment (HBOT)—the administration of 100% oxygen at atmospheric pressure (ATA) greater than 1 ATA—increases the proportion of dissolved oxygen in the blood five- to twenty-fold. This increase in accessible oxygen places the mitochondrion—the organelle that consumes most of the oxygen that [...] Read more.

Hyperbaric oxygen treatment (HBOT)—the administration of 100% oxygen at atmospheric pressure (ATA) greater than 1 ATA—increases the proportion of dissolved oxygen in the blood five- to twenty-fold. This increase in accessible oxygen places the mitochondrion—the organelle that consumes most of the oxygen that we breathe—at the epicenter of HBOT’s effects. As the mitochondrion is also a major site for the production of reactive oxygen species (ROS), it is possible that HBOT will increase also oxidative stress. Depending on the conditions of the HBO treatment (duration, pressure, umber of treatments), short-term treatments have been shown to have deleterious effects on both mitochondrial activity and production of ROS. Long-term treatment, on the other hand, improves mitochondrial activity and leads to a decrease in ROS levels, partially due to the effects of HBOT, which increases antioxidant defense mechanisms. Many diseases and conditions are characterized by mitochondrial dysfunction and imbalance between ROS and antioxidant scavengers, suggesting potential therapeutic intervention for HBOT. In the present review, we will present current views on the effects of HBOT on mitochondrial function and oxidative stress, the interplay between them and the implications for several diseases. Full article

(This article belongs to the Special Issue Oxygen Therapy)

► Show Figures

Figure 1

10 pages, 1571 KiB

Open AccessEditor’s ChoiceArticle

RNR-R2 Upregulation by a Short Non-Coding Viral Transcript

by Karin Broennimann, Inna Ricardo-Lax, Julia Adler, Eleftherios Michailidis, Ype P. de Jong, Nina Reuven and Yosef Shaul

Biomolecules 2021, 11(12), 1822; https://doi.org/10.3390/biom11121822 - 3 Dec 2021

Cited by 2 | Viewed by 2328

Abstract

DNA viruses require dNTPs for replication and have developed different strategies to increase intracellular dNTP pools. Hepatitis B virus (HBV) infects non-dividing cells in which dNTPs are scarce and the question is how viral replication takes place. Previously we reported that the virus [...] Read more.

DNA viruses require dNTPs for replication and have developed different strategies to increase intracellular dNTP pools. Hepatitis B virus (HBV) infects non-dividing cells in which dNTPs are scarce and the question is how viral replication takes place. Previously we reported that the virus induces the DNA damage response (DDR) pathway culminating in RNR-R2 expression and the generation of an active RNR holoenzyme, the key regulator of dNTP levels, leading to an increase in dNTPs. How the virus induces DDR and RNR-R2 upregulation is not completely known. The viral HBx open reading frame (ORF) was believed to trigger this pathway. Unexpectedly, however, we report here that the production of HBx protein is dispensable. We found that a small conserved region of 125 bases within the HBx ORF is sufficient to upregulate RNR-R2 expression in growth-arrested HepG2 cells and primary human hepatocytes. The observed HBV mRNA embedded regulatory element is named ERE. ERE in isolation is sufficient to activate the ATR-Chk1-E2F1-RNR-R2 DDR pathway. These findings demonstrate a non-coding function of HBV transcripts to support its propagation in non-cycling cells. Full article

► Show Figures

Figure 1

16 pages, 1314 KiB

Open AccessEditor’s ChoiceReview

Integration and Spatial Organization of Signaling by G Protein-Coupled Receptor Homo- and Heterodimers

by Roberto Maggio, Irene Fasciani, Marco Carli, Francesco Petragnano, Francesco Marampon, Mario Rossi and Marco Scarselli

Biomolecules 2021, 11(12), 1828; https://doi.org/10.3390/biom11121828 - 3 Dec 2021

Cited by 7 | Viewed by 2980

Abstract

Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex [...] Read more.

Information flow from a source to a receiver becomes informative when the recipient can process the signal into a meaningful form. Information exchange and interpretation is essential in biology and understanding how cells integrate signals from a variety of information-coding molecules into complex orchestrated responses is a major challenge for modern cell biology. In complex organisms, cell to cell communication occurs mostly through neurotransmitters and hormones, and receptors are responsible for signal recognition at the membrane level and information transduction inside the cell. The G protein-coupled receptors (GPCRs) are the largest family of membrane receptors, with nearly 800 genes coding for these proteins. The recognition that GPCRs may physically interact with each other has led to the hypothesis that their dimeric state can provide the framework for temporal coincidence in signaling pathways. Furthermore, the formation of GPCRs higher order oligomers provides the structural basis for organizing distinct cell compartments along the plasma membrane where confined increases in second messengers may be perceived and discriminated. Here, we summarize evidence that supports these conjectures, fostering new ideas about the physiological role played by receptor homo- and hetero-oligomerization in cell biology. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Compartmentalized GPCR Signaling)

► Show Figures

Figure 1

15 pages, 1000 KiB

Open AccessEditor’s ChoiceReview

Mollusc N-glycosylation: Structures, Functions and Perspectives

by Erika Staudacher

Biomolecules 2021, 11(12), 1820; https://doi.org/10.3390/biom11121820 - 3 Dec 2021

Cited by 12 | Viewed by 2686

Abstract

Molluscs display a sophisticated N-glycan pattern on their proteins, which is, in terms of involved structural features, even more diverse than that of vertebrates. This review summarises the current knowledge of mollusc N-glycan structures, with a focus on the functional aspects of the [...] Read more.

Molluscs display a sophisticated N-glycan pattern on their proteins, which is, in terms of involved structural features, even more diverse than that of vertebrates. This review summarises the current knowledge of mollusc N-glycan structures, with a focus on the functional aspects of the corresponding glycoproteins. Furthermore, the potential of mollusc-derived biomolecules for medical applications is addressed, emphasising the importance of mollusc research. Full article

(This article belongs to the Special Issue Glycosylation—The Most Diverse Post-Translational Modification)

► Show Figures

Figure 1

24 pages, 2494 KiB

Open AccessEditor’s ChoiceReview

Ubiquitin Ligase Redundancy and Nuclear-Cytoplasmic Localization in Yeast Protein Quality Control

by Carolyn Allain Breckel and Mark Hochstrasser

Biomolecules 2021, 11(12), 1821; https://doi.org/10.3390/biom11121821 - 3 Dec 2021

Cited by 19 | Viewed by 4832

Abstract

The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways [...] Read more.

The diverse functions of proteins depend on their proper three-dimensional folding and assembly. Misfolded cellular proteins can potentially harm cells by forming aggregates in their resident compartments that can interfere with vital cellular processes or sequester important factors. Protein quality control (PQC) pathways are responsible for the repair or destruction of these abnormal proteins. Most commonly, the ubiquitin-proteasome system (UPS) is employed to recognize and degrade those proteins that cannot be refolded by molecular chaperones. Misfolded substrates are ubiquitylated by a subset of ubiquitin ligases (also called E3s) that operate in different cellular compartments. Recent research in Saccharomyces cerevisiae has shown that the most prominent ligases mediating cytoplasmic and nuclear PQC have overlapping yet distinct substrate specificities. Many substrates have been characterized that can be targeted by more than one ubiquitin ligase depending on their localization, and cytoplasmic PQC substrates can be directed to the nucleus for ubiquitylation and degradation. Here, we review some of the major yeast PQC ubiquitin ligases operating in the nucleus and cytoplasm, as well as current evidence indicating how these ligases can often function redundantly toward substrates in these compartments. Full article

(This article belongs to the Special Issue Recent Insights Into the Role of the Ubiquitin System in Cellular Protein Quality Control)

► Show Figures

Figure 1

10 pages, 1581 KiB

Open AccessEditor’s ChoiceReview

L-Type Ca²⁺ Channel Regulation by Calmodulin and CaBP1

by James B. Ames

Biomolecules 2021, 11(12), 1811; https://doi.org/10.3390/biom11121811 - 2 Dec 2021

Cited by 16 | Viewed by 2774

Abstract

L-type voltage-gated Ca²⁺ channels (CaV1.2 and CaV1.3, called CaV) interact with the Ca²⁺ sensor proteins, calmodulin (CaM) and Ca²⁺ binding Protein 1 (CaBP1), that oppositely control Ca²⁺-dependent channel activity. CaM and CaBP1 can each bind to the IQ-motif [...] Read more.

L-type voltage-gated Ca²⁺ channels (CaV1.2 and CaV1.3, called CaV) interact with the Ca²⁺ sensor proteins, calmodulin (CaM) and Ca²⁺ binding Protein 1 (CaBP1), that oppositely control Ca²⁺-dependent channel activity. CaM and CaBP1 can each bind to the IQ-motif within the C-terminal cytosolic domain of CaV, which promotes increased channel open probability under basal conditions. At elevated cytosolic Ca²⁺ levels (caused by CaV channel opening), Ca²⁺-bound CaM binding to CaV is essential for promoting rapid Ca²⁺-dependent channel inactivation (CDI). By contrast, CaV binding to CaBP1 prevents CDI and promotes Ca²⁺-induced channel opening (called CDF). In this review, I provide an overview of the known structures of CaM and CaBP1 and their structural interactions with the IQ-motif to help understand how CaM promotes CDI, whereas CaBP1 prevents CDI and instead promotes CDF. Previous electrophysiology studies suggest that Ca²⁺-free forms of CaM and CaBP1 may pre-associate with CaV under basal conditions. However, previous Ca²⁺ binding data suggest that CaM and CaBP1 are both calculated to bind to Ca²⁺ with an apparent dissociation constant of ~100 nM when CaM or CaBP1 is bound to the IQ-motif. Since the neuronal basal cytosolic Ca²⁺ concentration is ~100 nM, nearly half of the neuronal CaV channels are suggested to be bound to Ca²⁺-bound forms of either CaM or CaBP1 under basal conditions. The pre-association of CaV with calcified forms of CaM or CaBP1 are predicted here to have functional implications. The Ca²⁺-bound form of CaBP1 is proposed to bind to CaV under basal conditions to block CaV binding to CaM, which could explain how CaBP1 might prevent CDI. Full article

(This article belongs to the Collection Advances in Metal Binding Proteins)

► Show Figures

Figure 1

17 pages, 2463 KiB

Open AccessEditor’s ChoiceArticle

The Nuts and Bolts of SARS-CoV-2 Spike Receptor-Binding Domain Heterologous Expression

by Mariano Maffei, Linda Celeste Montemiglio, Grazia Vitagliano, Luigi Fedele, Shaila Sellathurai, Federica Bucci, Mirco Compagnone, Valerio Chiarini, Cécile Exertier, Alessia Muzi, Giuseppe Roscilli, Beatrice Vallone and Emanuele Marra

Biomolecules 2021, 11(12), 1812; https://doi.org/10.3390/biom11121812 - 2 Dec 2021

Cited by 19 | Viewed by 4145

Abstract

COVID-19 is a highly infectious disease caused by a newly emerged coronavirus (SARS-CoV-2) that has rapidly progressed into a pandemic. This unprecedent emergency has stressed the significance of developing effective therapeutics to fight the current and future outbreaks. The receptor-binding domain (RBD) of [...] Read more.

COVID-19 is a highly infectious disease caused by a newly emerged coronavirus (SARS-CoV-2) that has rapidly progressed into a pandemic. This unprecedent emergency has stressed the significance of developing effective therapeutics to fight the current and future outbreaks. The receptor-binding domain (RBD) of the SARS-CoV-2 surface Spike protein is the main target for vaccines and represents a helpful “tool” to produce neutralizing antibodies or diagnostic kits. In this work, we provide a detailed characterization of the native RBD produced in three major model systems: Escherichia coli, insect and HEK-293 cells. Circular dichroism, gel filtration chromatography and thermal denaturation experiments indicated that recombinant SARS-CoV-2 RBD proteins are stable and correctly folded. In addition, their functionality and receptor-binding ability were further evaluated through ELISA, flow cytometry assays and bio-layer interferometry. Full article

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

► Show Figures

Figure 1

16 pages, 1437 KiB

Open AccessEditor’s ChoiceReview

The Use of Fluorescent Anti-CEA Antibodies to Label, Resect and Treat Cancers: A Review

by Michael A. Turner, Thinzar M. Lwin, Siamak Amirfakhri, Hiroto Nishino, Robert M. Hoffman, Paul J. Yazaki and Michael Bouvet

Biomolecules 2021, 11(12), 1819; https://doi.org/10.3390/biom11121819 - 2 Dec 2021

Cited by 15 | Viewed by 2736

Abstract

A major barrier to the diagnosis and effective treatment of solid-tumor cancers is the difficulty in detection and visualization of tumor margins in primary and metastatic disease. The use of fluorescence can augment the surgeon’s ability to detect cancer and aid in its [...] Read more.

A major barrier to the diagnosis and effective treatment of solid-tumor cancers is the difficulty in detection and visualization of tumor margins in primary and metastatic disease. The use of fluorescence can augment the surgeon’s ability to detect cancer and aid in its resection. Several cancer types express carcinoembryonic antigen (CEA) including colorectal, pancreatic and gastric cancer. Antibodies to CEA have been developed and tagged with near-infrared fluorescent dyes. This review article surveyed the use of CEA antibodies conjugated to fluorescent probes for in vivo studies since 1990. PubMed and Google Scholar databases were queried, and 900 titles and abstracts were screened. Fifty-nine entries were identified as possibly meeting inclusion/exclusion criteria and were reviewed in full. Forty articles were included in the review and their citations were screened for additional entries. A total of 44 articles were included in the final review. The use of fluorescent anti-CEA antibodies has been shown to improve detection and resection of tumors in both murine models and clinically. The cumulative results indicate that fluorescent-conjugated anti-CEA antibodies have important potential to improve cancer diagnosis and surgery. In an emerging technology, anti-CEA fluorescent antibodies have also been successfully used for photoimmunotherapy treatment for cancer. Full article

(This article belongs to the Special Issue Feature Paper from Biomolecules Journal Reviewers)

► Show Figures

Figure 1

35 pages, 1443 KiB

Open AccessEditor’s ChoiceReview

The Pathophysiology and Treatment of Essential Tremor: The Role of Adenosine and Dopamine Receptors in Animal Models

by Barbara Kosmowska and Jadwiga Wardas

Biomolecules 2021, 11(12), 1813; https://doi.org/10.3390/biom11121813 - 2 Dec 2021

Cited by 9 | Viewed by 5608

Abstract

Essential tremor (ET) is one of the most common neurological disorders that often affects people in the prime of their lives, leading to a significant reduction in their quality of life, gradually making them unable to independently perform the simplest activities. Here we [...] Read more.

Essential tremor (ET) is one of the most common neurological disorders that often affects people in the prime of their lives, leading to a significant reduction in their quality of life, gradually making them unable to independently perform the simplest activities. Here we show that current ET pharmacotherapy often does not sufficiently alleviate disease symptoms and is completely ineffective in more than 30% of patients. At present, deep brain stimulation of the motor thalamus is the most effective ET treatment. However, like any brain surgery, it can cause many undesirable side effects; thus, it is only performed in patients with an advanced disease who are not responsive to drugs. Therefore, it seems extremely important to look for new strategies for treating ET. The purpose of this review is to summarize the current knowledge on the pathomechanism of ET based on studies in animal models of the disease, as well as to present and discuss the results of research available to date on various substances affecting dopamine (mainly D3) or adenosine A1 receptors, which, due to their ability to modulate harmaline-induced tremor, may provide the basis for the development of new potential therapies for ET in the future. Full article

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

► Show Figures

Figure 1

21 pages, 1857 KiB

Open AccessEditor’s ChoiceReview

New Insights into the Role of Cysteine Cathepsins in Neuroinflammation

by Anja Pišlar, Lara Bolčina and Janko Kos

Biomolecules 2021, 11(12), 1796; https://doi.org/10.3390/biom11121796 - 30 Nov 2021

Cited by 11 | Viewed by 3238

Abstract

Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that [...] Read more.

Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that aggravate neurodegeneration. To date, most research on neuroinflammation has focused on the role of cysteine cathepsins, the largest cathepsin family. Cysteine cathepsins are primarily responsible for protein degradation in lysosomes; however, they also play a role in regulating a number of other important physiological and pathological processes. This review focuses on the functional roles of cysteine cathepsins in the central nervous system during neuroinflammation, with an emphasis on their roles in the polarization of microglia and neuroinflammation signaling, which in turn causes neuronal death and thus neurodegeneration. Full article

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

► Show Figures

Figure 1

Journal Menu

Journal Browser

Editor’s Choice Articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI